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11:30AM 11/13/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

11:30 a.m. – Keynote Speaker – Role of Genetics and Genomics in Pharmaceutical Development

 

Role of Genetics and Genomics in Pharmaceutical Development

There was a time when pharmaceutical companies attempted to develop drugs that could be used to treat large populations of individuals diagnosed with a particular disease. These drugs were used to treat large groups of patients and were not always effective for all patients. The paradigm of drug development is changing where highly targeted drugs that would be highly effective in specific sub populations of patients are becoming the new norm. Dr. Skovronsky will describe how the pharmaceutical industry as a whole and Lilly in particular is taking advantage of the new knowledge about the genetic basis of disease to develop highly effective therapies.

Role of Genetics and Genomics in Pharmaceutical Development

Daniel Skovronsky, M.D., Ph.D.
Vice President of Tailored Therapeutics, Lilly

@EliLillyCo

@LillyHealth

Alzheimer’s Disease

  •  early detection
  • how do drugs work in Alzheimer’s Disease (AD) – difficult to conduct Clinical Trials
  • Personalized the treatment as early on as possible: looking inside the brain and track the disease
  • images of the pathology of AD – Amyloid imaging using agents
  • diagnostics test on autopsy of AD brains after death
  • Risk of Progression
  • amyloid deposition over time – Dynamics of accumulations
  • Autopsy of brains of AD: MANY AD patients have negative scans
  • Clinical Trial definition of AD: 22% did not have amyloid — WERE TREATED WITH ANTI Amyloid DRUGS (22% Solanezumab, 16% Bapineuzumab)
  • 1/2 have DX of AD and treated with targeted drug — have negative Scans for Amyloid deposits — NOT PROGRESSING
  • those progressing are those with Positive Scans
  • 18 month and 36 month – Progression of Amyloid — Only at Positive scans
  • A4 Trial Dx Florbetapir
  • Rx solanezumab – symptomatic dementia vs AD
  • Markers o=for the disease – Neural degeneration – Tau in temporal lobe
  • Treat patient with start of Tau — avoid progression to amyloid deposition

 

CANCER

  • Companion Diagnostics (CD) vs Therapeutics – start to find the biomarkers at the same time: Drug and Diagnostics
  • DNA, RNA, Protein
  • Diagnostics –>> translation
  • CLIA lab at Eli Lilly for companion diagnostics
  • Biomarker Negative vs Positive ans a spectrum of results
  • Immunohistochemistry (IHC) for protein expression – simple assay, complicated test
  • two different agent at two different albs — give two different diagnostics
  • Tumor heterogeneity: Glioblastoma
  • Tissue scarce resource — it is separated in time Biopsy taken at different times
  • Detection of chromosomal – Liquid Biopsy – Exosomes
  • mRNA, miRNA
  • Summary: Prime key porters to quickly bring therapies to patients

 

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

 

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@LillyHealth

@FiercePharma

@PharmaNews

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10:15AM 11/13/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

10:15 a.m. Panel Discussion — IT/Big Data

IT/Big Data

The human genome is composed of 6 billion nucleotides (using the genetic alphabet of T, C, G and A). As the cost of sequencing the human genome is decreasing at a rapid rate, it might not be too far into the future that every human being will be sequenced at least once in their lifetime. The sequence data together with the clinical data are going to be used more and more frequently to make clinical decisions. If that is true, we need to have secure methods of storing, retrieving and analyzing all of these data.  Some people argue that this is a tsunami of data that we are not ready to handle. The panel will discuss the types and volumes of data that are being generated and how to deal with it.

IT/Big Data

   Moderator:

Amy Abernethy, M.D.
Chief Medical Officer, Flatiron

Role of Informatics, SW and HW in PM. Big data and Healthcare

How Lab and Clinics can be connected. Oncologist, Hematologist use labs in clinical setting, Role of IT and Technology in the environment of the Clinicians

Compare Stanford Medical Center and Harvard Medical Center and Duke Medical Center — THREE different models in Healthcare data management

Create novel solutions: Capture the voice of the patient for integration of component: Volume, Veracity, Value

Decisions need to be made in short time frame, documentation added after the fact

No system can be perfect in all aspects

Understanding clinical record for conversion into data bases – keeping quality of data collected

Key Topics

Panelists:

Stephen Eck, M.D., Ph.D.
Vice President, Global Head of Oncology Medical Sciences,
Astellas, Inc.

Small data expert, great advantage to small data. Populations data allows for longitudinal studies,

Big Mac Big Data – Big is Good — Is data been collected suitable for what is it used, is it robust, limitations, of what the data analysis mean

Data analysis in Chemical Libraries – now annotated

Diversity data in NOTED by MDs, nuances are very great, Using Medical Records for building Billing Systems

Cases when the data needed is not known or not available — use data that is available — limits the scope of what Valuable solution can be arrived at

In Clinical Trial: needs of researchers, billing clinicians — in one system

Translation of data on disease to data object

Signal to Noise Problem — Thus Big data provided validity and power

 

J. Michael Gaziano, M.D., M.P.H., F.R.C.P.
Scientific Director, Massachusetts Veterans Epidemiology Research
and Information Center (MAVERIC), VA Boston Healthcare System;
Chief Division of Aging, Brigham and Women’s Hospital;
Professor of Medicine, Harvard Medical School

at BWH since 1987 at 75% – push forward the Genomics Agenda, VA system 25% – VA is horizontally data integrated embed research and knowledge — baseline questionnaire 200,000 phenotypes – questionnaire and Genomics data to be integrated, Data hierarchical way to be curated, Simple phenotypes, validate phenotypes, Probability to have susceptibility for actual disease, Genomics Medicine will benefit Clinicians

Data must be of visible quality, collect data via Telephone VA – on Med compliance study, on Ability to tolerate medication

–>>Annotation assisted in building a tool for Neurologist on Alzheimer’s Disease (AlzSWAN knowledge base) (see also Genotator , a Disease-Agnostic Tool for Annotation)

–>>Curation of data is very different than statistical analysis of Clinical Trial Data

–>>Integration of data at VA and at BWH are tow different models of SUCCESSFUL data integration models, accessing the data is also using a different model

–>>Data extraction from the Big data — an issue

–>>Where the answers are in the data, build algorithms that will pick up causes of disease: Alzheimer’s – very difficult to do

–>>system around all stakeholders: investment in connectivity, moving data, individual silo, HR, FIN, Clinical Research

–>>Biobank data and data quality

 

Krishna Yeshwant, M.D.
General Partner, Google Ventures;
Physician, Brigham and Women’s Hospital

Computer Scientist and Medical Student. Were the technology is going?

Messy situation, interaction IT and HC, Boston and Silicon Valley are focusing on Consumers, Google Engineers interested in developing Medical and HC applications — HUGE interest. Application or Wearable – new companies in this space, from Computer Science world to Medicine – Enterprise level – EMR or Consumer level – Wearable — both areas are very active in Silicon Valley

IT stuff in the hospital HARDER that IT in any other environment, great progress in last 5 years, security of data, privacy. Sequencing data cost of big data management with highest security

Constrained data vs non-constrained data

Opportunities for Government cooperation as a Lead needed for standardization of data objects

 

Questions from the Podium:

  • Where is the Truth: do we have all the tools or we don’t for Genomic data usage
  • Question on Interoperability
  • Big Valuable data — vs Big data
  • quality, uniform, large cohort, comprehensive Cancer Centers
  • Volume of data can compensate quality of data
  • Data from Imaging – Quality and interpretation – THREE radiologist will read cancer screening

 

 

 

– See more at: http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

 

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@Duke_Medicine

@AstellasUS

@GoogleVentures

@harvardmed

@BrighamWomens

@kyeshwant

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1:45PM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

 

1:45 p.m. Panel Discussion – Oncology

Oncology

There has been a remarkable transformation in our understanding of the molecular genetic basis of cancer and its treatment during the past decade or so. In depth genetic and genomic analysis of cancers has revealed that each cancer type can be sub-classified into many groups based on the genetic profiles and this information can be used to develop new targeted therapies and treatment options for cancer patients. This panel will explore the technologies that are facilitating our understanding of cancer, and how this information is being used in novel approaches for clinical development and treatment.

Oncology

Opening Speaker & Moderator:

Lynda Chin, M.D.
Department Chair, Department of Genomic Medicine
MD Anderson Cancer Center     @MDAnderson   #endcancer

  • Who pays for personalized medicine?
  • potential of Big data, analytics, Expert systems, so not each MD needs to see all cases, Profile disease to get same treatment
  • business model: IP, Discovery, sharing, ownership — yet accelerate therapy
  • security of healthcare data
  • segmentation of patient population
  • management of data and tracking innovations
  • platforms to be shared for innovations
  • study to be longitudinal,
  • How do we reconcile course of disease with personalized therapy
  • phenotyping the disease vs a Patient in wait for cure/treatment

Panelists:

Roy Herbst, M.D., Ph.D.    @DrRoyHerbstYale

Ensign Professor of Medicine and Professor of Pharmacology;
Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital     @YaleCancer

Development new drugs to match patient, disease and drug – finding the right patient for the right Clinical Trial

  • match patient to drugs
  • partnerships: out of 100 screened patients, 10 had the gene, 5 were able to attend the trial — without the biomarker — all 100 patients would participate for the WRONG drug for them (except the 5)
  • patients wants to participate in trials next to home NOT to have to travel — now it is in the protocol
  • Annotated Databases – clinical Trial informed consent – adaptive design of Clinical Trial vs protocol
  • even Academic MD can’t read the reports on Genomics
  • patients are treated in the community — more training to MDs
  • Five companies collaborating – comparison of 6 drugs in the same class
  • if drug exist and you have the patient — you must apply personalized therapy

 

Lincoln Nadauld, M.D., Ph.D.
Director, Cancer Genomics, Huntsman Intermountain Cancer Clinic @lnadauld @intermountain

  • @Stanford, all patients get Tumor profiles Genomic results, interpretation – deliver personalized therapy
  • Outcomes from Genomics based therapies
  • Is survival superior
  • Targeted treatment – Health economic impact is cost lower or not for same outcome???
  • genomic profiling of tumors: Genomic information changes outcome – adverse events lower
  • Path ways and personalized medicine based on Genomics — integration not yet been worked out

Question by Moderator: Data Management

  • Platform development, clinical knowledge system,
  • build consortium of institutions to share big data – identify all patients with same profile

 

 

 

 

See more at  http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

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Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.

 

A report on how gamification mobile applications, like CyberDoctor’s PatientPartner, may improve patient adherence to oral chemotherapy.

(includes interviews with CyberDoctor’s CEO Akhila Satish and various oncologists)

 

Writer/Curator: Stephen J. Williams, Ph.D.

UPDATE 5/15/2019

Please see below for an UPDATE on this post including results from the poll conducted here on the value of a gamification strategy for oral chemotherapy patient adherence as well as a paper describing a well designed development of an application specifically to address this clinical problem.

Studies have pointed to a growing need to monitor and improve medical adherence, especially with outpatient prescription drugs across many diseases, including cancer.

The trend to develop oral chemotherapies, so patients can take their medications in the convenience of their home, has introduced produced a unique problem concerning cancer patient-medication adherence. Traditionally, chemotherapies were administered by a parental (for example intravenous) route by clinic staff, however, as noted by Jennifer M Gangloff in her article Troubling Trend: Medication Adherence:

 

with the trend of cancer patients taking their oral medication at home, the burden of adherence has shifted from clinicians to the patients and their families.

 

A few highlights from Jennifer Gangloff’s article highlight the degree and scope of the problem:

 

  1. There is a wide range of adherence for oral chemo– as low as 16% up to 100% adherence rates have been seen in multiple studies
  2. High cost in lives and money: estimates in US of 125,000 deaths and $300 billion in healthcare costs due to nonadherence to oral anticancer medications
  3. Factors not related to the patient can contribute to nonadherence including lack of information provided by the healthcare system and socioeconomic factors
  4. Numerous methods to improve adherence issues (hospital informative seminars, talking pill bottles, reminder phone calls etc.) have met with mixed results.

 

A review by Steve D`Amato of published literature also highlights the extent of problems with highly variable adherence rates including

  • 17-27% for hematologic malignancies
  • 53-98% for breast cancer
  • 97% for ovarian cancer

More strikingly, patient adherence rates can drastically decline over treatment, with one study showing an adherence rate drop from 87% to 50% over 4 years of adjuvant tamoxifen therapy.

 

Tackling The Oral Chemotherapy-Patient Adherence Problem

 

Documented factors leading to non-adherence to oral oncology medications include

  1. Patient feels better so stop taking the drug
  2. Patient feels worse so stops taking the drug
  3. Confusing and complicated dosing regimen
  4. Inability to afford medications
  5. Poor provider-patient relationships
  6. Adverse effects of medication
  7. Cognitive impairment (“chemo fog”; mental impairment due to chemotherapy
  8. Inadequate education/instruction of discharge

There are many examples of each reason why a patient stopped taking medication. One patient was prescribed capecitabine for her metastatic breast cancer and, upon feeling nausea, started to use antacids, which precipitated toxicities as a result of increased plasma levels of capecitabine.

In a white paper entitled Oral Oncology Treatment Regimens and the Role of Medication Therapy Management on Patient Adherence and Compliance, David Reese, Vice President Oncology at Tx Care Advantage discus how Medication Therapy Management (MTM) programs could intervene to improve medical adherence in both the oncology and non-oncology setting.

This review also documented the difficulties in accurately measuring patient adherence including:

  • Inaccuracy of self-reporting
  • Lack of applicability of external measurements such as pill counts
  • Hawthorne effect: i.e. patient pill documentation reminds them to take next dose

The group suggests that using MTM programs, especially telephony systems involving oncology nurses and pharmacists and utilizing:

  • Therapy support (dosing reminders)
  • Education
  • Side effect management

 

may be a cost-efficient methodology to improve medical adherence.

 

Although nurses are important intermediary educating patients about their oral chemotherapies, it does not appear that solely relying on nurses to monitor patient adherence will be sufficient, as indicated in a survey-based Japanese study.

