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Archive for the ‘CAR-T’ Category


Economic Potential of a Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) versus a Cancer Drug in Clinical Trials: CAR-T as a Case in Point, developed by Kite Pharma, under Arie Belldegrun, CEO, acquired by Gilead for $11.9 billion, 8/2017.

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 10/18/2017

Kite Pharma, under Arie Belldegrun, CEO, acquired by Gilead for $11.9 billion, 8/2017.

Kite’s Yescarta™ (Axicabtagene Ciloleucel) Becomes First CAR T Therapy Approved by the FDA for the Treatment of Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy

— Manufacturing Success Rate of 99 Percent in ZUMA-1 Pivotal Trial with a Median 17 Day Turnaround Time —

CAR T therapy is a breakthrough in hematologic cancer treatment in which a patient’s own T cells are engineered to seek and destroy cancer cells. CAR T therapy is manufactured specifically for each individual patient.

“The FDA approval of Yescarta is a landmark for patients with relapsed or refractory large B-cell lymphoma. This approval would not have been possible without the courageous commitment of patients and clinicians, as well as the ongoing dedication of Kite’s employees,” said Arie Belldegrun, MD, FACS, Founder of Kite. “We must also recognize the FDA for their ability to embrace and support transformational new technologies that treat life-threatening illnesses. We believe this is only the beginning for CAR T therapies.”

“Today is an important day for patients with relapsed or refractory large B-cell lymphoma who have run out of options and have been waiting for new treatments that may help them in their fight against cancer,” said John Milligan, PhD, President and Chief Executive Officer of Gilead Sciences. “With the combined innovation, talent and drive of the Kite and Gilead teams, we will rapidly advance cell therapy research and aim to bring new options to patients with many other types of cancer.”

The list price of Yescarta in the United States is $373,000.

Yescarta has been granted Priority Medicines (PRIME) regulatory support for DLBCL in the European Union. A Marketing Authorization Application (MAA) for axicabtagene ciloleucel is currently under review with the European Medicines Agency (EMA) and potential approval is expected in the first half of 2018.

Yescarta (axicabtagene ciloleucel) Pivotal Trial Results

The approval of Yescarta is supported by data from the ZUMA-1 pivotal trial. In this study, 72 percent of patients treated with a single infusion of Yescarta (n=101) responded to therapy (overall response rate) including 51 percent of patients who had no detectable cancer remaining (complete remission; 95% CI: 41, 62). At a median follow-up of 7.9 months, patients who had achieved a complete remission had not reached the estimated median duration of response (95% CI: 8.1 months, not estimable [NE]).

In the study, 13 percent of patients experienced grade 3 or higher cytokine release syndrome (CRS) and 31 percent experienced neurologic toxicities. The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections. Serious adverse reactions occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias (including neutropenia, thrombocytopenia and anemia), and serious infections. Fatal cases of CRS and neurologic toxicity occurred. FDA approved Yescarta with a Risk Evaluation and Mitigation Strategy.

Yescarta Indication

Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), accounting for three out of every five cases. In the United States each year, there are approximately 7,500 patients with refractory DLBCL who are eligible for CAR T therapy. Historically, when treated with the current standard of care, patients with refractory large B-cell lymphoma had a median overall survival of approximately six months, with only seven percent attaining a complete response. Currently, patients with large B-cell lymphoma in second or later lines of therapy have poor outcomes and greater unmet need, since nearly half of them either do not respond or relapse shortly after transplant.

“With CAR T therapy, we are reengineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” said Frederick L. Locke, MD, ZUMA-1 Co-Lead Investigator and Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “Many of the patients that received CAR T therapy had already relapsed several times with traditional treatments such as chemotherapy or hematopoietic stem cell transplant. Now, thanks to this new therapy many patients are in remission for months.”

“This therapy is a new option for patients with relapsed or refractory large B-cell lymphoma who have run out of treatment options and face a dire prognosis,” said Louis J. DeGennaro, PhD, President and Chief Executive Officer of The Leukemia & Lymphoma Society (LLS). “Early on, LLS recognized the potential of CAR T therapy and we are proud to be part of making this historic approval possible.”

“Engineered cell therapies like Yescarta represent the potential for a changing treatment paradigm for cancer patients,” said David Chang, MD, PhD, Worldwide Head of Research and Development and Chief Medical Officer at Kite. “Together, Gilead and Kite will accelerate studies of CAR T therapy in multiple blood cancers and advance other cell therapy approaches for solid tumors, with the goal of helping patients with diverse cancers benefit from this new era of personalized cancer therapy.”

http://www.businesswire.com/news/home/20171018006639/en/Kite%E2%80%99s-Yescarta%E2%84%A2-Axicabtagene-Ciloleucel-CAR-Therapy-Approved

This article has the following structure:

  • ABOUT Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent)
  • ABOUT Gilead’s $12 billion buy of Kite Pharma
  • ABOUT  the Drug Development process and the COMMERCIALIZATION GENIUS of Arie Belldegrun – Interviewed by Globes
  • ABOUT the Perspective of Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) following the Gilead’s $12 billion buy of Kite Pharma – Interviewed by Globes
  • ABOUT the Economic significance of Kite Pharma Acquisition for the Venture Capital Investment in Biotech in Israel
  • Key Opinion Leader’s View: Aviva Lev-Ari, PhD, RN

 

