Posts Tagged ‘chemo regimens’

Tang Prize for 2014: Immunity and Cancer

Curator: Larry Bernstein, MD, FCAP



2014 Tang Prize in Biopharmaceutical Sciences awards to James P. Allison and Tasuku Honjo For the discoveries of CTLA-4 and PD-1 as immune inhibitory molecules that led to their applications in cancer immunotherapy 2014/06/19.

Founded by Dr. Samuel Yin in December 2012, the Tang Prize recognizes scholars conducting revolutionary research in the four major fields of Sustainable Development, Biopharmaceutical Science, Sinology, and the Rule of Law. The Prize is awarded with each category a cash reward of over US$1 million (NT$50 million). The Tang Prize Foundation hopes that recipients of the Prize will continue to innovate while cultivating and nurturing new talent in their respective fields.
Academia Sinica was commissioned by the Tang-Prize Foundation to administer the selection of Tang-Prize Laureates for the category of Biopharmaceutical Science, recognizing original biopharmaceutical or biomedical research that has led to significant advances towards preventing, diagnosing and/or treating major human diseases to improve human health.
James P. Allison and Tasuku Honjo were chosen among nearly a hundred nominees for their discoveries of CTLA-4 and PD-1 as immune inhibitory molecules, revealing ways to harness our incredibly powerful immune system to fight cancer and marking the beginning of the immunotherapy revolution.
A critical process in the immune response involves presentation of antigens to T cells by antigen-presenting cells, two key cell types in our immune system. This process is highly regulated by molecules that stimulate the response to ensure our mounting a sufficient immune response, especially in the event of invasion by pathogens, but also by molecules that inhibit the process to ensure the response is not excessive. Indeed, there is now a family of proteins on T cells involved in this regulatory process, which is designated the “CD28 receptor family” co-receptors, as CD28 is the first protein identified to have such function. They are divided into co-receptors transmitting stimulatory signals and co-receptors transmitting inhibitory signals. Each of these has its counterpart (ligand) on antigen-presenting cells belonging to the “B7 family”. Two most prominent inhibitory receptors on T cells are called CTLA-4 (cytotoxic T lymphocyte antigen-4, as it is first identified on cytotoxic T lymphocytes) and PD-1 (program death-1, as it is first identified to be associated with a type of cell death process called programmed cell death). Their ligands are designated as B7-1/B7-2 and PD-L1/PD-L2, respectively. These are also referred to as immune checkpoint receptors and ligands.
Our immune system is not perfect and at times, the regulatory mechanisms might be faulty, which in fact may be the basis of a variety of diseases. For example, autoimmune diseases may be related to the suppressive mechanism becoming weak and the individuals can mount excessive immune responses even to their own cells and tissues. Also, our immune system is capable of recognizing cancer cells and attacking them, in a process called immune surveillance. However, cancer cells are also equipped with machineries to evade the host anti-tumor activity, which is described as immune escape. For example, cancer cells can also express B7 family ligands on their surfaces and, by engaging the co-receptors transmitting inhibitory signals on T cells, they can inhibit the host anti-tumor T cell activity. By recognizing how cancer cells escape the immune surveillance, scientists have developed novel approaches to interfere with the ability of cancer cells to suppress the immune response, thus enhancing the ability of the host immune system to inhibit cancer cell growth.
Dr. James Allison, Chairman, Department of Immunology and Executive Director, Immunotherapy Platform at the University of Texas, MD Anderson Cancer Center, is one of two scientist to identify CTLA-4 as an inhibitory receptor on T-cells in 1995 and was the first to recognize it as a potential target for cancer therapy.  His team then developed an antibody that blocks CTLA-4 activity and showed in 1996 that this antibody is able to help reject several different types of tumors in mouse models. This subsequently led to development of a monoclonal antibody drug, which has undergone clinical trials against stage 4 melanoma and been approved for treatment of melanoma by the U.S. FDA in 2011.
Dr. Tasuku Honjo, Professor, Department of Immunology and Genomic Medicine, Kyoto University, discovered PD-1 in 1992. His group subsequently established that PD-1 is an inhibitor regulator of the T cell response. Additional studies from his and other laboratories established that this protein plays a critical role in the regulation of tumor immunity and stimulated many groups to generate its blocker for the treatment of cancer. Antibodies against PD-1 have been approved by the U.S. FDA as an investigational new drug and developed for the treatment of cancer. One such antibody produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer in clinical trials, and is predicted to be launched in 2015 for treatment of non-small cell lung cancer; this has been stated by some as having the potential to “change the landscape” of the treatment for lung cancer. Another antibody, shown to achieve a substantial response rate also in patients with non-small cell lung cancer, is currently in clinical trial for many types of cancers. In addition, combination therapy (anti-CTLA-4 plus anti-PD-1) has been shown to dramatically improve the long-term survival rates in cancer patients.
This is an exciting time in our fight against cancer. The discoveries by Dr. Allison and Dr. Honjo have spurred additional development of therapeutic approaches along the line of immunotherapy and brought new hope that many types of cancers can be cured.
In addition, dysregulation in immune checkpoint pathways may be intimately involved in other illnesses, such as allergy, infectious diseases, and autoimmune diseases. Thus, the approach of targeting immune stimulatory and inhibitory molecules also promises to lead to the development of new therapies for these diseases.
Dr. Allison’s and Dr. Honjo’s discoveries have opened a new therapeutic era in medicine.