As reported in May 12, 2014 | Oncology Nursing By Leah Lawrence

 

Systematic Nurse Involvement Key as Oral Chemotherapy Use Grows– at: http://www.cancernetwork.com/oncology-nursing/systematic-nurse-involvement-key-oral-chemotherapy-use-grows

 

Survey results indicated that 90% of nurses reported asking patients on oral chemotherapy about emergency contacts, side effects, and family/friend support. Nurses also provided patients with education materials on their assigned medication.

However, less than one-third of nurses asked if their patients felt confident about managing their oral chemotherapy.

“Nurses were less likely to ask adherence-related questions of patients with refilled prescriptions than of new patients,” the researchers wrote. “Regarding unused doses of anticancer agents, 35.5% of nurses reported that they did not confirm the number of unused doses when patients had refilled prescriptions.”

From the Roswell Park Cancer Institute blog post Making Mobile Health Work

https://www.roswellpark.org/partners-practice/white-papers/making-mobile-health-work

US physicians are recognizing the need for the adoption of mobile in their practice but choice of apps and mobile strategies must be carefully examined before implementation. In addition, most physicians are using mobile communications as a free-complementary service and these physicians are not being reimbursed for their time.

 

Some companies are providing their own oncology-related mobile app services:

CollabRx Announces Oncology-Specific Mobile App with Leading Site for Healthcare Professionals, MedPage Today

(http://www.collabrx.com/collabrx-announces-oncology-specific-mobile-app-with-leading-site-for-healthcare-professionals-medpage-today/)

San Francisco, August 13, 2013CollabRx, Inc. (NASDAQ: CLRX), a healthcare information technology company focused on informing clinical decision making in molecular medicine, today announced a multi-year agreement with Everyday Health’s MedPage Today. The forthcoming app, which will target oncologists and pathologists, will focus on the molecular aspects of laboratory testing and therapy development. Over time, the expectation is that this app will serve as a comprehensive point of care resource for physicians and patients to obtain highly credible, expert-vetted and dynamically updated information to guide cancer treatment planning.

The McKesson Foundation’s Mobilizing for Health initiative

has awarded a grant to Partners HealthCare’s Center for Connected Health to develop a mobile health program that uses a smartphone application to help patients with cancer adhere to oral chemotherapy treatments and monitor their symptoms, FierceMobileHealthcare reports.

 

CancerNet announces mobile application (from cancer.net)

http://www.cancer.net/navigating-cancer-care/managing-your-care/mobile-applications

 

However, there is little evidence that the plethora of cancer-based apps is providing any benefit with regard to patient outcome or adherence, as reported in to an article in the Journal of Medical Internet Research, reported at FierceMobileHealthcare (Read more: Cancer smartphone apps for consumers lack effectiveness – FierceMobileHealthcare http://www.fiercemobilehealthcare.com/story/cancer-smartphone-apps-consumers-lack-effectiveness/2013-12-26#ixzz34ucdxVcU )

The report suggests that there are too many apps either offering information, suggesting behavior/lifestyle changes, or measuring compliance data but little evidence to suggest any of these are working the way they intended. The article suggests the plethora of apps may just be adding to the confusion.

Johnson&Johnson’s Wellness & Prevention unit has launched a health-tracking app Track Your Health. Although the company considers it a “gamification“ app, Track Your Health© operates to either feed data from other health tracking apps or allow the user to manually input data.
Read more: J&J launches ‘quantified self’ app to game patients into better behavior – FiercePharmaMarketing http://www.fiercepharmamarketing.com/story/jj-launches-quantified-self-app-game-patients-better-behavior/2014-05-28#ixzz34uhFDJr2

Even ASCO has a list of some oncology-related apps (http://connection.asco.org/commentary/article/id/3123/favorite-hematology-oncology-apps.aspx) and

NIH is offering grants for oncology-related app development (https://www.linkedin.com/groupItem?view=&gid=72923&type=member&item=5870221695683424259&qid=dbf53031-dd21-443c-9152-fad87f85d200&trk=groups_most_popular-0-b-ttl&goback=.gmp_72923)
As reports and clinicians have stated, we need health outcome data and clinical trials to determine the effective of these apps.

MyCyberDoctor™, a True Gamification App, Shows Great Results in Improving Diabetics Medical Adherence and Health Outcome

 

Most of the mobile health apps discussed above, would be classified as tracking apps, because the applications simply record a patient’s actions, whether filling a prescription, interacting with a doctor, nurse, pharmacist, or going to a website to gain information. However, as discussed before, there is no hard evidence this is really impacting health outcomes.

 

Another type of application, termed gamification apps, rely on role-playing by the patient to affect patient learning and ultimately behavior.

An interested twist on this method was designed by Akhila Satish, CEO and developer of CyberDoctor and a complementary application PatientPartner.

Akhila Satish Picture

 

 

Ms. Akhila Satish, CEO CyberDoctor

 

 

 

 

 

 

 

Please watch video of interview with Akhila Satish, CEO of CyberDoctor at the Health 2.0 conference http://vimeo.com/51695558

 

And a video of the results of the PatientPartner clinical trial here: http://vimeo.com/79537738

 

As reported here, the PatientPartner application was used in the first IRB-approved mhealth clinical-trial to see if the gamification app could improve medical adherence and outcomes in diabetic patients. PatientPartner is a story-driven game in changing health behavior and biomarkers (blood glucose levels in this trial). In the clinical trial, 100 non-adherent patients with diabetes played the PatientPartner game for 15 minutes. Results were amazing, as the trial demonstrated an increase in patient adherence, with only 15 minutes of game playing.

Results from the study

Patients with diabetes who used PatientPartner showed significant improvement in three key areas – medication, diet, and exercise:

  • Medication adherence increased by 37%, from 58% to 95% – equivalent to three additional days of medication adherence per week.
  • Diet adherence increased by 24% – equivalent to two days of additional adherence a week.
  • Exercise adherence increased by 14% – equivalent to one additional day of adherence per week.
  • HbA1c (a blood sugar measure) decreased from 10.7% to 9.7%.

As mentioned in the article:

The unique, universal, non-disease specific approach allows PatientPartner to be effective in improving adherence in all patient populations.

PatientPartner is available in the iTunes store and works on the iPhone and iPod Touch. For information on PatientPartner, visit www.mypatientpartner.com.

Ms. Satish, who was named one of the top female CEO’s at the Health Conference, gratuitously offered to answer a few questions for Leaders in Pharmaceutical Business Intelligence (LPBI) on the feasibility of using such a game (role-playing) application to improve medical adherence in the oncology field.

LPBI: The results you had obtained with patient-compliance in the area of diabetes are compelling and the clinical trial well-designed.  In the oncology field, due to the increase in use of oral chemotherapeutics, patient-compliance has become a huge issue. Other than diabetes, are there plans for MyCyberDoctor and PatientPartner to be used in other therapeutic areas to assist with patient-compliance and patient-physician relations?

Ms. Satish: Absolutely! We tested the application in diabetes because we wanted to measure adherence from an objective blood marker (hbA1c). However, the method behind PatientPartner- teaching patients how to make healthy choices- is universal and applicable across therapeutic areas. 

LPBI: Recently, there have been a plethora of apps developed which claim to impact patient-compliance and provide information. Some of these apps have been niche (for example only providing prescription information but tied to pharmacy records and company databases). Your app seems to be the only one with robust clinical data behind it and approaches from a different angle, namely adjusting behavior using a gamefying experience and teaching the patient the importance of compliance. How do you feel this approach geared more toward patient education sets PatientPartner apart from other compliance-based apps?

Ms. Satish: PatientPartner really focuses on the how of patient decision making, rather than the specifics of each decision that is made. It’s a unique approach, and part of the reason PatientPartner works so effectively with such a short initial intervention! We are able to achieve more with less “app” time as a result of this method.  

LPBI: There have been multiple studies attempting to correlate patient adherence, decision-making, and health outcome to socioeconomic status. In some circumstances there is a socioeconomic correlation while other cases such as patient-decision to undergo genetic testing or compliance to breast cancer treatment in rural areas, level of patient education may play a bigger role. Do you have data from your diabetes trial which would suggest any differences in patient adherence, outcome to any socioeconomic status? Do you feel use of PatientPartner would break any socioeconomic barriers to full patient adherence?

Ms. Satish: Within our trial, we had several different clinical sites. This helped us test the product out in a broad, socioeconomically diverse population. It is our hope that with a tool as easy to scale and use as PatientPartner we have the opportunity to see the product used widely, even in populations that are traditionally harder to reach.  

LPBI: There has been a big push for the development of individual, personalized physician networks which use the internet as the primary point of contact between a primary physician and the patient. Individuals may sign up to these networks bypassing the traditional insurance-based networks. How would your application assist in these types of personalized networks?

Ms. Satish: PatientPartner can easily be plugged into any existing framework of communication between patient and provider. We facilitate patient awareness, engagement and accountability- all of which are important regardless of the network structure.

LBPI: Thank you Akhila!

A debate has begun about regulating mobile health applications, and although will be another post, I would just like to summarize a nice article in May, 2014 Oncology Times by Sarah Digiulo “Mobile Health Apps: Should They be Regulated?

In general, in the US there are HIPAA regulations about the dissemination of health related information between a patient and physician. Most of the concerns are related to personal health information made public in an open-access platform such as Twitter or Facebook.

In addition, according to Dr. Don Dizon M.D., Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, it may be more difficult to design applications directed against a vast, complex disease like cancer with its multiple subtypes than for diabetes.

 

Mobile Health Applications on Rise in Developing World: Worldwide Opportunity

 

According to International Telecommunication Union (ITU) statistics, world-wide mobile phone use has expanded tremendously in the past 5 years, reaching almost 6 billion subscriptions. By the end of this year it is estimated that over 95% of the world’s population will have access to mobile phones/devices, including smartphones.

This presents a tremendous and cost-effective opportunity in developing countries, and especially rural areas, for physicians to reach patients using mHealth platforms.

Drs. Clara Aranda-Jan Neo Mohutsiwa and Svetla Loukanova had conducted a systematic review of the literature on mHealth projects conducted in Africa[1] to assess the reliability of mobile phone and applications to assist in patient-physician relationships and health outcomes. The authors reviewed forty four studies on mHealth projects in Africa, determining their:

  • strengths
  • weaknesses
  • opportunities
  • threats

to patient outcomes using these mHealth projects. In general, the authors found that mHealth projects were beneficial for health-related outcomes and their success related to

  • accessibility
  • acceptance and low-cost
  • adaptation to local culture
  • government involvement

while threats to such projects could include

  • lack of funding
  • unreliable infrastructure
  • unclear healthcare system responsibilities

Dr.Sreedhar Tirunagari, an oncologist in India, agrees that mHealth, especially gamification applications could greatly foster better patient education and adherencealthough he notes that mHealth applications are not really used in India and may not be of much use for those oncology patients living in rural areas, as  cell phone use is not as prevalent as in the bigger inner cities such as Delhi and Calcutta.

 

Dr. Louis Bretes, an oncologist from Portugal, when asked

1) do you see a use for such apps which either track drug compliance or use gamification systems to teach patients the importance of continuing their full schedule of drug therapy

2) do you feel patient- drug compliance issues in the oncology practice is due to lack of information available to the patient or issues related to drug side effects?

“I think that Apps could help in this setting, we are in
Informatics era but..
The main question is that chronic patients are special ones.
Cancer patients have to deal with prognosis, even in therapies
with curative intent such as aromatase inhibitors are potent
Drugs that can cure; only in the future the patients know.
But meanwhile he or she has to deal with side-effects every day. A PC can help but suffer this symptoms…it. Is a real problem believe me!”

“The main app is his/her doctor”

I would like to invite all oncologists to answer the poll question ABOVE about the use of such gamification apps, like PatientPartner, for improving medical adherence to oral chemotherapy.

UPDATE 5/15/2019

The results of the above poll, although limited, revealed some interesting insights.  Although only five oncologists answered the poll whether they felt gamification applications could help with oral chemotherapy patient adherence, all agreed it would be worthwhile to develop apps based on gamification to assist in the outpatient setting.  In addition, one oncologist felt that the success of mobile patient adherence application would depend on the type of cancer.  None of the oncologist who answered the survey thought that gamification apps would have no positive effect on patient adherence to their chemotherapy.  With this in light, a recent paper by Joel Fishbein of University of Colorado and Joseph Greer from Massachusetts General Hospital, describes the development of a mobile application, in clinical trial, to promote patient adherence to their oral chemotherapy. 

 

Mobile Applications to Promote Adherence to Oral Chemotherapy and Symptom Management: A Protocol for Design and Development 

 

Mobile Application to Promote Adherence to Oral Chemotherapy and Symptom Management: A Protocol for Design and Development. Fishbein JNNisotel LEMacDonald JJAmoyal Pensak NJacobs JMFlanagan CJethwani K Greer JA. JMIR Res Protoc. 2017 Apr 20;6(4):e62. doi: 10.2196/resprot.6198. 

 

Abstract 

BACKGROUND: 

Oral chemotherapy is increasingly used in place of traditional intravenous chemotherapy to treat patients with cancer. While oral chemotherapy includes benefits such as ease of administration, convenience, and minimization of invasive infusions, patients receive less oversight, support, and symptom monitoring from clinicians. Additionally, adherence is a well-documented challenge for patients with cancer prescribed oral chemotherapy regimens. With the ever-growing presence of smartphones and potential for efficacious behavioral intervention technology, we created a mobile health intervention for medication and symptom management. 

OBJECTIVE: 

The objective of this study was to develop and evaluate the usability and acceptability of a smartphone app to support adherence to oral chemotherapy and symptom management in patients with cancer. 

METHODS: 

We used a 5-step development model to create a comprehensive mobile app with theoretically informed content. The research and technical development team worked together to develop and iteratively test the app. In addition to the research team, key stakeholders including patients and family members, oncology clinicians, health care representatives, and practice administrators contributed to the content refinement of the intervention. Patient and family members also participated in alpha and beta testing of the final prototype to assess usability and acceptability before we began the randomized controlled trial. 