  1. I agree with Prof. Zelig Eshhar that this Case in Point is “one more invention, or parts of an invention, came from an Israeli laboratory (at the Weizmann Institute in this case) and fell into foreign hands. It is another enormous missed opportunity in the field of biomedicine and ethical drugs.”
  2. I agree with Prof. Zelig Eshhar that this Case in Point should have been a TEVA commercialization effort. It is a regrettable reality that the development and the manufacturing will not benefit the State of Israel, home of the Weitzman Institute where the Patentable invention took place by Prof. Zelig Eshhar.
  3. It is to be acknowledged that for CAR-T – the process of treatment using the drug – personalized genetic engineering of each patient’s cells – a grafting process with no precedent in the pharmaceutical industry (Juno has related process) – is bringing to the Oncology arena a NOVEL treatment for hematological malignancies cancer patients
  4. I agree with Prof. Zelig Eshhar that the Barriers in the pharmaceutical industry are especially high. Developing ethical drugs is a process requiring huge amounts of time, patience, money, and failures. It is exactly, therefore, all need to acknowledge that the Drug Development process and the COMMERCIALIZATION GENIUS of Arie Belldegrun is inseparable from the breakthrough invention of Prof. Zelig Eshhar to develop the drug from the Lab bench to the FDA accelerated process of Drug approval.
  5. The Biotech industry in Israel needs to develop more MDs, PhDs with the level of training of Arie Belldegrun and with his entrepreneur acumen, keenness and depth of perception, discernmentdiscrimination especially in practical aspects of Translation Medicine, Clinical Research, Clinical Trial Design and abilities to engage in innovating the FDA processes.
  6. The Biotech industry in US needs to develop more MDs, PhDs with the level of training of Prof. Zelig Eshhar to carry the scientific gravitas and the creativity to become inventors of novel drugs.

 

ABOUT Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent)

Pioneers of Cancer Cell Therapy:  Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/19/pioneers-of-cancer-cell-therapy-turbocharging-the-immune-system-to-battle-cancer-cells-success-in-hematological-cancers-vs-solid-tumors/

 

ABOUT Gilead’s $12 billion buy of Kite Pharma

FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/08/30/fda-has-approved-the-worlds-first-car-t-therapy-novartis-for-kymriah-tisagenlecleucel-and-gileads-12-billion-buy-of-kite-pharma-no-approved-drug-and-canakinumab-for-lung-cancer-may-be/

 

ABOUT  the Drug Development process and the COMMERCIALIZATION GENIUS of Arie Belldegrun – Interviewed by Globes

“Chemotherapy will become just a bad memory”

More energetic than ever, Arie Belldegrun talks to “Globes” about Kite Pharma’s remarkable journey and the future of cancer treatment.

http://www.globes.co.il/en/article-chemotherapy-will-become-just-a-bad-memory-1001206978

 

ABOUT the Perspective of Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) following the Gilead’s $12 billion buy of Kite Pharma – Interviewed by Globes

Kite Pharma was a $12b missed opportunity for Israel – Interview with Professor Zelig Eshhar

Some Israeli media headlines depicted Kite as an Israeli exit. But it is a US company that does no business in Israel and has no employees here.

Professor Zelig Eshhar is the man who registered the patent on the cancer treatment drug developed by Kite Pharma, recently acquired by Gilead for $11.9 billion.

“Globes”: Do you believe that any party in Israel could have financed the product and brought it where it is today?

Eshhar: “On the one hand, yes. The level of investment in the product before it reached Nasdaq was something that an Israeli concern could certainly have financed. On the other hand, Kite Pharma founder Professor Arie Belldegrun, with his energy and connections, brought it to a completely different place (Eshhar previously tried to interest various concerns in Israel in financing the drug, but all of them told him that it was too early, or that the product was not effective enough, E.T.).

Was the development already in its final form in the 1980s?

“Almost. I went to the National Institutes of Health (NIH), where I met for the first time Professor Steven Rosenberg, who later became the first doctor to conduct clinical trials with the technology. Rosenberg heard about my technology, and offered me exceptional conditions. We set up a team there, and had the best of everything. I only wish I had it now.”

They say that Belldegrun didn’t want the product at first. Today, he’s devoting all his efforts to it.

“When Arie founded Cougar Biotechnology, which developed a drug for prostate cancer, and was eventually sold to Johnson & Johnson for $1 billion, I contacted him and offered him the technology, but he was busy with Cougar’s product, and maybe didn’t think that he had enough capital for such a production. Only after he sold Cougar did he get back to me with an offer to buy the rights to my patent. At that time (2009-2010), the technology was already arousing great interest, and there were negotiations with several large companies.” (from an April 2015 “Globes” interview with Eshhar, who was awarded the Israel Prize).

Israelis can be very provincial. In at least some of the media headlines, Kite Pharma was portrayed as a “huge Israeli exit,” and the impression was given that it was an Israeli company. The truth is very different. Kite Pharma is not an Israeli company; it is a 100% US company. It does no business in Israel; its nearly $12 billion exit has no significance whatsoever for the Israeli economy, and will contribute nothing to it: no jobs, and the tax contribution will be marginal, and certainly not on the scale of Mobileye, for example. Let me say it again: Kite Pharma does not have even one employee in Israel (and has no reason to employ anyone here), and certainly does not pay taxes in Israel. There are no Israelis on the company’s management team or board of directors. This is a US company for all intents and purposes. The word “Israel” appears exactly once in the company’s full documents – where registration of the company’s patents is concerned. The fact that every story about the company mentions the small holdings of several Israeli financial institutions in it is a bad joke. Everyone should remember that Israeli financial institutions are of course entitled to invest in any foreign share, such as Google, Amazon, Facebook, Apple Computers, and so forth. Kite Pharma is one of those foreign shares, and nothing more.