Supplementary figure:

unleashes immune system to attack cancer cells

unleashes immune system to attack cancer cells














Dr. Samuel Yin, founder of the Tang Prize, is currently chairman of the Ruentex Group and chief development officer, chief technology officer, and chief engineer of Ruentex Construction & Development. He is also an adjunct professor in the department of civil engineering at National Taiwan University and a professor at Peking University, where he advises PhD students.

Dr. Yin read history at Chinese Culture University. He received a master’s degree in business administration at National Taiwan University and a doctorate in business administration at National Chengchi University.

In addition to his academic background in the humanities and business administration, Dr. Yin’s great interest in and devotion to interdisciplinary studies have made him an award-winning civil engineer and educator.

In 2004, Dr. Yin was named fellow of the Chinese Institute of Civil and Hydraulic Engineering. In 2008, he was invited to join Russia’s International Academy of Engineering and also awarded the Engineering Prowess Medal, the academy’s highest honour. In 2010, Dr. Yin received the Henry L. Michel Award for Industry Advancement of Research by the prestigious American Society of Civil Engineers (ASCE) for his contribution in the area of construction technology research. He was the first person without an academic background in engineering to receive the award.

Driven by a firm belief that he should give back to the society that has enabled him to achieve so much, Dr. Yin has been investing in philanthropy and education for a long time, in the hope of creating a positive force in society and making a better world.

Dr. Yin’s biggest dream was to set up an international award. He has long had great respect and admiration for the Nobel Prize, so he established an award modeled on the Nobel. The Tang Prize rewards excellent research in the areas of Sustainable Development, Biopharmaceutical Science, Sinology (excluding literary works), and Rule of Law. Dr. Yin hopes to encourage experts to dedicate themselves to innovative research in these fields and to spur human development with first-class research.

Dr. Yin’s relentless enthusiasm for philanthropy was instilled through his upbringing, particularly the example set by his late father Yin Shu-Tien. Dr. Yin established a foundation in memory of his grandfather, Yin Xun-Ruo, to provide scholarships to students of families originating in Shandong Province to study Chinese literature and history. When Yin senior passed away, Dr. Yin also set up the Kwang-Hua Education Foundation to help with China’s higher education programs.

In the past few years, Dr. Yin has set up a number of foundations to serve people on both sides of the Taiwan Strait and to foster more talented people for the nation (the Yin Xun-Ruo Educational Foundation, the Yin Shu-Tien Medical Foundation, the Kwang-Hua Education Foundation, and the Guanghua School of Management of Peking University). In 2012, Dr. Yin set up a global award, the Tang Prize, to spread his philanthropy across the world.