RESULTS: 

We incorporated app components based on the stakeholder feedback we received in focus groups and alpha and beta testing. App components included medication reminders, self-reporting of medication adherence and symptoms, an education library including nutritional information, Fitbit integration, social networking resources, and individually tailored symptom management feedback. We are conducting a randomized controlled trial to determine the effectiveness of the app in improving adherence to oral chemotherapy, quality of life, and burden of symptoms and side effects. At every stage in this trial, we are engaging stakeholders to solicit feedback on our progress and next steps. 

CONCLUSIONS: 

To our knowledge, we are the first to describe the development of an app designed for people taking oral chemotherapy. The app addresses many concerns with oral chemotherapy, such as medication adherence and symptom management. Soliciting feedback from stakeholders with broad perspectives and expertise ensured that the app was acceptable and potentially beneficial for patients, caregivers, and clinicians. In our development process, we instantiated 7 of the 8 best practices proposed in a recent review of mobile health app development. Our process demonstrated the importance of effective communication between research groups and technical teams, as well as meticulous planning of technical specifications before development begins. Future efforts should consider incorporating other proven strategies in software, such as gamification, to bolster the impact of mobile health apps. Forthcoming results from our randomized controlled trial will provide key data on the effectiveness of this app in improving medication adherence and symptom management. 

TRIAL REGISTRATION: 

ClinicalTrials.gov NCT02157519; https://clinicaltrials.gov/ct2/show/NCT02157519 (Archived by WebCite at http://www.webcitation.org/6prj3xfKA). 

 In this paper, Fishbein et al. describe the  methodology of the developoment of a mobile application to promote oral chemotherapy adherence.   This mobile app intervention was named CORA or ChemOtheRapy Assistant. 

 

 Of the approximately 325,000 health related apps on the market (as of 2017), the US Food and Drug Administration (FDA) have only reviewed approximately 20 per year and as of 2016 cleared only about 36 health related apps. 

According to industry estimates, 500 million smartphone users worldwide will be using a health care application by 2015, and by 2018, 50 percent of the more than 3.4 billion smartphone and tablet users will have downloaded mobile health applications.  However, there is not much scientific literature providing a framework for design and creation of quality health related mobile applications. 

Methods 

The investigators separated the app development into two phases: Phase 1 consisted of the mobile application development process and initial results of alpha and beta testing to determine acceptability among the major stakeholders including patients, caregivers, oncologists, nurses, pharmacists, pharmacologists, health payers, and patient advocates.  Phase 1 methodology and results were the main focus of this paper.  Phase 2 consists of an ongoing clinical trial to determine efficacy and reliability of the application in a larger number of patients at different treatment sites and among differing tumor types. 

The 5 step development process in phase 1 consisted of identifying features, content, and functionality of a mobile app in an iterative process, including expert collaboration and theoretical framework to guide initial development.   

There were two distinct teams: a research team and a technical team. The multidisciplinary research team consisted of the principal investigator, co-investigators (experts in oncology, psychology and psychiatry), a project director, and 3 research assistants. 

The technical team consisted of programmers and project managers at Partners HealthCare Connected Health.  Stakeholders served as expert consultants including oncologists, health care representatives, practice administrators, patients, and family members (care givers).  All were given questionaires (HIPAA compliant) and all involved in alpha and beta testing of the product. 

There were 5 steps in the development process 

  1. Implementing a theoretical framework: Patients and their family caregivers now bear the primary responsibility for their medical adherence especially to oral chemotherapy which is now more frequently administered in the home setting not in the clinical setting.  Four factors were identified as the most important barriers to oral chemotherapy adherence: complexity of medication regimessymptom burdenpoor self-management of side effects, and low clinical support.  These four factors were integral in the design of the mobile app and made up a conceptual framework in its design. 
  1. Conducting Initial Focus Group Interviews with key stakeholders: Stakeholders were taken from within and outside the local community.  In all 32 stakeholders served as study collaborators including 8 patient/families, 8 oncologists/clinicians, 8 cancer practice administrators, and 8 representatives of the health system, community, and overall society.   The goal of these focus groups were to obtain feedback on the proposed study and design included perceived importance of monitoring of adherence to oral chemotherapy, barriers to communication between patients and oncology teams regarding side effects and medication adherence, potential role of mobile apps to address barriers of quality of cancer care, potential feasibility, acceptability, and usage and feedback on the overall study design. 
  1. Creation of Wireframes (like storyboards or page designs) and Collecting Initial Feedback:  The research and design team, in conjunction with stakeholder input, created content wireframes, or screen blueprints) to provide a visual guide as to what the app would look like.  These wireframes also served as basis for what the patient interviews would look like on the application.  A total of 10 MGH (Massachusetts General Hospital) patients (6 female, 4 male) and most with higher education (BS or higher) participated in the interviews and design of wireframes.  Eight MGH clinicians participated in this phase of wireframe design. 
  1. Developing, Programming, and Refining the App:  CORA was designed to be supported by PHP/MySQL databases and run on LAMP hosts (Linux, Apache, MySQL, Perl/PHP/Python) and fully HIPAA compliant.  Alpha testing was conducted with various stakeholders and the app refined by the development team (technical team) after feedback. 
  1. Final beta testing and App prototype for clinical trial: The research team considered the first 5 participants enrolled in the subsequent clinical trial for finalization of the app prototype. 

There were 7 updated versions of the app during the initial clinical trial phase and 4 updates addressed technical issues related to smartphone operating system upgrades. 

Finally, the investigators list a few limitations in their design and study of this application.  First the patient population was homogenous as all were from an academic hospital setting.   Second most of the patients were of Caucasian ethnic background and most were highly educated, all of which may introduce study bias.  In addition, CORA was available on smartphone and tablet only, so a larger patient population who either have no access to these devices or are not technically savvy may experience issues related to this limitation. 

In addition other articles on this site related to Mobile Health applications and Health Outcomes include

Medical Applications and FDA regulation of Sensor-enabled Mobile Devices: Apple and the Digital Health Devices Market

How Social Media, Mobile Are Playing a Bigger Part in Healthcare

E-Medical Records Get A Mobile, Open-Sourced Overhaul By White House Health Design Challenge Winners

Qualcomm Ventures Qprize Regional Competition: MediSafe, an Israeli start-up in the personal health field, is the 2014 Winner of a $100,000 Prize

Friday, April 4 8:30 am- 9:30 am Science Track: Mobile Technology and 3D Printing: Technologies Gaining Traction in Biotech and Pharma – MassBio Annual Meeting 2014, Royal Sonesta Hotel, Cambridge, MA

Information Security and Privacy in Healthcare is part of the 2nd Annual Medical Informatics World, April 28-29, 2014, World Trade Center, Boston, MA

Post Acute Care – Driver of Variation in Healthcare Costs

Kaiser data network aims to improve cancer, heart disease outcomes

 

Additional references

  1. Aranda-Jan CB, Mohutsiwa-Dibe N, Loukanova S: Systematic review on what works, what does not work and why of implementation of mobile health (mHealth) projects in Africa. BMC public health 2014, 14:188.

 

 

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Improving imaging based assessment of tumours’ response to treatment

Writer: Dror Nir, PhD.

The protocol for imaging-based assessment of cancer patients’ response to oncological drugs is known as the RECIST 1.1 criteria; The Role of Medical Imaging in Personalized Medicine . RECIST is mainly relying on morphological evaluation of tumors’ size . I recently participated to a webinar organised by Oncodesign which presented the potential use of more advanced imaging techniques as tools to improve the assessment of cancer patients’ response during oncological clinical trials.

It’s first part, describes a methodology developed based on the original approach of the DITEP* at the “Institut Gustave Roussy”. A method that takes into account kinetics of tumor growth at the pre-treatment phase and along the entire treatment sequence. The conclusion is that adding Tumor Growth Rate (TGR) assessment in Phase I and Phase III clinical trials is simple and provides clinically relevant information: (i) It allows for an early and precise assessment of the tumor growth, (ii) It reveals drug-specific profiles, suggesting its potential use for the early assessment of drug activity, (iii)TGR is independently associated with prognosis both in early clinical trials and in phase III setting.

The second part  presents two functional imaging modalities based on MRI: diffusion-weighted imaging (Dw-MRI) and Dynamic Contrast-Enhanced MRI (DCE-MRI). Dw-MRI gives measures of tissue architecture at the cellular level, whereas DCE-MRI provides information on the vascular status of tumors. Both methods have been standardized and used extensively as early PD biomarkers of the efficacy of anticancer therapies. The presentation goes through preclinical and clinical case studies illustrating how these two techniques can be used to evaluate the activity of novel drug candidates.

I recommend watching a recording of this webinar on YouTube . Note, the voice recording is not so good but, the effort is worthwhile….

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Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013-11-27/larryhbern/Cancer Biomarkers for Companion Diagnostics

Scientists from around the world gathered to share some of their newest biomarker research at the “Oncology Biomarkers Conference”.

Honing in on Cancer Biomarkers

Caitlin Smith
G
EN  15 Nov 2013; 33(20)

Introduction and Goals

Some of the newest cancer treatments aim to individualize the therapy to the specific type of cancer and patient. The large and growing number of different genetic alterations that researchers observe in cancer cells have made it unfeasible to test for only a handful of targets. Instead, clinical testing is moving toward testing for many targets simultaneously.

“This approach of multiplexed tumor genotyping allows for the simultaneous evaluation of a broad range of common and rare tumor alterations,” said Darrell Borger, Ph.D., director of biomarker and co-director of translational research laboratories at the Massachusetts General Hospital Cancer Center. “This is important for expanding the application of targeted therapy across a greater number of patients who undergo testing, and directing those patients into the most relevant clinical trials.”

Dr. Borger and colleagues are uncovering “molecular signatures of tumors,” or collections of targets present in specific tumor types. “A molecular signature of a tumor is in essence a map of the abnormalities within a particular tumor that are thought to be critical in driving the disease process,” said Dr. Borger. “We know that each tumor will have a unique combination of genetic alterations.”

These signatures are useful because the ability to genotype a certain kind of cancer can help find the most effective treatment possible. “The more comprehensive the tumor profiling, the more detailed the roadmap we can draw for directing that patient’s care,” Dr. Borger said.

Uncovering the molecular signatures of tumors has another important role—to better understand the differences among cells within the same tumor. “Tumor heterogeneity is an important mechanism of emerging drug resistance,” said Dr. Borger. “Broad-based tumor profiling and the use of sensitive testing platforms are essential in identifying these potential mechanisms of disease resistance, so that targeted approaches can be aimed at circumventing those mechanisms.”

Target Signaling

Also working to help physicians figure out which treatments among many might work best for individual patients is Selventa. Focusing on gene expression biomarkers, Selventa researchers correlate gene expression patterns from patient data with changes in target signaling mechanisms.

“We operate on the hypothesis that patients with high or low levels of target (or downstream target) pathway signaling correspond to potential responders or nonresponders to target therapy, respectively,” said Renée Deehan Kenney, Ph.D., vp of research. “If we know who responded and who did not respond to treatment, then we can use that information to hone the biomarker using machine-learning approaches.”

Selventa is using its Systems Diagnostics (SysDx) platform to identify biomarkers used in diagnosing immune disorders such as rheumatoid arthritis (RA). Their product Clarify-RA is based on the SysDx approach using a blood biomarker. It is designed to aid clinicians in matching RA patients with those RA drugs that will be most beneficial to them. Such matching is valuable because RA is a heterogeneous disease, but different patients respond differently to the over 15 RA drugs that are available. Moreover, RA is a debilitating disease that cannot wait for a trial-and-error treatment approach.

“To compound this clinical challenge, drugs approved for RA offer about 50% improvement for only 40% of the patients,” said Dr. Deehan Kenney. For example, one biomarker Selventa found can identify RA patients who are likely to respond to anti-TNF therapy. Similarly, Selventa’s SysDx approach also found a biomarker from tumor biopsy tissue that identifies ER+ breast cancer patients whose cancer tends to progress with tamoxifen treatment.

IHC-Based Testing

President and CEO of Precision Biologics, Philip Arlen, M.D., discussed his company’s research on a new monoclonal antibody (NPC-1C), which targets tumors in both pancreatic and colorectal cancer. The antibody’s target is specific to tumors, and the antibody has negligible reactions with normal tissue, he said.

Precision Biologics took an unconventional tack to making NPC-1C, using a cancer vaccine that had been developed from colorectal cancer tissue removed from patients with varying stages of disease. They screened for antibodies that were specific for tumors, but nonreactive with normal tissue.

In both cell cultures and in animal models, they found that NPC-1C destroyed pancreatic cancer cells. “Furthermore, we had very encouraging Phase I/IIa data demonstrating prolongation in overall survival in patients that had exhausted all standards of therapy,” said Dr. Arlen.

Precision Biologics has developed an immunohistochemistry-based diagnostic test for expression of NPC-1C’s target. “Patients’ tumors are tested, and if the target is present, the patients can receive treatment with NPC-1C,” said Dr. Arlen. “We are also developing a diagnostic assay with NPC-1C for early detection and prognosis of colorectal and pancreatic cancer.”

NMR Technology

LipoScience researchers using NMR technology to look for cancer biomarkers expect that panels of metabolites covering a range biochemical processes will need to be analyzed. They produced these 1H NMR spectra of unprocessed serum focusing on (A) macromolecular signals and (B) the small molecule metabolome.

LipoScience is also developing new ways to search for biomarkers. Specifically, to find biomarkers of clinical value, they are using NMR technology. “We take advantage of two of the key features of the NMR platform,” explained Thomas O’Connell, Ph.D., senior director of research and development. “These are the lack of required sample preparation for routine biofluids and the inherently quantitative signals.” This means that they can profile large sample sets very quickly.

LipoScience researchers are now using NMR to look for cancer biomarkers. “Given the heterogeneity of most cancers, it is not likely that a single biomarker will provide the necessary clinical performance,” said Dr. O’Connell, “so we are examining panels of metabolites that cover a range of biochemical processes, including lipid and lipoprotein metabolism, energy perturbations, inflammatory processes, and others.”

They plan to use NMR and metabolomic profiling to develop clinical assays that help to choose patient-specific therapies. “We are hopeful that one day in the near future, panels of biomarkers could provide clinicians with much more objective, quantifiable, and personalized information regarding the diagnosis and management of their patients,” added Dr. O’Connell.