Of course, there is cause for pride in the fact that Eshhar, owner of the patent for Kite Pharma’s drug is “one of ours,” i.e. an Israeli researcher at the Weizmann Institute of Science. Another source of pride is Kite Pharma founder and CEO Arie Belldegrun, a graduate of the Hebrew University Medical School who did his post-doctorate at the Weizmann Institute, where he met Eshhar, and Kite Pharma later bought his patent for the cancer drug. Belldegrun was also a director at Teva Pharmaceutical Industries Ltd. (NYSE: TEVA; TASE: TEVA) until recently, resigning at the peak of that company’s crisis. Beyond this Israeli connection, however, the Kite Pharma exit has no great significance for Israel. All it means is that one more invention, or parts of an invention, came from an Israeli laboratory (at the Weizmann Institute in this case) and fell into foreign hands. It is another enormous missed opportunity in the field of biomedicine and ethical drugs.

It is necessary to realize that while Belldegrun is indeed a big biomedical brain with many achievements in the field, he is a brain that has left Israel, and we all have to ask ourselves why he left, why Kite Pharma is not an Israeli company, and why its (as yet non-existent) product was not developed in Israel and will not be manufactured there. The headline in Israel for the Kite Pharma exit should ask why Israel lost out on it, even though the patent came from Israeli laboratories, albeit with US cooperation.

Belldegrun is likely to keep his experiences on the Teva board of directors to himself. Of all the directors in the company, what he has to say is the most interesting, but he is unlikely to divulge what happened there with the inflated deal with Allergan, and exactly what he said at the board of directors meeting that approved the deal that led Teva into its current major crisis. The Kite Pharma exit and his other exits only highlight the lost opportunity. Kite Pharma, still without a product and without approval for a product, was sold for $11.9 billion in cash. Teva yesterday hit another low point, with a market cap of $16 billion. It is simply inconceivable: a company with an enormous potential, but no product, is worth three quarters of a huge veteran company with at least dozens of products, including products in the ethical drug sector. Kite Pharma is actually one of the indirect reasons for Teva’s decline – for the fact that Teva, which could have been a hothouse for developments like Copaxone, chose a huge inflated gamble on the generics market – a gamble that is now jeopardizing Teva’s future and very existence.

It is true that developing drugs is a very long process, requires huge amounts of capital, and involves many failures, but Teva decided to neglect it, and when a major company like Teva neglects Israeli developments, there are enough competitors in the pharma industry ready to turn Israeli research into gold. Kite Pharma is one example of this research.

The Weizmann Institute is a fruitful source of biomedical research. According to previous estimates published in “Globes,” the Weizmann Institute gets NIS 1 billion each year in royalties on medical and other developments, amounting to half of its budget. Directly and indirectly, the Weizmann Institute, together with other universities in Israel, is responsible for tens of billions of pharmaceutical sales. Only a few billions of this, however, results from drugs developed in Israel, like Copaxone, and far less than that is also made in Israel. The reports by Yeda R&D Company Ltd., the technology transfer arm of the Weizmann Institute of Science, are top secret, and there is a good reason for that. Exposing them will only highlight the scale of the missed opportunities. Instead of these inventions providing a base for a major pharmaceutical industry here, the commercialization companies are benefiting only the inventors and the Weizmann Institute itself (that is certainly natural and legitimate, and they are entitled to it), even though the research infrastructure from which they sprung is Israeli know-how, as in the case of Eshhar.

Barriers in the pharmaceutical industry are especially high. Developing ethical drugs is a process requiring huge amounts of time, patience, money, and failures. When it succeeds, however, the profit is enormous – for the industry, the employees, and the state (provided that some tax is paid). For example, Pfizer’s peak sales of Lipitor, a very popular drug for reducing cholesterol and fat in the bloodstream, reached $11 billion, and its profit on the drug was $9 billion, before competition from a generic version began. In addition to money, a great deal of experience and marketing power is required, and that is the reason why most developments wind up in the hands of major companies like Pfizer, Merck, and others at some stage. After all these qualifying statements, everyone who celebrated Kite Pharma’s exit should weep over it – it is another part of the sale of Israeli know-how overseas for a mess of pottage. Instead of consolidating a splendid pharma industry here, Israel is selling the brains with their know-how to foreigners. More than anything else, Teva’s decline and the Kite Pharma exit epitomize this sad and dangerous trend.

Published by Globes [online], Israel Business News – www.globes-online.com – on August 30, 2017

© Copyright of Globes Publisher Itonut (1983) Ltd. 2017

http://www.globes.co.il/en/article-kite-pharma-the-huge-exit-that-israel-missed-1001203173

 

ABOUT the Economic significance of Kite Pharma Acquisition for the Venture Capital Investment in Biotech in Israel

Israeli investors profit from $11.9b Kite acquisition

Pontifax fund and Israeli institutional investors will profit from the US personalized cancer drug company’s huge sale.  Part of the technology was developed at the Weizmann Institute

Pharmaceutical company Gilead Sciences Inc. has announced that it will acquire US company Kite Pharma Inc., developer of personalized cancer treatment drugs, at a company value of $11.9 billion. This is one of the biggest ever acquisitions of a company whose products have not yet been approved for marketing. The company value for the acquisition reflects a 29% premium on the market price.