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Reporter: Aviva Lev-Ari, PhD, RN


Inform Genomics Developing SNP Test to Predict Side Effects, Help MDs Choose among Chemo Regimens

October 10, 2012

Inform Genomics, a Boston-based diagnostics company, said its “Oncology Preferences and Risk of Toxicity,” or OnPART, test showed greater than 90 percent accuracy in predicting which cancer patients are at risk of experiencing serious side effects to various chemotherapy regimens in an early-stage study.

The company is developing the test to predict a patient’s risk for six common adverse events to combination chemotherapy regimens for colorectal, breast, lung, or ovarian cancer.

Inform Genomics’ president and CEO, Ed Rubenstein, told PGx Reporter that the company is narrowing down a set of SNP signatures that can predict six common moderate to serious side effects linked to different, but equally effective chemotherapy regimens, including dose-dense doxorubicin, cyclophosphamide and paclitaxel for breast cancer; oxaliplatin-based regimens for colorectal cancer; and carboplatin plus paclitaxel-based regimens for lung and ovarian cancer.

Rubenstein said that results from the discovery study, performed at the West Clinic in Memphis, Tenn., showed the signatures for all six side effects — nausea and vomiting, mouth sores, diarrhea, fatigue, cognitive dysfunction, and peripheral neuropathy — had greater than 90 percent predictive accuracy.

“What’s unique about [OnPART],” he said, “is that [it analyzes] not only genomic risk of six common side effects of combination chemotherapy regimens the way they are actually used in clinical practice, but it also includes a way to quantify patients’ concerns for how they view these side effects,” through a copyrighted patient questionnaire the company calls “Preference Assessment Inventory.”

He explained that Inform Genomics intends the test to display for oncologists the risk of these six side effects across different chemotherapy regimens that are considered “relatively equivalent” from an efficacy standpoint “but have wide variation in their toxicity profile.”

The company hopes this will allow patients to discuss with doctors, before beginning therapy, what their real risks are “as opposed to theoretical risks from population-based studies,” Rubenstein said.

He cited the example of a cancer patient who is a professional musician with a high genetic risk for neuropathy, according to OnPART. This patient’s quality of life would be greatly impacted if the chemotherapy regimen he or she was on caused debilitating nerve damage. “When they fill out their concerns and say neuropathy is a concern for them, that allows the doctor to help them understand their risk, and switch their chemotherapy regimen to another that is equally effective but does not put the patient at risk for neuropathy,” Rubenstein explained.

In the company’s discovery study, researchers tested saliva from 384 patients at the West Clinic who had been followed for a minimum of two cycles of chemotherapy and who had reported symptoms of the six side effects using a validated questionnaire.

Using Illumina microarrays, the group profiled 2.5 million potential SNPs to find those that correlated with particular side effects and regimens. Then the team used Inform Genomics’ proprietary Bayesian analysis algorithms to look at interactions between these SNPs.

“We have list of SNPs, and then from that we look at location on genes or outside genes and look at functional pathways and biology to make sure that what we are looking at makes sense,” Rubenstein explained.

Though the exact number of SNPs to be used for each side effect-predictor in OnPART has not yet been determined, Rubenstein said the marketed panel would likely include about 400 SNPs.

“[Our] commercial product is likely to be a custom chip because we don’t need 2.5 million once we’ve narrowed down the predictive SNPs,” he said. “So, let’s say we have six symptoms and each have 80 to 100 SNPs; maybe the chip would be 400 SNPs.”

The company plans to release a more detailed picture of the study and its results at future oncology meetings.

Rubenstein said the next step will be to raise additional capital and then design prospective validation studies for both OnPART and another test the company is developing to predict oral and gastrointestinal mucositis: side effects of high-dose chemotherapy administered before autologous stem cell transplant for multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphoma.

He said Inform Genomics is currently “in dialogue” with large practices and oncology networks who may be part of these future validation efforts.

“Our current plan is that we would launch the [OnPART] product by the third quarter of 2014,” he said. According to the company’s website, the transplant test would follow in 2015.

Molika Ashford is a GenomeWeb contributing editor and covers personalized medicine and molecular diagnostics. E-mail her here.


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