Single Molecule Arrays

The Simoa (for single molecule array) instrument from Quanterix uses a digital ELISA technique, trapping fluorescent reaction product in indiv-idual wells, to speed blood testing for HIV.

Researchers at Quanterix have developed a method of testing for a different type of biomarker—one that indicates the early and acute (and most contagious) stage of HIV infection. Their method is faster, cheaper, and more sensitive than previous tests.

Previously, the gold standard HIV test with the highest sensitivity was nucleic acid testing, which detects viral genetic material. The new test from Quanterix, called Simoa for “single molecule arrays,” is a digital ELISA technique. Simoa works by preventing the sensitivity loss that can occur in conventional ELISAs because of the dilution of reaction product into the reaction volume. Simoa essentially miniaturizes the ELISA principle, trapping fluorescent reaction product in individual wells to prevent dilution.

“The technology basically supercharges a standard ELISA to give 1,000-times greater sensitivity,” said David Wilson, Ph.D., vp of product development. “Due to this extreme sensitivity of Simoa to enzyme label, label molecules can be reduced, which lowers nonspecific interactions and improves signal background. This drives the sensitivity of Simoa digital immunoassays down to the level of nucleic acid testing.”

Simoa assays are easily amenable to high-throughput fluidics instrumentation and automation. So Dr. Wilson hopes Simoa will be applied to HIV screening in blood banks, as well as other blood-borne viruses to which Quanterix is developing new Simoa assays. “A key need in many blood banking centers is high throughput,” Dr. Wilson said. “Blood units are screened for a number of pathogens, so effective throughput is measured in number of units processed in a given period of time.”

Simoa immunoassays can be multiplexed to test for up to 10 different target proteins simultaneously, which may benefit blood banks. However, blood banking is highly regulated, so introducing Simoa assays may take time. “As with any new test used to ensure a blood unit is pathogen-free,” explained Dr. Wilson, “a substantial amount of data is needed to prove to regulatory bodies that the test exhibits the claimed performance, and that the manufacturing processes are fully validated and controlled.”

Perhaps one day, it will be possible to detect biomarkers of viral infection, cancer, and other diseases for many people very quickly. Then, armed with the relevant information, healthcare providers will be able to fight disease more effectively.

 

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The Delicate Connection:  IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Author and Curator: Demet Sag, PhD, CRA, GCP      

Table of Contents:

  1. Abstract
  2. Dual role for IDO
  3. Immune System and IDO
  4. Autoimmune disorders and IDO
  5. Cancer and Ido
  6. Clinical Interventions
  7. Clinical Trials
  8. Future Actions for Molecular Dx and Targeted Therapies:
  9. Conclusion
  10. References

TABLE 1- IDO Clinical Trials

TABLE 2- Kyn induced Genes

TABLE 3 Possible biomarkers and molecular diagnostics targets

TABLE 4: Current Interventions ______________________________________________________________________________________________________________

ABSTRACT:

Overall purpose is to find a method to manipulate IDO for clinical applications, mainly the focus of this review is is cancer prevention and treatment.  The first study proving the connection between IDO and immune response came from, a very natural event, a protection of pregnancy in human. This led to discover that high IDO expression is a common factor in cancer tumors. Thus, attention promoted investigations on IDO’s role in various disease states, immune disorders, transplantation, inflammation, women health, mood disorders.
Many approaches, vaccines and adjuvants are underway to find new immunotherapies by combining the power of DCs in immune response regulation and specific direction of siRNA.  As a result, with this unique qualities of IDO, DCs and siRNA, we orchestrated a novel intervention for immunomodulation of IDO by inhibiting with small interference RNA, called siRNA-IDO-DCvax.  Proven that our DCvax created a delay and regression of tumor growth without changing the natural structure and characterization of DCs in melanoma and breast cancers in vivo. (** The shRNA IDO- DCvax is developed by Regen BioPhrama, San Diego, CA ,  Thomas Ichim, Ph.D, CSO. and David Koos, CEO)

______________________________________________________________________________________________________________

Double-Edged Sword of IDO: The Good and The Bad for Clinical intervention and Developments

IDO almost has a dual role. There is a positive side of high expression of IDO during pregnancy (29; 28; 114), transplants (115; 116; 117; 118; 119), infectious diseases (96) and but this tolerance is negative during autoimmune-disorders (120; 121; 122), tumors of cancer (123; 124; 117; 121; 125; 126; 127) (127), and mood disorders (46). The increased IDO expression has a double-edged sword in human physiology provides a positive role during protection of fetus and grafts after transplantations but becomes a negative factor during autoimmune disorders, cancer, sepsis and mood disorders.

Prevention of allogeneic fetal rejection is possible by tryptophan metabolism (26) rejecting with lack of IDO but allocating if IDO present (29; 28; 114). These studies lead to find “the natural regulation mechanism” for protecting the transplants from graft versus host disease GVHD (128) and getting rid of tumors.

The plasticity of  mammary and uterus during reproduction may hold some more answers to prevent GVHD and tumors of cancer with good understanding of IDO and tryptophan mechanism (129; 130). After allogeneic bone marrow transplants the risk of solid tumor development increased about 80% among 19,229 patients even with a greater risk among patients under 18 years old (117).  The adaptation of tolerance against host mechanism is connected to the IDO expression (131). During implantation and early pregnancy IDO has a role by making CD4+CD25+Foxp3+ regulatory T cells (Tregs) and expressing in DCs and  MQs  (114; 132; 133).

Clonal deletion mechanism prevents mother to react with paternal products since female mice accepted the paternal MHC antigen-expressing tumor graft during pregnancy and rejected three weeks after delivery (134). CTLA-4Ig gene therapy alleviates abortion through regulation of apoptosis and inhibition of spleen lymphocytes (135).  

 Immune System and IDO DCs are the orchestrator of the immune response (56; 57; 58) with list of functions in uptake, processing, and presentation of antigens; activation of effector cells, such as T-cells and NK-cells; and secretion of cytokines and other immune-modulating molecules to direct the immune response. The differential regulation of IDO in distinct DC subsets is widely studied to delineate and correct immune homeostasis during autoimmunity, infection and cancer and the associated immunological outcomes. Genesis of antigen presenting cells (APCs), eventually the immune system, require migration of monocytes (MOs), which is originated in bone marrow. Then, these MOs move from bloodstream to other tissues to become macrophages and DCs (59; 60).

Initiation of immune response requires APCs to link resting helper T-cell with the matching antigen to protect body. DCs are superior to MQs and MOs in their immune action model. When DCs are first described (61) and classified, their role is determined as a highly potent antigen-presenting cell (APC) subset with 100 to 1000-times more effective than macrophages and B-cells in priming T-cells. Both MQs and monocytes phagocytize the pathogen, and their cell structure contains very large nucleus and many internal vesicles. However, there is a nuance between MQ and DCs, since DCs has a wider capacity of stimulation, because MQs activates only memory T cells, yet DCs can activate both naïve and memory T cells.

DCs are potent activators of T cells and they also have well controlled regulatory roles. DC properties determine the regulation regardless of their origin or the subset of the DCs. DCs reacts after identification of the signals or influencers for their inhibitory, stimulatory or regulatory roles, before they express a complex repertoire of positive and negative cytokines, transmembrane proteins and other molecules. Thus, “two signal theory” gains support with a defined rule.  The combination of two signals, their interaction with types of cells and time are critical.

In short, specificity and time are matter for a proper response. When IDO mRNA expression is activated with CTL40 ligand and IFNgamma, IDO results inhibition of T cell production (4).  However, if DCs are inhibited by 1MT, an inhibitor of IDO, the response stop but IgG has no affect (10).  In addition, if the stimulation is started by a tryptophan metabolite, which is downstream of IDO, such as 3-hydroxyantranilic or quinolinic acids, it only inhibits Th1 but not Th2 subset of T cells (62).

Furthermore, inclusion of signal molecules, such as Fas Ligand, cytochrome c, and pathways also differ in the T cell differentiation mechanisms due to combination, time and specificity of two-signals.  The co-culture experiments are great tool to identify specific stimuli in disease specific microenvironment (63; 12; 64) for discovering the mechanism and interactions between molecules in gene regulation, biochemical mechanism and physiological function during cell differentiation.

As a result, the simplest differential cell development from the early development of DCs impact the outcome of the data. For example, collection of MOs from peripheral blood mononuclear cells (PBMCs) with IL4 and GM-CSF leads to immature DCs (iDCs). On next step, treatment of iDCs with tumor necrosis factor (TNF) or other plausible cytokines (TGFb1, IFNgamma, IFNalpha,  IFNbeta, IL6 etc.) based on the desired outcome differentiate iDCs  into mature DCs (mDCs). DCs live only up to a week but MOs and generated MQs can live up to a month in the given tissue. B cells inhibit T cell dependent immune responses in tumors (65).

AutoImmune Disorders:

The Circadian Clock Circuitry and the AHR

The balance of IDO expression becomes necessary to prevent overactive immune response self-destruction, so modulation in tryptophan and NDA metabolisms maybe essential.  When splenic IDO-expressing CD11b (+) DCs from tolerized animals applied, they suppressed the development of arthritis, increased the Treg/Th17 cell ratio, and decreased the production of inflammatory cytokines in the spleen (136).

The role of Nicotinamide prevention on type 1 diabetes and ameliorates multiple sclerosis in animal model presented with activities of  NDAs stimulating GPCR109a to produce prostaglandins to induce IDO expression, then these PGEs and PGDs converted to the anti-inflammatory prostaglandin, 15d-PGJ(2) (137; 138; 139).  Thus, these events promotes endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma. (137).

Modulating the immune response at non-canonical at canonocal pathway while keeping the non-canonical Nf-KB intact may help to mend immune disorders. As a result, the targeted blocking in canonical at associated kinase IKKβ and leaving non-canonocal Nf-kB pathway intact, DCs tips the balance towards immune supression. Hence, noncanonical NF-κB pathway for regulatory functions in DCs required effective IDO induction, directly or indirectly by endogenous ligand Kyn and negative regulation of proinflammatory cytokine production. As a result, this may help to treat autoimmune diseases such as rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, and multiple sclerosis, or allergy or transplant rejection.

While the opposite action needs to be taken during prevention of tumors, that is inhibition of non-canonical pathway.  Inflammation induces not only relaxation of veins and lowering blood pressure but also stimulate coagulopathies that worsen the microenvironment and decrease survival rate of patients after radio or chemotherapies.Cancer Generating tumor vaccines and using adjuvants underway (140).

Clinical correlation and genetic responses also compared in several studies to diagnose and target the system for cancer therapies (127; 141; 131).  The recent surveys on IDO expression and human cancers showed that IDO targeting is a candidate for cancer therapy since IDO expression recruiting Tregs, downregulates MHC class I and creating negative immune microenvironment for protection of development of tumors (125; 27; 142).  Inhibition of IDO expression can make advances in immunotherapy and chemotherapy fields (143; 125; 131; 144).

IDO has a great importance on prevention of cancer development (126). There are many approaches to create the homeostasis of immune response by Immunotherapy.  However, given the complexity of immune regulations, immunomodulation is a better approach to correct and relieve the system from the disease.  Some of the current IDO targeted immunotherapy or immmunomodulations with RNA technology for cancer prevention (145; 146; 147; 148; 149; 150) or applied on human or animals  (75; 151; 12; 115; 152; 9; 125) or chemical, (153; 154) or  radiological (155).  The targeted cell type in immune system generally DCs, monocytes (94)T cells (110; 156)and neutrophils (146; 157). On this paper, we will concentrate on DCvax on cancer treatments.

 T-reg, regulatory T cells; Th, T helper; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; TCR, T cell receptor; IDO, indoleamine 2,3-dioxygenase. (refernece: http://www.pnas.org/content/101/28/10398/suppl/DC)

T-reg, regulatory T cells; Th, T helper; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; TCR, T cell receptor; IDO, indoleamine 2,3-dioxygenase. (refernece: http://www.pnas.org/content/101/28/10398/suppl/DC)

IDO and the downstream enzymes in tryptophan pathway produce a series of immunosuppressive tryptophan metabolites that may lead into Tregs proliferation or increase in T cell apoptosis (62; 16; 27; 158), and some can affect NK cell function (159).

The interesting part of the mechanism is even without presence of IDO itself, downstream enzymes of IDO in the kynurenine tryptophan degradation still show immunosuppressive outcome (160; 73) due to not only Kyn but also TGFbeta stimulated long term responses. DC vaccination with IDO plausible (161) due to its power in immune response changes and longevity in the bloodstream for reversing the system for Th17 production (162).

Clinical Interventions are taking advantage of the DC’s central role and combining with enhancing molecules for induction of immunity may overcome tolerogenic DCs in tumors of cancers (163; 164).

The first successful application of DC vaccine used against advanced melanoma after loading DCs with tumor peptides or autologous cell lysate in presence of adjuvants keyhole limpet hematocyanin (KLH) (165).  Previous animal and clinical studies show use of DCs against tumors created success (165; 166; 167) as well as some problems due to heterogeneity of DC populations in one study supporting tumor growth rather than diminishing (168).

DC vaccination applied onto over four thousand clinical trial but none of them used siRNA-IDO DC vaccination method. Clinical trials evaluating DCs loaded ex vivo with purified TAAs as an anticancer immunotherapeutic interventions also did not include IDO (Table from (169). This table presented the data from 30 clinical trials, 3 of which discontinued, evaluating DCs loaded ex vivo with TAAs as an anticancer immunotherapy for 12 types of cancer [(AML(1), Breast cancer (4), glioblastoma (1), glioma (2), hepatocellular carcinoma (1), hematological malignancies (1), melanoma (6), neuroblastoma sarcoma (2), NSCLC (1), ovarian cancer (3), pancreatic cancer (3), prostate cancer (10)] at phase I, II or I/II.

Tipping the balance between Treg and Th17 ratio has a therapeutic advantage for restoring the health that is also shown in ovarian cancer by DC vaccination with adjuvants (161).  This rebalancing of the immune system towards immunogenicity may restore Treg/Th17 ratio (162; 170) but it is complicated. The stimulation of IL10 and IL12 induce Treg produce less Th17 and inhibiting CTL activation and its function (76; 171; 172) while animals treated with anti-TGFb before vaccination increase the plasma levels of IL-15 for tumor specific T cell survival in vivo (173; 174) ovarian cancer studies after human papilloma virus infection present an increase of IL12 (175).