Kite Pharma has developed a new method for genetically engineering immune system cells, so that they will make a focused attack on the malignant tumor. The company was founded in the US by Israeli-American Professor Arie Belldegrun, who already has two exits to his credit. He is also a former director at Teva Pharmaceutical Industries Ltd. (NYSE: TEVA; TASE: TEVA) (whose current value is not much more than the value at which Kite Pharma, a company with no products approved for marketing yet, is being acquired).

A significant part of the technology on which the product is based was developed by Professor Zelig Eshhar of the Weizmann Institute of Science.

The main Israeli beneficiary of the acquisition is the Pontifax fund, which invested $3.8 million in Kite Pharma at an early stage, but which distributed Kite Pharma shares worth $120 million to its investors. Among the investors in Pontifax that received shares in Kite Pharma are Menorah Mivtachim Holdings Ltd. (TASE: MORA) (which also bought shares on the market, and whose stake in the company is now worth over $100 million), The Phoenix Holdings Ltd. (TASE: PHOE1;PHOE5), Altshuler Shaham Ltd.Meitav Dash Investments Ltd. (TASE:MTDS), Harel Insurance Investments and Financial Services Ltd. (TASE: HARL), and Mori Arkin.

Kite Pharma is waiting for marketing approval of its first product, following a successful trial on 100 patients on a very abbreviated track for innovative cancer products. The product was initially designed for treatment of blood cancer, but it is now hoped that its use can later be expanded to treatment of other types of cancer. Gilead is making a big gamble, first of all that the US Food and Drug Administration (FDA) will fulfill its commitment to approve the product, even though the development plan it devised, together with the company, was very short and limited. The second gamble involves the process of treatment using the drug – personalized genetic engineering of each patient’s cells – a grafting process with no precedent in the pharmaceutical industry.

Speaking about the talks to sell Kite, Prof. Arie Belldegrun told “Globes.” “We handled like in the IDF 669 unit. Nobody knew anything. Nobody heard anything. We held meetings in places where nobody would see us. And before we announced it only five employees knew about it.”

Published by Globes [online], Israel Business News – www.globes-online.com – on August 28, 2017

© Copyright of Globes Publisher Itonut (1983) Ltd. 2017

http://www.globes.co.il/en/article-israeli-investors-profit-from-119b-kite-acquisition-1001202841

 

Other related articles published in this Open Access Online Scientific Journal include the following: 

Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

  • Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

  • Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2) – on Amazon since 5/18/2017

http://www.amazon.com/dp/B071VQ6YYK

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Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston

Top, from left: James Allison and Lieping Chen. Bottom, from left: Gordon Freeman, Tasuku Honjo (NOT ATTENDED), Arlene Sharpe.

Aviva Lev-Ari, PhD, RN was in attendance and covered this event LIVE

 

The 2017 Warren Alpert Foundation Prize has been awarded to five scientists for transformative discoveries in the field of cancer immunology.

Collectively, their work has elucidated foundational mechanisms in cancer’s ability to evade immune recognition and, in doing so, has profoundly altered the understanding of disease development and treatment. Their discoveries have led to the development of effective immune therapies for several types of cancer.

The 2017 award recipients are:

  • James Allison, professor of immunology and chair of the Department of Immunology, The University of Texas MD Anderson Cancer Center – Immune checkpoint blockage in Cancer Therapystrictly Genomics based drug
  1. 2017 FDA approved a gemonics based drug
  2. and co-stimulatory signals
  3. CTLA-4 blockade, CD28, AntiCTLA-4 induceses regression of Transplantable Murine tumo
  4. enhance tumor-specific immune response
  5. Fully antibody human immune response in 10,000 patients – FDA approved 2011
  6. Metastatic melanoma – 3 years survival, programmed tumor death, PD-1, MHC-A1
  7. Ipi/Nivo vs. Ipi – combination – 60% survival vs Ipi alone
  8. Anti CTA4 va Anti-PD-1
  9. responsive T cell population – MC38 TILs
  10. MC38 Infiltrating T cell populations: Treg, CD4, Effector, CD8, NKT/gamma-delta
  11. Checkpoint blockage modulates infiltrating T cell population frequencies
  12. T reg correlated with Tumor growth
  13. Combination therapy lead to CURE survival at 80% rate vs CTAL-4 40% positive outcome

Not Attended — Tasuku Honjo, professor of immunology and genomic medicine, Kyoto University – Immune regulation of Cancer Therapy by PD-1 Blockade

 