Opposing signal mechanism downregulates the TGFb to activate CTL and Th1 population with IL12 and IL15 expression (162; 173).  The effects of IL17 on antitumor properties observed by unique subset of CD4+ T cells (176) called also CD8+ T cells secrete even more IL17 (177).

Using cytokines as adjuvants during vaccination may improve the efficacy of vaccination since cancer vaccines unlike infections vaccines applied after the infection or disease started against the established adoptive immune response.  Adjuvants are used to improve the responses of the given therapies commonly in immunotherapy applications as a combination therapy (178).

Enhancing cancer vaccine efficacy via modulation of the microenvironment is a plausible solution if only know who are the players.  Several molecules can be used to initiate and lengthen the activity of intervention to stimulate IDO expression without compromising the mechanism (179).  The system is complicated so generally induction is completed ex-vivo stimulation of DCs in cell lysates, whole tumor lysates, to create the microenvironment and natural stimulatory agents. Introduction of molecules as an adjuvants on genetic regulation on modulation of DCs are critical, because order and time of the signals, specific location/ tissue, and heterogeneity of personal needs (174; 138; 180). These studies demonstrated that IL15 with low TGFb stimulates CTL and Th1, whereas elevated TGFb with IL10 increases Th17 and Tregs in cancer microenvironments.

IDO and signaling gene regulation

For example Ret-peptide antitumor vaccine contains an extracellular fragment of Ret protein and Th1 polarized immunoregulator CpG oligonucleotide (1826), with 1MT, a potent inhibitor of IDO, brought a powerful as well as specific cellular and humoral immune responses in mice (152).

The main idea of choosing Ret to produce vaccine in ret related carcinomas fall in two criterion, first choosing patients self-antigens for cancer therapy with a non-mutated gene, second, there is no evidence of genetic mutations in Ret amino acids 64-269. Demonstration of proliferating hemangiomas, benign endothelial tumors and often referred as hemangiomas of infancy appearing at head or neck, express IDO and slowly regressed as a result of immune mediated process.

After large scale of genomic analysis show insulin like growth factor 2 as the key regulator of hematoma growth (Ritter et al. 2003). We set out to develop new technology with our previous expertise in immunotherapy and immunomodulation (181; 182; 183; 184), correcting Th17/Th1 ratio (185), and siRNA technology (186; 187).  We developed siRNA-IDO-DCvax. Patented two technologies “Immunomodulation using Altered DCs (Patent No: US2006/0165665 A1) and Method of Cancer Treatments using siRNA Silencing (Patent No: US2009/0220582 A1).

In melanoma cancer DCs were preconditioned with whole tumor lysate but in breast cancer model pretreatment completed with tumor cell lysate before siRNA-IDO-DCvax applied. Both of these studies was a success without modifying the autanticity of DCs but decreasing the IDO expression to restore immunegenity by delaying tumor growth in breast cancer (147) and in melanoma (188).  Thus, our DCvax specifically interfere with Ido without disturbing natural structure and content of the DCs in vivo showed that it is possible to carry on this technology to clinical applications.

Furthermore, our method of intervention is more sophisticated since it has a direct interaction mechanism with ex-vivo DC modulation without creating long term metabolism imbalance in Trp/Kyn metabolite mechanisms since the action is corrective and non-invasive.

There were several reasons.

First, prevention of tumor development studies targeting non-enzymatic pathway initiated by pDCs conditioned with TGFbeta is specific to IDO1 (189).

Second, IDO upregulation in antigen presenting cells allowing metastasis show that most human tumors express IDO at high levels (123; 124).

Third, tolerogenic DCs secretes several molecules some of them are transforming growth factor beta (TGFb), interleukin IL10), human leukocyte antigen G (HLA-G), and leukemia inhibitory factor (LIF), and non-secreted program cell death ligand 1 (PD-1 L) and IDO, indolamine 2.3-dioxygenase, which promote tumor tolerance. Thus, we took advantage of DCs properties and Ido specificity to prevent the tolerogenicity with siRNA-IDO DC vaccine in both melanoma and breast cancer.

Fourth, IDO expression in DCs make them even more potent against tumor antigens and create more T cells against tumors. IDOs are expressed at different levels by both in broad range of tumor cells and many subtypes of DCs including monocyte-derived DCs (10), plasmacytoid DCs (142), CD8a+ DCs (190), IDO compotent DCs (17), IFNgamma-activated DCs used in DC vaccination.  These DCs suppress immune responses through several mechanisms for induction of apoptosis towards activated T cells (156) to mediate antigen-specific T cell anergy in vivo (142) and for enhancement of Treg cells production at sites of vaccination with IDO-positive DCs+ in human patients (142; 191; 192; 168; 193; 194). If DCs are preconditioned with tumor lysate with 1MT vaccination they increase DCvax effectiveness unlike DCs originated from “normal”, healthy lysate with 1MT in pancreatic cancer (195).  As a result, we concluded that the immunesupressive effect of IDO can be reversed by siRNA because Treg cells enhances DC vaccine-mediated anti-tumor-immunity in cancer patients.

Gene silencing is a promising technology regardless of advantages simplicity for finding gene interaction mechanisms in vitro and disadvantages of the technology is utilizing the system with specificity in vivo (186; 196).  siRNA technology is one of the newest solution for the treatment of diseases as human genomics is only producing about 25,000 genes by representing 1% of its genome. Thus, utilizing the RNA open the doors for more comprehensive and less invasive effects on interventions. Thus this technology is still improving and using adjuvants. Silencing of K-Ras inhibit the growth of tumors in human pancreatic cancers (197), silencing of beta-catenin in colon cancers causes tumor regression in mouse models (198), silencing of vascular endothelial growth factor (VGEF) decreased angiogenesis and inhibit tumor growth (199).

Combining siRNA IDO and DCvax from adult stem cell is a novel technology for regression of tumors in melanoma and breast cancers in vivo. Our data showed that IDO-siRNA reduced tumor derived T cell apoptosis and tumor derived inhibition of T cell proliferation.  In addition, silencing IDO made DCs more potent against tumors since treated or pretreated animals showed a delay or decreased the tumor growth (188; 147)

 

Clinical Trials:

First FDA approved DC-based cancer therapies for treatment of hormone-refractory prostate cancer as autologous cellular immunotherapy (163; 164).  However, there are many probabilities to iron out for a predictive outcome in patients.

Table 2 demonstrates the current summary of clinical trials report.  This table shows 38 total studies specifically Ido related function on cancer (16), eye (3), surgery (2), women health (4), obesity (1), Cardiovascular (2), brain (1), kidney (1), bladder (1), sepsis shock (1), transplant (1),  nervous system and behavioral studies (4), HIV (1) (Table 4).  Among these only 22 of which active, recruiting or not yet started to recruit, and 17 completed and one terminated.

Most of these studies concentrated on cancer by the industry, Teva GTC ( Phase I traumatic brain injury) Astra Zeneca (Phase IV on efficacy of CRESTOR 5mg for cardiovascular health concern), Incyte corporation (Phase II ovarian cancer) NewLink Genetics Corporation Phase I breast/lung/melanoma/pancreatic solid tumors that is terminated; Phase II malignant melanoma recruiting, Phase II active, not recruiting metastatic breast cancer, Phase I/II metastatic melanoma, Phase I advanced malignancies) , HIV (Phase IV enrolling by invitation supported by Salix Corp-UC, San Francisco and HIV/AIDS Research Programs).

Many studies based on chemotherapy but there are few that use biological methods completed study with  IDO vaccine peptide vaccination for Stage III-IV non-small-cell lung cancer patients (NCT01219348), observational study on effect of biological therapy on biomarkers in patients with untreated hepatitis C, metastasis melanoma, or Crohn disease by IFNalpha and chemical (ribavirin, ticilimumab (NCT00897312), polymorphisms of patients after 1MT drug application in treating patients with metastatic or unmovable refractory solid tumors by surgery (NCT00758537), IDO expression analysis on MSCs (NCT01668576), and not yet recruiting intervention with adenovirus-p53 transduced dendric cell vaccine , 1MT , radiation, Carbon C 11 aplha-methyltryptophan- (NCT01302821).

Among the registered clinical trials some of them are not interventional but  observational and evaluation studies on Trp/Kyn ratio (NCT01042847), Kyn/Trp ratio (NCT01219348), Kyn levels (NCT00897312, NCT00573300),  RT-PCR analysis for Kyn metabolism (NCT00573300, NCT00684736, NCT00758537), and intrinsic IDO expression of mesenchymal stem cells in lung transplant with percent inhibition of CD4+ and CD8+ T cell proliferation toward donor cells (NCT01668576), determining polymorphisms (NCT00426894). These clinical trials/studies are immensely valuable to understand the mechanism and route of intervention development with the data collected from human populations   

Future Actions for Molecular Dx and Targeted Therapies:

Viable tumor environment. Tumor survival is dependent upon an exquisite interplay between the critical functions of stromal development and angiogenesis, local immune suppression and tumor tolerance, and paradoxical inflammation. TEMs: TIE-2 expressing monocytes; “M2” TAMs: tolerogenic tumor-associated macrophages; MDSCs: myeloid-derived suppressor cells; pDCs: plasmacytoid dendritic cells; co-stim.: co-stimulation; IDO: indoleamine 2,3-dioxygenase; VEGF: vascular endothelial growth factor; EGF: epidermal growth factor; MMP: matrix metaloprotease; IL: interleukin; TGF-β: transforming growth factor-beta; TLRs: toll-like receptors.  (reference: http://www.hindawi.com/journals/cdi/2012/937253/fig1/)

Viable tumor environment. Tumor survival is dependent upon an exquisite interplay between the critical functions of stromal development and angiogenesis, local immune suppression and tumor tolerance, and paradoxical inflammation. TEMs: TIE-2 expressing monocytes; “M2” TAMs: tolerogenic tumor-associated macrophages; MDSCs: myeloid-derived suppressor cells; pDCs: plasmacytoid dendritic cells; co-stim.: co-stimulation; IDO: indoleamine 2,3-dioxygenase; VEGF: vascular endothelial growth factor; EGF: epidermal growth factor; MMP: matrix metaloprotease; IL: interleukin; TGF-β: transforming growth factor-beta; TLRs: toll-like receptors. (reference: http://www.hindawi.com/journals/cdi/2012/937253/fig1/)

Current survival or response rate is around 40 to 50 % range.  By using specific cell type, selected inhibition/activation sequence based on patient’s genomic profile may improve the efficacy of clinical interventions on cancer treatments. Targeted therapies for specific gene regulation through signal transduction is necessary but there are few studies with genomics based approach.

On the other hand, there are surveys, observational or evaluations (listed in clinical trials section) registered with www.clinicaltrials.gov that will provide a valuable short-list of molecules.  Preventing stimulation of Ido1 as well as Tgfb-1gene expression by modulating receptor mediated phosphorylation between TGFb/SMAD either at Mad-Homology 1 (MH1) or Mad-Homology 1 (MH2) domains maybe possible (79; 82; 80). Within Smads are the conserved Mad-Homology 1 (MH1) domain, which is a DNA binding module contains tightly bound Zinc atom.

Smad MH2 domain is well conserved and one the most diverse protein-signal interacting molecule during signal transduction due to two important Serine residues located extreme distal C-termini at Ser-Val-Ser in Smad 2 or at pSer-X-PSer in RSmads (80). Kyn activated orphan G protein–coupled receptor, GPR35 with unknown function with a distinct expression pattern that collides with IDO sites since its expression at high levels of the immune system and the gut (63) (200; 63).  

The first study to connect IDO with cancer shows that group (75).  The directly targeting to regulate IDO expression is another method through modulating ISREs in its promoter with RNA-peptide combination technology. Indirectly, IDO can be regulated through Bin1 gene expression control over IDO since Bin1 is a negative regulator of IDO and prevents IDO expression.  IDO is under negative genetic control of Bin1, BAR adapter–encoding gene Bin1 (also known as Amphiphysin2). Bin1 functions in cancer suppression since attenuation of Bin1 observed in many human malignancies (141; 201; 202; 203; 204; 205; 206) .  Null Bin-/- mice showed that when there is lack of Bin1, upregulation of IDO through STAT1- and NF-kB-dependent expression of IDO makes tumor cells to escape from T cell–dependent antitumor immunity.

This pathway lies in non-enzymatic signal transducer function of IDO after stimulation of DCs by TGFb1.  The detail study on Bin1 gene by alternative spicing also provided that Bin1 is a tumor suppressor.  Its activities also depends on these spliced outcome, such as  Exon 10, in muscle, in turn Exon 13 in mice has importance in role for regulating growth when Bin1 is deleted or mutated C2C12 myoblasts interrupted due to its missing Myc, cyclinD1, or growth factor inhibiting genes like p21WAF1 (207; 208).

On the other hand alternative spliced Exon12A contributing brain cell differentiation (209; 210). Myc as a target at the junction between IDO gene interaction and Trp metabolism.  Bin1 interacts with Myc either early-dependent on Myc or late-independent on Myc, when Myc is not present. This gene regulation also interfered by the long term signaling mechanism related to Kynurenine (Kyn) acting as an endogenous ligand to AHR in Trp metabolite and TGFb1 and/or IFNalpha and IFNbeta up regulation of DCs to induce IDO in noncanonical pathway for NF-kB and myc gene activations (73; 74).  Hence, Trp/Kyn, Kyn/Trp, Th1/Th17 ratios are important to be observed in patients peripheral blood. These direct and indirect gene interactions place Bin1 to function in cell differentiation (211; 212; 205).

Regulatory T-cel generation via reverse and non-canonical signaliing to pDCs

Table 3 contains the microarray analysis for Kyn affect showed that there are 25 genes affected by Kyn, two of which are upregulated and 23 of them downregulated (100). This list of genes and additional knowledge based on studies creating the diagnostics panel with these genes as a biomarker may help to analyze the outcomes of given interventions and therapies. Some of these molecules are great candidate to seek as an adjuvant or co-stimulation agents.  These are myc, NfKB at IKKA, C2CD2, CREB3L2, GPR115, IL2, IL8, IL6, and IL1B, mir-376 RNA, NFKB3, TGFb, RelA, and SH3RF1. In addition, Lip, Fox3P, CTLA-4, Bin1, and IMPACT should be monitored.

In addition, Table 4 presents the other possible mechanisms. The highlights of possible target/biomarkers are specific TLRs, conserved sequences of IDO across its homologous structures, CCR6, CCR5, RORgammat, ISREs of IDO, Jak, STAT, IRFs, MH1 and MH2 domains of Smads. Endothelial cell coagulation activation mechanism and pDC maturation or immigration from lymph nodes to bloodstream should marry to control not only IDO expression but also genesis of preferred DC subsets. Stromal mesenchymal cells are also activated by these modulation at vascular system and interferes with metastasis of cancer. First, thrombin (human factor II) is a well regulated protein in coagulation hemostasis has a role in cell differentiation and angiogenesis.

Protein kinase activated receptors (PARs), type of GPCRs, moderate the actions. Second, during hematopoietic response endothelial cells produce hematopoietic growth factors (213; 214). Third, components of bone marrow stroma cells include monocytes, adipocytes, and mesenchymal stem cells (215). As a result, addressing this issue will prevent occurrence of coagulapathologies, namely DIC, bleeding, thrombosis, so that patients may also improve response rate towards therapies. Personal genomic profiles are powerful tool to improve efficacy in immunotherapies since there is an influence of age (young vs. adult), state of immune system (innate vs. adopted or acquired immunity). Table 5 includes some of the current studies directly with IDO and indirectly effecting its mechanisms via gene therapy, DNA vaccine, gene silencing and adjuvant applications as an intervention method to prevent various cancer types.

CONCLUSION

IDO has a confined function in immune system through complex interactions to maintain hemostasis of immune responses. The genesis of IDO stem from duplication of bacterial IDO-like genes.  Inhibition of microbial infection and invasion by depleting tryptophan limits and kills the invader but during starvation of trp the host may pass the twilight zone since trp required by host’s T cells.  Thus, the host cells in these small pockets adopt to new microenvironment with depleted trp and oxygen poor conditions. Hence, the cell metabolism differentiate to generate new cellular structure like nodules and tumors under the protection of constitutively expressed IDO in tumors, DCs and inhibited T cell proliferation.

On the other hand, having a dichotomy in IDO function can be a potential limiting factor that means is that IDOs impact on biological system could be variable based on several issues such as target cells, IDO’s capacity, pathologic state of the disease and conditions of the microenvironment. Thus, close monitoring is necessary to analyze the outcome to prevent conspiracies since previous studies generated paradoxical results.

Current therapies through chemotherapies, radiotherapies are costly and effectiveness shown that the clinical interventions require immunotherapies as well as coagulation and vascular biology manipulations for a higher efficacy and survival rate in cancer patients. Our siRNA and DC technologies based on stem cell modulation will provide at least prevention of cancer development and hopefully prevention in cancer.

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Abstract:

The immune response mechanism is the holy grail of the human defense system for health.   IDO, indolamine 2, 3-dioxygenase, is a key gene for homeostasis of immune responses and producing an enzyme catabolizing the first rate-limiting step in tryptophan degradation metabolism. The hemostasis of immune system is complicated.  In this review, the  properties of IDO such as basic molecular genetics, biochemistry and genesis will be discussed.

IDO belongs to globin gene family to carry oxygen and heme.  The main function and genesis of IDO comes from the immune responses during host-microbial invasion and choice between tolerance and immunegenity.  In human there are three kinds of IDOs, which are IDO1, IDO2, and TDO, with distinguished mechanisms and expression profiles. , IDO mechanism includes three distinguished pathways: enzymatic acts through IFNgamma, non-enzymatic acts through TGFbeta-IFNalpha/IFNbeta and moonlighting acts through AhR/Kyn.

The well understood functional genomics and mechanisms is important to translate basic science for clinical interventions of human health needs. In conclusion, overall purpose is to find a method to manipulate IDO to correct/fix/modulate immune responses for clinical applications.

The first part of the review concerns the basic science information gained overall several years that lay the foundation where translational research scientist should familiar to develop a new technology for clinic. The first connection of IDO and human health came from a very natural event that is protection of pregnancy in human. The focus of the translational medicine is treatment of cancer or prevention/delay cancer by stem cell based Dendritic Cell Vaccine (DCvax) development.

Table of Contents:

  • Abstract

1         Introduction: IDO gene encodes a heme enzyme

2        Location, location, location

3        Molecular genetics

4        Types of IDO:

4.1       IDO1,

4.2       IDO2,

4.3       IDO-like proteins

5        Working mechanisms of IDO

6        Infection Diseases and IDO

7. Conclusion

  1. 1.     Indoleamine 2, 3-dioxygenase (IDO) gene encodes a heme enzyme

IDO is a key homeostatic regulator and confined in immune system mechanism for the balance between tolerance and immunity.  This gene encodes indoleamine 2, 3-dioxygenase (IDO) – a heme enzyme (EC=1.13.11.52) that catalyzes the first rate-limiting step in tryptophan catabolism to N-formyl-kynurenine and acts on multiple tryptophan substrates including D-tryptophan, L-tryptophan, 5-hydroxy-tryptophan, tryptamine, and serotonin.

The basic genetic information describes indoleamine 2, 3-dioxygenase 1 (IDO1, IDO, INDO) as an enzyme located at Chromosome 8p12-p11 (5; 6) that active at the first step of the Tryptophan catabolism.    The cloned gene structure showed that IDO contains 10 exons ad 9 introns (7; 8) producing 9 transcripts.

After alternative splicing only five of the transcripts encode a protein but the other four does not make protein products, three of transcripts retain intron and one of them create a nonsense code (7).  Based on IDO related studies 15 phenotypes of IDO is identified, of which, twelve in cancer tumor models of lung, kidney, endometrium, intestine, two in nervous system, and one HGMD- deletion.

  1. 2.     Location, Location and Location

The specific cellular location of IDO is in cytosol, smooth muscle contractile fibers and stereocilium bundle. The expression specificity shows that IDO is present very widely in all cell types but there is an elevation of expression in placenta, pancreas, pancreas islets, including dendritic cells (DCs) according to gene atlas of transcriptome (9).  Expression of IDO is common in antigen presenting cells (APCs), monocytes (MO), macrophages (MQs), DCs, T-cells, and some B-cells. IDO present in APCs (10; 11), due to magnitude of role play hierarchy and level of expression DCs are the better choice but including MOs during establishment of three DC cell subset, CD14+CD25+, CD14++CD25+ and CD14+CD25++ may increase the longevity and efficacy of the interventions.

IDO is strictly regulated and confined to immune system with diverse functions based on either positive or negative stimulations. The positive stimulations are T cell tolerance induction, apoptotic process, and chronic inflammatory response, type 2 immune response, interleukin-12 production (12).  The negative stimulations are interleukin-10 production, activated T cell proliferation, T cell apoptotic process.  Furthermore, there are more functions allocating fetus during female pregnancy; changing behavior, responding to lipopolysaccharide or multicellular organismal response to stress possible due to degradation of tryptophan, kynurenic acid biosynthetic process, cellular nitrogen compound metabolic process, small molecule metabolic process, producing kynurenine process (13; 14; 15).

IDO plays a role in a variety of pathophysiological processes such as antimicrobial and antitumor defense, neuropathology, immunoregulation, and antioxidant activity (16; 17; 18; 19).

 

 3.     Molecular Genetics of IDO:

A: Structure of human IDO2 gene and transcripts. Complete coding region is 1260 bps encoding a 420 aa polypeptide. Alternate splice isoforms lacking the exons indicated are noted. Hatch boxes represent a frameshift in the coding region to an alternate reading frame leading to termination. Black boxes represent 3' untranslated regions. Nucleotide numbers, intron sizes, and positioning are based on IDO sequence files NW_923907.1 and GI:89028628 in the Genbank database. (reference: http://atlasgeneticsoncology.org/Genes/IDO2ID44387ch8p11.html)

A: Structure of human IDO2 gene and transcripts. Complete coding region is 1260 bps encoding a 420 aa polypeptide. Alternate splice isoforms lacking the exons indicated are noted. Hatch boxes represent a frameshift in the coding region to an alternate reading frame leading to termination. Black boxes represent 3′ untranslated regions. Nucleotide numbers, intron sizes, and positioning are based on IDO sequence files NW_923907.1 and GI:89028628 in the Genbank database.
(reference: http://atlasgeneticsoncology.org/Genes/IDO2ID44387ch8p11.html)

Molecular genetics data from earlier findings based on reporter assay results showed that IDO promoter is regulated by ISRE-like elements and GAS-sequence at -1126 and -1083 region (20).  Two cis-acting elements are ISRE1 (interferon sequence response element 1) and interferon sequence response element 2 (ISRE2).

Analyses of site directed and deletion mutation with transfected cells demonstrated that introduction of point mutations at these elements decreases the IDO expression. Removing ISRE1 decreases the effects of IFNgamma induction 50 fold and deleting ISRE1 at -1126 reduced by 25 fold (3). Introducing point mutations in conserved t residues at -1124 and -1122 (from T to C or G) in ISRE consensus sequence NAGtttCA/tntttNCC of IFNa/b inducible gene ISG4 eliminates the promoter activity by 24 fold (21).

ISRE2 have two boxes, X box (-114/1104) and Y Box 9-144/-135), which are essential part of the IFNgamma response region of major histocompatibility complex class II promoters (22; 23).  When these were removed from ISRE2 or introducing point mutations at two A residues of ISRE2 at -111 showed a sharp decrease after IFNgamma treatment by 4 fold (3).

The lack of responses related to truncated or deleted IRF-1 interactions whereas IRF-2, Jak2 and STAT91 levels were similar in the cells, HEPg2 and ME180 (3). Furthermore, 748 bp deleted between these elements did not affect the IDO expression, thus the distance between ISRE1 and ISRE2 elements have no function or influence on IDO (3; 24)

B: Amino acid alignment of IDO and IDO2. Amino acids determined by mutagenesis and the crystal structure of IDO that are critical for catalytic activity are positioned below the human IDO sequence. Two commonly occurring SNPs identified in the coding region of human IDO2 are shown above the sequence which alter a critical amino acid (R248W) or introduce a premature termination codon (Y359stop).

B: Amino acid alignment of IDO and IDO2. Amino acids determined by mutagenesis and the crystal structure of IDO that are critical for catalytic activity are positioned below the human IDO sequence. Two commonly occurring SNPs identified in the coding region of human IDO2 are shown above the sequence which alter a critical amino acid (R248W) or introduce a premature termination codon (Y359stop).

4.     There are three types of IDO in human genome:

IDO was originally discovered in 1967 in rabbit intestine (25). Later, in 1990 the human IDO gene is cloned and sequenced (7).  However, its importance and relevance in immunology was not created until prevention of allocation of fetal rejection and founding expression in wide range of human cancers (26; 27).

There are three types of IDO, pro-IDO like, IDO1, and IDO2.  In addition, another enzyme called TDO, tryptophan 2, 3, dehydrogenase solely degrade L-Trp at first-rate limiting mechanism in liver and brain.

4.1.  IDO1:

IDO1 mechanism is the target for immunotherapy applications. The initial discovery of IDO in human physiology is protection of pregnancy (1) since lack of IDO results in premature recurrent abortion (28; 26; 29).   The initial rate-limiting step of tryptophan metabolism is catalyzed by either IDO or tryptophan 2, 3-dioxygenase (TDO).

Structural studies of IDO versus TDO presenting active site environments, conserved Arg 117 and Tyr113, found both in TDO and IDO for the Tyr-Glu motif, but His55 in TDO replaced by Ser167b in IDO (30; 2). As a result, they are regulated with different mechanisms (1; 2) (30).  The short-lived TDO, about 2h, responds to level of tryptophan and its expression regulated by glucorticoids (31; 32).  Thus, it is a useful target for regulation and induced by tryptophan so that increasing tryptophan induces NAD biosynthesis. Whereas, IDO is not activated by the level of Trp presence but inflammatory agents with its interferon stimulated response elements (ISRE1 and ISRE2) in its (33; 34; 35; 36; 3; 10) promoter.

TDO promoter contains glucorticoid response elements (37; 38) and regulated by glucocorticoids and other available amino acids for gluconeogenesis. This is how IDO binds to only immune response cells and TDO relates to NAD biosynthesis mechanisms. Furthermore, TDO is express solely in liver and brain (36).  NAD synthesis (39) showed increased IDO ubiquitous and TDO in liver and causing NAD level increase in rat with neuronal degeneration (40; 41).  NAM has protective function in beta-cells could be used to cure Type1 diabetes (40; 42; 43). In addition, knowledge on NADH/NAD, Kyn/Trp or Trp/Kyn ratios as well as Th1/Th2, CD4/CD8 or Th17/Threg are equally important (44; 40).

Active site of IDO–PI complex. (A) Stereoview of the residues around the heme of IDO viewed from the side of heme plane. The proximal ligand H346 is H-bonded to wa1. The 6-propionate of the heme contacts with wa2 and R343 Nε. The wa2 is H-bonded to wa1, L388 O, and 6-propionate. Mutations of F226, F227, and R231 do not lose the substrate affinity but produce the inactive enzyme. Two CHES molecules are bound in the distal pocket. The cyclohexan ring of CHES-1 (green) contacts with F226 and R231. The 7-propionate of the heme interacts with the amino group of CHES-1 and side chain of Ser-263. The mutational analyses for these distal residues are shown in Table 1. (B) Top view of A by a rotation of 90°. The proximal residues are omitted. (http://www.pnas.org/content/103/8/2611/F3.expansion.html)

Active site of IDO–PI complex. (A) Stereoview of the residues around the heme of IDO viewed from the side of heme plane. The proximal ligand H346 is H-bonded to wa1. The 6-propionate of the heme contacts with wa2 and R343 Nε. The wa2 is H-bonded to wa1, L388 O, and 6-propionate. Mutations of F226, F227, and R231 do not lose the substrate affinity but produce the inactive enzyme. Two CHES molecules are bound in the distal pocket. The cyclohexan ring of CHES-1 (green) contacts with F226 and R231. The 7-propionate of the heme interacts with the amino group of CHES-1 and side chain of Ser-263. The mutational analyses for these distal residues are shown in Table 1. (B) Top view of A by a rotation of 90°. The proximal residues are omitted. (http://www.pnas.org/content/103/8/2611/F3.expansion.html)

4.2. IDO2:

The third type of IDO, called IDO2 exists in lower vertebrates like chicken, fish and frogs (45) and in human with differential expression properties. The expression of IDO2 is only in DCs, unlike IDO1 expresses on both tumors and DCs in human tissues.  Yet, in lower invertebrates IDO2 is not inhibited by general inhibitor of IDO, D-1-methyl-tryptophan (1MT) (46).   Recently, two structurally unusual natural inhibitors of IDO molecules, EXIGUAMINES A and B, are synthesized (47).  LIP mechanism cannot be switch back to activation after its induction in IDO2 (46).