  • Lieping Chen, United Technologies Corporation Professor in Cancer Research and Professor of immunobiology, of dermatology and of medicine, Yale University – Adoptive Resistance: Molecular Pathway t Cancer Therapy – focus on solid tumors
  1. Enhancement – Enhance normal immune system – Co-stimulation/Co-inhibition Treg, and Cytokines, adoptive cell therapy, Lymphoid organs stores
  2. Normalization – to correct defective immune system – normalizing tumor immunity, diverse tumor escape mechanisms
  3. Anti-PD therapy: regression of large solid tumors: normalizing tumor immunity targeting tumor microenvironment: Heterogeneity, functional modulation, cellular and molecular components – classification by LACK of inflamation, adaptive resistance, other inhibitory pathways, intrinsic induction
  4. avoid autoimmune toxicity,
  5. Resetting immune response (melanoma)
  6. Understad Resistance: Target missing resistance or Adaptive resistance Type II= acquired immunity
  • Gordon Freeman, professor of medicine, Dana-Farber Cancer Institute, Harvard Medical School – PD-L1/PD-1 Cancer Immunotherapy
  1. B7 antibody
  2. block pathway – checkpoint blockage, Expand the T cells after recognition of the disease. T cell receptor signal, activation, co -stimulatory: B71 molecule, B72 – survival signals and cytokine production,.Increased T cell proliferation,
  3. PDL-1 is a ligand of PD 1. How T cell die? genes – PD1 Gene was highly expressed,
  4. Interferon gamma upregulate PD-L1 expression
  5. Feedback loop Tumor – stimulating immune response, interferon turn off PD1
  6. PD-L1 and PD-L2 Expression: Interferom
  7. Trancefuctor MHC, B7-2
  8. PD-L! sisgnat inhibit T-cell activation: turn off Proliferation and cytokine production — Decreasing the immune response
  9. T cell DNA Content: No S-phase devided cell
  10. PD-L1 engagement of PD-1 results in activation : Pd-1 Pathway inhibits T Cell Actiivation – lyposite motility,
  11. Pd-L2 is a second ligand for PD-1 and inhibits T cell activation
  12. PDl-1 expression: BR CA, Ovarian, Colonol-rectal, tymus, endothelial
  13. Blockage of the Pathway – Immune response enhanced
  14. Dendritic cells express PD-L1, PD-L2 and combination of Two, Combination was best of all by increase of cytokine production, increasing the immune response.
  15. PD-L1 blockade enhanced the immune response , increase killing and increased production of cytokines,
  16. anti-tumor efficacy of anti-PD-1/Pd-L1
  17. Pancreatic and colono-rector — PD-L, PDL1, PDL2 — does not owrkd.
  18. In menaloma: PD-1 works better than CYLA-4
  19. Comparison of Targeted Therapy: BRAF TKI vs Chemo high % but short term
  20. Immunotherapy – applies several mechanism: pre-existing anti-therapy
  21. Immune desert: PD=L does not work for them
  22. COMBINATION THERAPY: BLOCK TUMOR INVASION THEN STIMULATE IMMUNE RESPONSE — IT WILL WORK
  23. PD blockage + nutrients and probiotic
  24. Tumor Genome Therapy
  25. Tumore Immuno-evasion Score
  26. Antigens for immune response – choose the ones
  27. 20PD-1 or PD-L1 drugs in development
  28. WHO WILL THE DRUG WORK FOR?

 

  • Arlene Sharpe, the George Fabyan Professor of Comparative Pathology, Harvard Medical School; senior scientist, department of pathology, Brigham and Women’s Hospital – Multi-faceted Functionsof the PD-1 Pathway
  1. function of the pathway: control T cell activation and function of maintain immune tolerance
  2. protect tissues from damage by immune response
  3. T cell dysfunction during cancer anf viral infection
  4. protection from autoimmunity, inflammation,
  5. Mechanism by which PD-1 pathway inhibits anti-tumor immunity
  6. regulation of memoryT cell responce of PD-1
  7. PD-1 signaling inhibit anti-tumor immunity
  8. Compare: Mice lacking CD8-Cre- (0/5) cleared vs PD-1-/-5/5 – PD-1 DELETION: PARTIAL AND TIMED: DELETION OF PD-1 ON HALF OG TILS STARTING AT DAY 7 POSTTUMOR IMPLANTATION OF BOTH PD-1 AND PD-1 TILS: – Tamoxifen days 7-11
  9. Transcription profile: analysis of CD8+ TILs reveal altered metabolism: Fatty Acid Metabolism vs Oxidative Phosphorylation
  10. DOes metabolic shift: WIld type mouth vs PD-1-/_ P14: analyze Tumor cell killingPD-1-/- enhanced FAO increases CD8+ T cell tocicity
  11. Summary: T cell memory development and PD-1: T effectors vs T cell memory: Primary vs Secondary infection: In the absent of PD-1, CD8+ T cels show increase expansion of T cells
  12. INFLUENZA INFECTION: PRIMARY more virus in lung in PD-1 is lacking
  13. Acute infection: PD-1 controls memory T cell differentiation vs PD-1 increase expansion during effector phase BUT impaired persistence during memory phase: impaired cytokine production post re-challenge
  14. PD-1 immunotherapy work for patients with tumor: Recall Response and Primary response
  15. TIL density Primary vs Long term survivor – 5 days post tumor implantation – rechallenged long term survival
  16. Hot tumor vs Cold tumor – Deletion of PD-1 impairs T memory cell development

 

Opening Remarks: George Q. Daley, MD, PhD, DEAN, HMS

  • Scientific collaboration check point – avoid the body attacking itself, sabotaging the immune system
  • 1987 – Vaccine for HepB
  • Eight of the awardees got the Nobel Prize

 