Crucial cancer progression can continue with production of IL6, IL10 and TGF-beta1 to help invasion and metastasis.  Inclusion of two common SNPs affects the function of IDO2 in certain populations.  SNP1 reduces 90% of IDO2 catalytic activity in 50% of European and Asian descent and SNP2 produce premature protein through inclusion of stop-codon in 25% of African descent lack functional IDO2 (Uniport).

4.3. IDO-like proteins: The Origin of IDO:

Knowing the evolutionary steps will helps us to identify how we can manage the regulator function to protect human health in cancer, immune disorders, diabetes, and infectious diseases.

Bacterial IDO has two types of IDOs that are group I and group II IDO (48).  These are the earliest version of the IDO, pro-IDO like, proteins with a quite complicated function.  Each microorganism recognized by a specific set of receptors, called Toll-Like Receptors (TLR), to activate the IDO-like protein expression based on the origin of the bacteria or virus (49; 35).   Thus, the genesis of human IDO originates from gene duplication of these early bacterial versions of IDO-like proteins after their invasion interactions with human host.  IDO1 only exists in mammals and fungi.

Fungi also has three types of IDO; IDOa, IDO beta, and IDO gamma (50) with different properties than human IDOs, perhaps multiple IDO is necessary for the world’s decomposers.

All globins, haemoglobins and myoglobins are destined to evolve from a common ancestor, which  is only 14-16kDa (51) length. Binding of a heme and being oxygen carrier are central to the enzyme mechanism of this family.  Globins are classified under three distinct origins; a universal globin, a compact globin, and IDO-like globin (52) IDO like globin widely distributed among gastropodic mollusks (53; 51).  The indoleamine 2, 3-dioxygenase 1–like “myoglobin” (Myb) was discovered in 1989 in the buccal mass of the abalone Sulculus diversicolor (54).

The conserved region between Myb and IDO-like Myb existed for at least 600 million years (53) Even though the splice junction of seven introns was kept intact, the overall homolog region between Myb and IDO is only about 35%.

No significant evolutionary relationship is found between them after their amino acid sequence of each exon is compared to usual globin sequences. This led the hint that molluscan IDO-like protein must have other functions besides carrying oxygen, like myoglobin.   Alignment of S. cerevisiae cDNA, mollusk and vertebrate IDO–like globins show the key regions for controlling IDO or myoglobin function (55). These data suggest that there is an alternative pathways of myoglobin evolution.  In addition, understanding the diversity of globin may help to design better protocols for interventions of diseases.

Mechanisms of IDO:

The dichotomy of IDO mechanism lead the discovery that IDO is more than an enzyme as a versatile regulator of innate and adaptive immune responses in DCs (66; 67; 68). Meantime IDO also involve with Th2 response and B cell mediated autoimmunity showing that it has three paths, short term (acute) based on enzymatic actions, long term (chronic) based on non-enzymatic role, and moonlighting relies of downstream metabolites of tryptophan metabolism (69; 70).

IFNgamma produced by DC, MQ, NK, NKT, CD4+ T cells and CD8+ T cells, after stimulation with IL12 and IL8.  Inflammatory cytokine(s) expressed by DCs produce IFNgamma to stimulate IDO’s enzymatic reactions in acute response.  Then, TDO in liver and tryptophan catabolites act through Aryl hydrocarbon receptor induction for prevention of T cell proliferation. This mechanism is common among IDO, IDO2 (expresses in brain and liver) and TDO expresses in liver) provide an acute response for an innate immunity (30). When the pDCs are stimulated with IFNgamma, activation of IDO is go through Jak, STAT signaling pathway to degrade Trp to Kyn causing Trp depletion. The starvation of tryptophan in microenvironment inhibits generation of T cells by un-read t-RNAs and induce apoptosis through myc pathway.  In sum, lack of tryptophan halts T cell proliferation and put the T cells in apoptosis at S1 phase of cell division (71; 62).

The intermediary enzymes, functioning during Tryptophan degradation in Kynurenine (Kyn) pathway like kynurenine 3-hydroxylase and kynureninase, are also induced after stimulation with liposaccaride and proinflammatory cytokines (72). They exhibit their function in homeostasis through aryl-hydrocarbon receptor (AhR) induction by kynurenine as an endogenous signal (73; 74).  The endogenous tumor-promoting ligand of AhR are usually activated by environmental stress or xenobiotic toxic chemicals in several cellular processes like tumorigenesis, inflammation, transformation, and embryogenesis (Opitz ET. Al, 2011).

Human tumor cells constitutively produce TDO also contributes to production of Kyn as an endogenous ligand of the AhR (75; 27).  Degradation of tryptophan by IDO1/2 in tumors and tumor-draining lymph nodes occur. As a result, there are animal studies and Phase I/II clinical trials to inhibit the IDO1/2 to prevent cancer and poor prognosis (NewLink Genetics Corp. NCT00739609, 2007).

 IDO mechanism for immune response

Systemic inflammation (like in sepsis, cerebral malaria and brain tumor) creates hypotension and IDO expression has the central role on vascular tone control (63).  Moreover, inflammation activates the endothelial coagulation activation system causing coagulopathies on patients.  This reaction is namely endothelial cell activation of IDO by IFNgamma inducing Trp to Kyn conversion. After infection with malaria the blood vessel tone has decreases, inflammation induce IDO expression in endothelial cells producing Kyn causing decreased trp, lower arterial relaxation, and develop hypotension (Wang, Y. et. al 2010).  Furthermore, existing hypotension in knock out Ido mice point out a secondary mechanism driven by Kyn as an endogenous ligand to activate non-canonical NfKB pathway (63).

Another study also hints this “back –up” mechanism by a significant outcome with a differential response in pDCs against IMT treatment.  Unlike IFN gamma conditioned pDC blocks T cell proliferation and apoptosis, methyl tryptophan fails to inhibit IDO activity for activating naïve T cells to make Tregs at TGF-b1 conditioned pDCs (77; 78).

 Indoleamine-Pyrrole 2,3,-Dioxygenase; IDO dioxygenase; Indeolamine-2,3

The second role of the IDO relies on non-enzymatic action as being a signal molecule. Yet, IDO2 and TDO are devoid of this function. This role mainly for maintenance of microenvironment condition. DCs response to TGFbeta-1 exposure starts the kinase Fyn induce phosphorylation of IDO-associated immunoreceptor tyrosine–based inhibitory motifs (ITIMs) for propagation of the downstream signals involving non-canonical (anti-inflammatory) NF-kB pathway for a long term response. When the pDCs are conditioned with TGF-beta1 the signaling (68; 77; 78) Phospho Inositol Kinase3 (PIK-3)-dependent and Smad independent pathways (79; 80; 81; 82; 83) induce Fyn-dependent phosphorylation of IDO ITIMs.  A prototypic ITIM has the I/V/L/SxYxxL/V/F sequence (84), where x in place of an amino acid and Y is phosphorylation sites of tyrosines (85; 86).

Smad independent pathway stimulates SHP and PIK3 induce both SHP and IDO phosphorylation. Then, formed SHP-IDO complex can induce non-canonical (non-inflammatory) NF-kB pathway (64; 79; 80; 82) by phosphorylation of kinase IKKa to induce nuclear translocation of p52-Relb towards their targets.  Furthermore, the SHP-IDO complex also may inhibit IRAK1 (68). SHP-IDO complex activates genes through Nf-KB for production of Ido1 and Tgfb1 genes and secretion of IFNalpha/IFNbeta.  IFNa/IFNb establishes a second short positive feedback loop towards p52-RelB for continuous gene expression of IDO, TGFb1, IFNa and IFNb (87; 68).  However, SHP-IDO inhibited IRAK1 also activates p52-RelB.  Nf-KB induction at three path, one main and two positive feedback loops, is also critical.  Finally, based on TGF-beta1 induction (76) cellular differentiation occurs to stimulate naïve CD4+ T cell differentiation to regulatory T cells (Tregs).  In sum, TGF-b1 and IFNalpha/IFNbeta stimulate pDCs to keep inducing naïve T cells for generation of Treg cells at various stages, initiate, maintain, differentiate, infect, amplify, during long-term immune responses (67; 66).

Moonlighting function of Kyn/AhR is an adaptation mechanism after the catalytic (enzymatic) role of IDO depletes tryptophan and produce high concentration of Kyn induce Treg and Tr1 cell expansion leading Tregs to use TGFbeta for maintaining this environment (67; 76). In this role, Kyn pathway has positive-feedback-loop function to induce IDO expression.

In T cells, tryptophan starvation induces Gcn2-dependent stress signaling pathway, which initiates uncharged Trp-tRNA binding onto ribosomes. Elevated GCN2 expression stimulates elF2alfa phosphorylation to stop translation initiation (88). Therefore, most genes downregulated and LIP, an alternatively initiated isoform of the b/ZIP transcription factor NF-IL6/CEBP-beta (89).

This mechanism happens in tumor cells based on Prendergast group observations. As a result, not only IDO1 propagates itself while producing IFNalpha/IFNbeta, but also demonstrates homeostasis choosing between immunegenity by production of TH17or tolerance by Tregs. This mechanism acts like a see-saw. Yet, tolerance also can be broken by IL6 induction so reversal mechanism by SOC-3 dependent proteosomal degradation of the enzyme (90).  All proper responses require functional peripheral DCs to generate mature DCs for T cells to avoid autoimmunity (91).

Niacin (vitamin B3) is the final product of tryptophan catabolism and first molecule at Nicotinomic acid (NDA) Biosynthesis.  The function of IDO in tryptophan and NDA metabolism has a great importance to develop new clinical applications (40; 42; 41).  NAD+, biosynthesis and tryptophan metabolisms regulate several steps that can be utilize pharmacologically for reformation of healthy physiology (40).

IDO for protection in Microbial Infection with Toll-like Receptors

The mechanism of microbial response and infectious tolerance are complex and the origination of IDO based on duplication of microbial IDO (49).  During microbial responses, Toll-like receptors (TLRs) play a role to differentiate and determine the microbial structures as a ligand to initiate production of cytokines and pro-inflammatory agents to activate specific T helper cells (92; 93; 94; 95). Uniqueness of TLR comes from four major characteristics of each individual TLR by ligand specificity, signal transduction pathways, expression profiles and cellular localization (96). Thus, TLRs are important part of the immune response signaling mechanism to initiate and design adoptive responses from innate (naïve) immune system to defend the host.

TLRs are expressed cell type specific patterns and present themselves on APCs (DCs, MQs, monocytes) with a rich expression levels (96; 97; 98; 99; 93; 100; 101; 102; 87). Induction signals originate from microbial stimuli for the genesis of mature immune response cells.  Co-stimulation mechanisms stimulate immature DCs to travel from lymphoid organs to blood stream for proliferation of specific T cells (96).  After the induction of iDCs by microbial stimuli, they produce proinflammatory cytokines such as TNF and IL-12, which can activate differentiation of T cells into T helper cell, type one (Th1) cells. (103).

Utilizing specific TLR stimulation to link between innate and acquired responses can be possible through simple recognition of pathogen-associated molecular patterns (PAMPs) or co-stimulation of PAMPs with other TLR or non-TLR receptors, or even better with proinflammatory cytokines.   Some examples of ligand- TLR specificity shown in Table1, which are bacterial lipopeptides, Pam3Cys through TLR2 (92; 104; 105).  Double stranded (ds) RNAs through TLR3 (106; 107), Lipopolysaccharide (LPS) through TLR4, bacterial flagellin through TLR5 (108; 109), single stranded RNAs through TLR7/8 (97; 98), synthetic anti-viral compounds imiquinod through TLR 7 and resiquimod through TLR8, unmethylated CpG DNA motifs through TLR9 (Krieg, 2000).

IDO action

Then, the specificity is established by correct pairing of a TLR with its proinflammatory cytokines, so that these permutations influence creation and maintenance of cell differentiation. For example, leading the T cell response toward a preferred Th1 or Th2 response possible if the cytokines TLR-2 mediated signals induce a Th2 profile when combined with IL-2 but TLR4 mediated signals lean towards Th1 if it is combined with IL-10 or Il-12, (110; 111)  (112).

TLR ligand TLR Reference
Lipopolysaccharide, LPS TLR4 (96).  (112).
Lipopeptides, Pam3Cys TLR2 (92; 104; 105)
Double stranded (ds) RNAs TLR3 (106; 107)
Bacterial flagellin TLR5 (108; 109)
Single stranded RNAs TLR7/8 (97; 98)
Unmethylated CpG DNA motifs TLR9 (Krieg, 2000)
Synthetic anti-viral compounds imiquinod and resiquimod TLR7 and TLR8 (Lee J, 2003)

Furthermore, if the DCs are stimulated with IL-6, DCs relieve the suppression of effector T cells by regulatory T cells (113).

The modification of IDO+ monocytes manage towards specific subset of T cell activation with specific TLRs are significantly important (94).

The type of cell with correct TLR and stimuli improves or decreases the effectiveness of stimuli. Induction of IDO in monocytes by synthetic viral RNAs (isRNA) and CMV was possible, but not in monocyte derived DCs or TLR2 ligand lipopeptide Pam3Cys since single- stranded RNA ligands target TLR7/8 in monocytes derive DCs only (Lee J, 2003).  These data show that TLRs has ligand specificity, signal transduction pathways, expression profiles and cellular localization so design of experiments should follow these rules.

Conclusion:

Overall our purpose of this information is to find a method to manipulate IDO to correct/fix/modulate immune responses for clinical applications.  This first part of the review concerns the basic science information gained overall several years that lay the foundation that translational research scientist should familiar to develop a new technology for clinic. The first connection of IDO and human health came from a very natural event that is protection of pregnancy in human. The focus of the translational medicine is treatment of cancer or prevention/delay cancer by stem cell based Dendritic Cell Vaccine (DCvax) development.

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99. The role of CpG motifs in innate immunity. Krieg, A.M. 2000., Curr Opin Immunol., pp. 12:35–43.

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101. Impaired impression of Indolamine 2,3-deoxygenase in monocyte derived DCs in response to TLR-7/8. Furset, G., Floisand, Y., Sioud, M. 2007, Immunology, pp. 263-271.

102. Activationof the noncanonical NF-kB pathway by HIV controls a Dendritic cell immunoregulatory phenotype. Manches, O. Fernandez, V.M.,, Plumas, J., Chaperot, L., and Bhardwaj, N. 2012, PNAS, pp. vol: 109, 14122-14127.

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Treatment for Endocrine Tumors and Side Effects

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Surgery

The purpose of surgery is typically to remove the entire tumor, along with some of the healthy tissue around it, called the margin. If the tumor cannot be removed entirely, “debulking” surgery may be performed. Debulking surgery is a procedure in which the goal is to remove as much of the tumor as possible. Side effects of surgery include weakness, fatigue, and pain for the first few days following the procedure.

Chemotherapy

Chemotherapy is the use of drugs to kill tumor cells, usually by stopping the cells’ ability to grow and divide. Systemic chemotherapy is delivered through the bloodstream to reach tumor cells throughout the body. A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a set period of time. A patient may receive one drug at a time or combinations of different drugs at the same time. The side effects of chemotherapy depend on the individual and the dose used, but they can include fatigue, risk of infection, nausea and vomiting, loss of appetite, and diarrhea. These side effects usually go away once treatment is finished.

Radiation therapy

Radiation therapy is the use of high-energy x-rays or other particles to kill tumor cells. The most common type of radiation treatment is called external-beam radiation therapy, which is radiation given from a machine outside the body. When radiation treatment is given using implants, it is called internal radiation therapy or brachytherapy. A radiation therapy regimen usually consists of a specific number of treatments given over a set period of time. Side effects from radiation therapy may include fatigue, mild skin reactions, upset stomach, and loose bowel movements. Most side effects go away soon after treatment is finished.

Hormone therapy

The goal of hormone therapy is often to lower the levels of hormones in the body. Hormone therapy may be given to help stop the tumor from growing or to relieve symptoms caused by the tumor. In addition, for thyroid cancer, hormone therapy will be given if the thyroid gland has been removed, to replace the hormone that is needed by the body to function properly.

Immunotherapy

Immunotherapy (also called biologic therapy) is designed to boost the body’s natural defenses to fight the tumor. It uses materials made either by the body or in a laboratory to bolster, target, or restore immune system function. Examples of immunotherapy include cancer vaccines, monoclonal antibodies, and interferons. Alpha interferon is a form of biologic therapy given as an injection under the skin. This is sometimes used to help relieve symptoms caused by the tumor, but it can have severe side effects including fatigue, depression, and flu-like symptoms.

Targeted therapy

Targeted therapy is a treatment that targets the tumor’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of tumor cells while limiting damage to normal cells, usually leading to fewer side effects than other cancer medications.

Recent studies show that not all tumors have the same targets. To find the most effective treatment, the doctor may run tests to identify the genes, proteins, and other factors in the tumor. As a result, doctors can better match each patient with the most effective treatment whenever possible.

Depending on the type of endocrine tumor, targeted therapy may be a possible treatment option. For instance, targeted therapies, such as sunitinib (Sutent) and everolimus (Afinitor), have been approved for treating advanced islet cell tumors. Early results of clinical trials (research studies) with targeted therapy drugs for other types of endocrine tumors are promising, but more research is needed to prove they are effective.

Recurrent endocrine tumor

Once the treatment is complete and there is a remission (absence of symptoms; also called “no evidence of disease” or NED). Many survivors feel worried or anxious that the tumor will come back. If the tumor does return after the original treatment, it is called a recurrent tumor. It may come back in the same place (called a local recurrence), nearby (regional recurrence), or in another place (distant recurrence). When this occurs, a cycle of testing will begin again to learn as much as possible about the recurrence. Often the treatment plan will include the therapies described above (such as surgery, chemotherapy, and radiation therapy) but may be used in a different combination or given at a different pace. People with a recurrent tumor often experience emotions such as disbelief or fear. Patients are encouraged to talk with their health care team about these feelings and ask about support services to help them cope.

Metastatic endocrine tumor

If a cancerous tumor has spread to another location in the body, it is called metastatic cancer. A treatment plan that includes a combination of surgery, chemotherapy, radiation therapy, hormone therapy, immunotherapy, or targeted therapy may be recommended if required.

In addition to treatment to slow, stop, or eliminate the cancer (also called disease-directed treatment), an important part of cancer care is relieving a person’s symptoms and side effects. It includes supporting the patient with his or her physical, emotional, and social needs, an approach called palliative or supportive care. People often receive disease-directed therapy and treatment to ease symptoms at the same time.

Source References:

http://www.cancer.net/cancer-types/endocrine-tumor/treatment

 

http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Endocrine/Endocrinetumours.aspx

 

http://cancer.osu.edu/patientsandvisitors/cancerinfo/cancertypes/endocrine/Pages/index.aspx

 

http://cancer.northwestern.edu/cancertypes/cancer_type.cfm?category=8

 

http://www.cancervic.org.au/about-cancer/cancer_types/endocrine_cancer

 

http://www.oncolink.org/types/types1.cfm?c=4

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State of the art in oncologic imaging of breast.

Author-Writer: Dror Nir, PhD

In the coming posts I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications.

In this post I summaries the chapter on breast cancer imaging.

Breast Cancer Imaging

As a start the authors describes the evolution in the ACS imaging guidelines for breast cancer screening. Most interesting to learn is how age limits are changing. The most recent: “In 2010, the Society of Breast Imaging and the Breast Imaging Commission of the ACS issued recommendations for breast cancer screening to provide guidance in light of the controversies and emerging technologies.5 These recommendations were based on multiple prospective randomized trials as well as population-based experience.

Recommendations for screening with non-mammographic imaging are based not on evidence showing mortality reduction but largely on surrogate indicators, i.e., tumor size and nodal status, suggesting improved survival compared with women who are not screened.” I have referred to these guidelines in my recent post: Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

As long as imaging interpretation is based mainly on observations related to lesion morphology:

“The imaging characteristics of malignant lesions are nonspecific and usually do not allow a definitive diagnosis. When a biopsy is recommended based on mammography, it has a 25% to 45% likelihood of resulting in a diagnosis of carcinoma.11 Similar positive predictive values are reported for biopsies recommended based on MRI.”

It is worthwhile noting that these results do not reflect purely the specificity of the imaging device but rather the specificity of the whole workflow; i.e imaging, biopsy and histopathology. All imaging techniques have false negatives: Mammography screening of general population misses approximately 20% of the cancers. This rate increases as breast density increases. MRI is not applied to general population. When applied to highly suspicious cases MRI misses ~10% of the invasive cancers. Although ultrasound has proven to be useful in detecting cancer especially in women with dense breasts: Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need! Based on the literature reviewed by the authors of this paper they do not recommend routine sonography for these women.

For women with locally advanced breast cancer (Fig. 2) who undergo neoadjuvant therapy before breast surgery, the authors recommends post-treatment staging using MRI, which has been found to predict complete response with sensitivity above 60% and specificity as high as 90%.26

A 27-year-old female with locally advanced poorly differentiated invasive ductal carcinoma underwent evaluation of extent of disease before starting neoadjuvant chemotherapy. Sagittal fat-suppressed T1-weighted postcontrast MR images demonstrate an almost 6-cm heterogeneously enhancing mass (A) involving the skin of the lower breast (arrow) with (B) right axillary (arrow) and (C) right internal mammary adenopathy (arrow).

A 27-year-old female with locally advanced poorly differentiated invasive ductal carcinoma underwent evaluation of extent of disease before starting neoadjuvant chemotherapy. Sagittal fat-suppressed T1-weighted postcontrast MR images demonstrate an almost 6-cm heterogeneously enhancing mass (A) involving the skin of the lower breast (arrow) with (B) right axillary (arrow) and (C) right internal mammary adenopathy (arrow).

Same is recommended for women who have undergone lumpectomy if the surgical margins are positive. As post therapy follow-up, a new baseline mammogram of the treated breast is recommended followed by annual mammography.

In regards to emerging technology the following are discussed: Mammographic tomosynthesis – see also Improving Mammography-based imaging for better treatment planning

Contrast-enhanced digital mammography – “involves the injection of iodinated contrast material, as is done for computed tomography (CT); this enables hypervascular lesions to be seen with modified mammography technology, potentially providing the same information obtained through MRI. Little has been published on the clinical application of this technology, but diagnostic accuracy better than that of mammography and approaching that of MRI has been reported.3132

MR choline spectroscopy – has been shown to improve the positive predictive value of breast MRI and may be useful in reducing the number of lesions that require biopsy (Fig. 4).33 Studies of spectroscopy have reported sensitivities of 70% to 100% and specificities of 67% to 100% in the detection of breast cancer. Decreasing choline concentrations may also be a useful indication of tumor response to treatment before any change in tumor volume can be detected.3435 Technical factors have limited the use of spectroscopy to lesions 1 cm in size or larger.”

Sagittal fat-suppressed T1-weighted postcontrast MR image is shown (A) of the right breast of a 48-year-old female who was status post–contralateral mastectomy for DCIS with the spectroscopy voxel placed over an enhancing mass (arrow). The magnified spectrum (B) demonstrated no choline peak. Biopsy yielded fibroadenoma.

Sagittal fat-suppressed T1-weighted postcontrast MR image is shown (A) of the right breast of a 48-year-old female who was status post–contralateral mastectomy for DCIS with the spectroscopy voxel placed over an enhancing mass (arrow). The magnified spectrum (B) demonstrated no choline peak. Biopsy yielded fibroadenoma.

Diffusion-weighted MRI (DW-MRI) – “adding DW-MRI data to other imaging characteristics of lesions on breast MRI may increase the positive predictive value of the examination, in turn decreasing the number of benign lesions requiring biopsy for diagnosis.” See also Imaging: seeing or imagining? (Part 2).

Axial T1-weighted fat-suppressed postcontrast MR image is shown (A) of the left breast of a 42-year-old female with biopsy-proven contralateral cancer undergoing evaluation of disease extent. An enhancing mass (arrow) was seen in the left breast. This mass (arrow) was also demonstrated on the axial diffusion-weighted MR image (B). Biopsy yielded fibroadenoma with atypical ductal hyperplasia and lobular carcinoma in situ.

Axial T1-weighted fat-suppressed postcontrast MR image is shown (A) of the left breast of a 42-year-old female with biopsy-proven contralateral cancer undergoing evaluation of disease extent. An enhancing mass (arrow) was seen in the left breast. This mass (arrow) was also demonstrated on the axial diffusion-weighted MR image (B). Biopsy yielded fibroadenoma with atypical ductal hyperplasia and lobular carcinoma in situ.

Ultrasound-elastography – “Ultrasound elastography has been reported to differentiate benign from malignant breast lesions with sensitivities of 78% to 100% and specificities of 21% to 98%.39 When added to other US techniques, it may improve radiologists’ performance in distinguishing malignant breast lesions.”

Positron emission tomography (PET) – “alone or combined with CT, allows noninvasive, quantitative assessment of biochemical and functional processes at the molecular level in the body. It is most often performed with the radiolabeled glucose analogue [18F] fluorodeoxyglucose ([18F]FDG) to detect the elevated glucose metabolism that is a hallmark of cancer. In breast cancer, its utility depends on the pretest probability for advanced disease, and thus the clinical stage.” The authors found that the use of [18F] FDG PET to patients with stage I and II disease is “limited”. Specifically, they claim that it is not sufficiently accurate for axillary nodal staging in this subset of patients.40 The did find enough evidence to recommend the use of FDG PET in patients with advanced disease: “where it accurately defines disease extent,41 and frequently eliminates the need for other imaging tests, and provides an early readout of treatment response as well as prognostic information.”

Combined PET/MRI is mentioned as a promising technology for predicting response to therapy “but this remains to be proven”.

Positron emission mammography (PEM) – “adapts full-body PET imaging to the breast. In a multicenter study, the interpretation of PEM in conjunction with mammographic and clinical findings yielded a sensitivity of 91% and a specificity of 93% for breast cancer.47 “. However, the authors mention that its use for screening (applying to healthy women) has been criticized because of the need to administer a radioactive tracer.

Lung Cancer Imaging

To be followed…

Other research papers related to the management of breast cancer were published on this Scientific Web site:

The unfortunate ending of the Tower of Babel construction project and its effect on modern imaging-based cancer patients’ management

 Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Introducing smart-imaging into radiologists’ daily practice.

Will Bio-Tech make Medical Imaging redundant?

Improving Mammography-based imaging for better treatment planning

Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA.

New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com

Predicting Tumor Response, Progression, and Time to Recurrence

“The Molecular pathology of Breast Cancer Progression”

Personalized medicine gearing up to tackle cancer

Whole-body imaging as cancer screening tool; answering an unmet clinical need?

What could transform an underdog into a winner?

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Nanotech Therapy for Breast Cancer

A Strategy to Handle the Most Aggressive Breast Cancer: Triple-negative Tumors

Optical Coherent Tomography – emerging technology in cancer patient management

Breakthrough Technique Images Breast Tumors in 3-D With Great Clarity, Reduced Radiation

Closing the Mammography gap

Imaging: seeing or imagining? (Part 1)

Imaging: seeing or imagining? (Part 2)

 

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