Moderated by Joan Brugge, PhD, HMS, Prof. of Cell Biology

  • Evolution of concepts of Immunotherapy: William Coley’s Toxin streptoccocus skin infection.
  • 20th century: Immuno-surveilence, Immune response – field was dead in 1978 replaced by Immunotherapy
  • Rosenberg at NIH, high dose of costimulatory molecule prevented tumor reappearanceantbody induce tumor immunity–>> immune theraphy by check point receptor blockade – incidence of tumor in immune compromised mice – transfer T cell
  • T cell defficient, not completely defficient, self recognition of tumor,
  • suppress immmune – immune evasion
  • Michael Atkins, MD, Detupy Director, Georgetown-Lombardi, Comprehensive Cancer Center Clinical applications of Checkpoint inhibitors: Progress and Promise
  1. Overwhelm the Immune system, hide, subvert, Shield, defend-deactivating tumor trgeting T cells that ATTACK the immune system
  2. Immune system to TREAT the cancer
  3. Monotherapy – anti PD1/PD-L1: Antagonist activity
  4. Evading immune response: prostate, colcn
  5. MMR deficiency
  6. Nivolumab in relaped/Refractory HODGKIN LYMPHOMAS – over expression of PD-L1 and PDL2in Lymphomas
  7. 18 month survival better with Duv in Lung cancer stage 3 – anti PD-1- adjuvant therapy with broad effectiveness
  8. Biomarkers for pD-L1 Blockage
  9. ORR higher in PD-L1
  10. Improve Biomarkers: Clonality of T cells in Tumors
  11. T-effector Myeloid Inflammation Low – vs Hogh:
  12. Biomarker Model: Neoantigen burden vs Gene expression vs CD8+
  13. Tissue DIagnostic Labs: Tumor microenveironmenr
  14. Microbiome
  15. Combination: Nivo vs Nivo+Ipi is superior: DETERMINE WHEN TO STOP TREATMENT
  16. 15/16 stopped treatment – Treatment FREE SURVIVAL
  17. Sequencing with Standard Therapies
  18. Brain metastasis – Immune Oncology Therapy – crosses the BBB
  19. Less Toxic regimen, better toxicity management,
  20. Use Immuno therapy TFS
  21. combination – survival must be justified
  22. Goal: to make Cancer a curable disease vs cancer becoming a CHronic disease

 

Closing Remarks: George Q. Daley, MD, PhD, DEAN, HMS

 

The honorees will share a $500,000 prize and will be recognized at a day-long symposium on Oct. 5 at Harvard Medical School.

The Warren Alpert Foundation, in association with Harvard Medical School, honors trailblazing scientists whose work has led to the understanding, prevention, treatment or cure of human disease. The award recognizes seminal discoveries that hold the promise to change our understanding of disease or our ability to treat it.

“The discoveries honored by the Warren Alpert Foundation over the years are remarkable in their scope and potential,” said George Q. Daley, dean of Harvard Medical School. “The work of this year’s recipients is nothing short of breathtaking in its profound impact on medicine. These discoveries have reshaped our understanding of the body’s response to cancer and propelled our ability to treat several forms of this recalcitrant disease.”

The Warren Alpert Foundation Prize is given internationally. To date, the foundation has awarded nearly $4 million to 59 scientists. Since the award’s inception, eight honorees have also received a Nobel Prize.

“We commend these five scientists. Allison, Chen, Freeman, Honjoand Sharpe are indisputable standouts in the field of cancer immunology,” said Bevin Kaplan, director of the Warren Alpert Foundation. “Collectively, they are helping to turn the tide in the global fight against cancer. We couldn’t honor more worthy recipients for the Warren Alpert Foundation Prize.”

The 2017 award: Unraveling the mysterious interplay between cancer and immunity

Understanding how tumor cells sabotage the body’s immune defenses stems from the collective work of many scientists over many years and across multiple institutions.

Each of the five honorees identified key pieces of the puzzle.

The notion that cancer and immunity are closely connected and that a person’s immune defenses can be turned against cancer is at least a century old. However, the definitive proof and demonstration of the steps in this process were outlined through findings made by the five 2017 Warren Alpert prize recipients.

Under normal conditions, so-called checkpoint inhibitor molecules rein in the immune system to ensure that it does not attack the body’s own cells, tissues and organs. Building on each other’s work, the five award recipients demonstrated how this normal self-defense mechanism can be hijacked by tumors as a way to evade immune surveillance and dodge an attack. Subverting this mechanism allows cancer cells to survive and thrive.

A foundational discovery made in the 1980s elucidated the role of a molecule on the surface of T cells, the body’s elite assassins trained to seek, spot and destroy invaders.

A protein called CTLA-4 emerged as a key regulator of T cell behavior—one that signals to T cells the need to retreat from an attack. Experiments in mice lacking CTLA-4 and use of CTLA-4 antibodies demonstrated that absence of CTLA-4 or blocking its activity could lead to T cell activation and tumor destruction.

Subsequent work identified a different protein on the surface of T cells—PD-1—as another key regulator of T cell response. Mice lacking this protein developed an autoimmune disease as a result of aberrant T cell activity and over-inflammation.

Later on, scientists identified a molecule, B7-H1, subsequently renamed PD-L1, which binds to PD-1, clicking like a key in a lock. This was followed by the discovery of a second partner for PD-1—the molecule PD-L2—which also appeared to tame T-cell activity by binding to PD-1.

The identification of these molecules led to a set of studies showing that their presence on human and mouse tumors rendered the tumors resistant to immune eradication.

A series of experiments further elucidated just how tumors exploit the interaction between PD-1 and PD-L1 to survive. Specifically, some tumor cells appeared to express PD-L1, essentially “wrapping” themselves in it to avoid immune recognition and destruction.

Additional work demonstrated that using antibodies to block this interaction disarmed the tumors, rendering them vulnerable to immune destruction.

Collectively, the five scientists’ findings laid the foundation for antibody-based therapies that modulate the function of these molecules as a way to unleash the immune system against cancer cells.

Antibody therapy that targets CTLA-4 is currently approved by the FDA for the treatment of melanoma. PD-1/PD-L1 inhibitors have already shown efficacy in a broad range of cancers and have been approved by the FDA for the treatment of melanoma; kidney; lung; head and neck cancer; bladder cancer; some forms of colorectal cancer; Hodgkin lymphoma and Merkel cell carcinoma.

In their own words

“I am humbled to be included among the illustrious scientists who have been honored by the Warren Alpert Foundation for their contributions to the treatment and cure of human disease in its 30+ year history.  It is also recognition of the many investigators who have labored for decades to realize the promise of the immune system in treating cancer.”
        -James Allison


“The award is a great honor and a wonderful recognition of our work.”
         Lieping Chen



I am thrilled to have made a difference in the lives of cancer patients and to be recognized by fellow scientists for my part in the discovery of the PD-1/PD-L1 and PD-L2 pathway and its role in tumor immune evasion.  I am deeply honored to be a recipient of the Alpert Award and to be recognized for my part in the work that has led to effective cancer immunotherapy. The success of immunotherapy has unleashed the energies of a multitude of scientists to further advance this novel strategy.”
                                        -Gordon Freeman


I am extremely honored to receive the Warren Alpert Foundation Prize. I am very happy that our discovery of PD-1 in 1992 and subsequent 10-year basic research on PD-1 led to its clinical application as a novel cancer immunotherapy. I hope this development will encourage many scientists working in the basic biomedical field.”
-Tasuku Honjo


“I am truly honored to be a recipient of the Alpert Award. It is especially meaningful to be recognized by my colleagues for discoveries that helped define the biology of the CTLA-4 and PD-1 pathways. The clinical translation of our fundamental understanding of these pathways illustrates the value of basic science research, and I hope this inspires other scientists.”
-Arlene Sharpe

Previous winners

Last year’s award went to five scientists who were instrumental in the discovery and development of the CRISPR bacterial defense mechanism as a tool for gene editing. They were RodolpheBarrangou of North Carolina State University, Philippe Horvath of DuPont in Dangé-Saint-Romain, France, Jennifer Doudna of the University of California, Berkeley, Emmanuelle Charpentier of the Max Planck Institute for Infection Biology in Berlin and Umeå University in Sweden, and Virginijus Siksnys of the Institute of Biotechnology at Vilnius University in Lithuania.

Other past recipients include:

  • Tu Youyou of the China Academy of Chinese Medical Science, who went on to receive the 2015 Nobel Prize in Physiology or Medicine with two others, and Ruth and Victor Nussenzweig, of NYU Langone Medical Center, for their pioneering discoveries in chemistry and parasitology of malaria and the translation of their work into the development of drug therapies and an anti-malarial vaccine.
  • Oleh Hornykiewicz of the Medical University of Vienna and the University of Toronto; Roger Nicoll of the University of California, San Francisco; and Solomon Snyder of the Johns Hopkins University School of Medicine for research into neurotransmission and neurodegeneration.
  • David Botstein of Princeton University and Ronald Davis and David Hogness of Stanford University School of Medicine for contributions to the concepts and methods of creating a human genetic map.
  • Alain Carpentier of Hôpital Européen Georges-Pompidou in Paris and Robert Langer of MIT for innovations in bioengineering.
  • Harald zur Hausen and Lutz Gissmann of the German Cancer Research Center in Heidelberg for work on the human papillomavirus (HPV) and cancer of the cervix. Zur Hausenand others were honored with the Nobel Prize in Physiology or Medicine in 2008.

The Warren Alpert Foundation

Each year the Warren Alpert Foundation receives between 30 and 50 nominations from scientific leaders worldwide. Prize recipients are selected by the foundation’s scientific advisory board, which is composed of distinguished biomedical scientists and chaired by the dean of Harvard Medical School.

Warren Alpert (1920-2007), a native of Chelsea, Mass., established the prize in 1987 after reading about the development of a vaccine for hepatitis B. Alpert decided on the spot that he would like to reward such breakthroughs, so he picked up the phone and told the vaccine’s creator, Kenneth Murray of the University of Edinburgh, that he had won a prize. Alpert then set about creating the foundation.

To award subsequent prizes, Alpert asked Daniel Tosteson (1925-2009), then dean of Harvard Medical School, to convene a panel of experts to identify scientists from around the world whose research has had a direct impact on the treatment of disease.

SOURCE

https://hms.harvard.edu/news/warren-alpert-foundation-honors-pioneers-cancer-immunology

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Koch Institute Immune Engineering Symposium on October 16 & 17, 2017, Kresge, MIT

Reporter: Aviva Lev-Ari, PhD, RN

 

Koch Institute Immune Engineering Symposium on October 16 & 17, 2017.

 

Summary: Biological, chemical, and materials engineers are engaged at the forefront of immunology research. At their disposal is an analytical toolkit honed to solve problems in the petrochemical and materials industries, which share the presence of complex reaction networks, and convective and diffusive molecular transport. Powerful synthetic capabilities have also been crafted: binding proteins can be engineered with effectively arbitrary specificity and affinity, and multifunctional nanoparticles and gels have been designed to interact in highly specific fashions with cells and tissues. Fearless pursuit of knowledge and solutions across disciplinary boundaries characterizes this nascent discipline of immune engineering, synergizing with immunologists and clinicians to put immunotherapy into practice.

SPEAKERS:

Michael Birnbaum – MIT, Koch Institute

Arup Chakraborty – MIT, Insititute for Medical Engineering & Sciences

Jianzhu Chen – MIT, Koch Institute

Jennifer R. Cochran – Stanford University

Jennifer Elisseeff – Johns Hopkins University

K. Christopher Garcia – Stanford University

George Georgiou – University of Texas at Austin

Darrell Irvine – MIT, Koch Institute

Tyler Jacks – MIT, Koch Institute

Doug Lauffenburger – MIT, Biological Engineering and Koch Institute

Wendell Lim – University of California, San Francisco

Harvey Lodish – Whitehead Institute and Koch Institute

Marcela Maus – Massachusetts General Hospital

Garry P. Nolan – Stanford University

Sai Reddy – ETH Zurich

Nicholas Restifo – National Cancer Institute

William Schief – The Scripps Research Institute

Stefani Spranger – MIT, Koch Institute

Susan Napier Thomas – Georgia Institute of Technology

Laura Walker – Adimab, LLC

Jennifer Wargo – MD Anderson Cancer Center

Dane Wittrup – MIT, Koch Institute

Kai Wucherpfennig – Dana-Farber Cancer Institute

Please contact ki-events@mit.edu with any questions.

SOURCE

From: Koch Institute Immune Engineering Symposium <ki-events@mit.edu>

Reply-To: <ki-events@mit.edu>

Date: Friday, September 8, 2017 at 9:06 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Reminder – Register Today

 

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FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 9/7/2017

Here’s the inside account of Gilead’s 11-week sprint to its $12B Kite buyout – ENDPOINTS NEWS

UPDATED on 8/31/2017

Gilead-Kite: A New Transformative Deal For Biotech, AUG 30, 2017

Gilead has made a big bet on new technology in Kite’s immunotherapy platforms and has reduced the number of credible large players in the space.

With a reputation for intense diligence and dynamism in its business development efforts, Gilead’s management team will only bolster the immunotherapy field as it prepares to face off with Novartis, its immediate competitor, and enters squarely in the province of Merck and Bristol Myers Squibb, two of the leaders in immuno-oncology.

Gilead has reinvented the transformative transaction for the sector.

https://www.forbes.com/sites/stephenbrozak/2017/08/30/gilead-kite-a-new-transformative-deal-and-maybe-the-new-future-of-healthcare-deals/#fc64fca65d49

 

I attended this week the Cambridge Healthtech Institute’s 4th Annual

Adoptive T Cell Therapy

Delivering CAR, TCR, and TIL from Research to Reality
August 29 – 30, 2017 | Sheraton Boston | Boston, MA

 

The following talks on 8/29/2017 presented the frontier of CAR-T Therapies and Technologies from lab to bed side:

  • Building Better T Cell Therapies: The Power of Molecular Profiling

Mark Bonyhadi, Ph.D., Head, Research and Academic Affairs, Juno Therapeutics

  • Tricked-Out Cars, the Next Generation of CAR T Cells

Richard Morgan, Ph.D., Vice President, Immunotherapy, Bluebird Bio

  • The Generation of Lentiviral Vector-Modified CAR-T Cells Using an Automated Process

Boro Dropulic, Ph.D., General Manager and CSO, Lentigen Technology, Inc.

I covered this event in Real Time for the Press

LIVE – 8/29 – CHI’s Oncolytic Virus Immunotherapy and ADOPTIVE CELL THERAPY, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

https://pharmaceuticalintelligence.com/2017/08/29/live-829-chis-oncolytic-virus-immunotherapy-and-adoptive-cell-therapy-august-28-29-2017-sheraton-boston-hotel-boston-ma/

 

One year ago we published the following:

What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Celebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial

https://pharmaceuticalintelligence.com/2016/07/09/what-does-this-mean-for-immunotherapy-fda-put-a-temporary-hold-on-jcar015-three-death-of-celebral-edema-in-car-t-clinical-trial-and-kite-pharma-announced-phase-ii-portion-of-its-car-t-zuma-1-trial/

 

SOURCE

Is Canakinumab the Next Viagra?

In this Revolution and Revelation, Milton Packer explains how safety data can sometimes trump a primary endpoint

by Milton PackerAugust 30, 2017

https://www.medpagetoday.com/Blogs/RevolutionandRevelation/67605

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FDA: CAR-T therapy outweigh its risks tisagenlecleucel, manufactured by Novartis of Basel – 52 out of 63 participants — 82.5% — experienced overall remissions – young patients with Leukaemia [ALL]

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Basel, July 12, 2017 – Novartis announced today that the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) unanimously (10-0) recommended approval of CTL019 (tisagenlecleucel), an investigational chimeric antigen receptor T cell (CAR-T) therapy, for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL).

“The panel’s unanimous recommendation in favor of CTL019 moves us closer to potentially delivering the first-ever commercially approved CAR-T cell therapy to patients in need,” said Bruno Strigini, CEO, Novartis Oncology. “We’re very proud to be expanding new frontiers in cancer treatment by advancing immunocellular therapy for children and young adults with r/r B-cell ALL and other critically ill patients who have limited options. We look forward to working with the FDA as they complete their review.”

Acute lymphoblastic leukemia comprises approximately 25% of cancer diagnoses among children under 15 years old and is the most common childhood cancer in the US[1]. Effective treatment options for patients with r/r ALL are limited. In pediatric and young adult patients with B-cell ALL that have relapsed multiple times or become refractory to treatment, the five-year disease-free survival is less than 10-30%[2],[3],[4].

CTL019 was first developed by the University of Pennsylvania (Penn) and uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular responses as well as persistence of CTL019 after it is infused into the patient, which may be associated with long-lasting remissions in patients. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers. Children’s Hospital of Philadelphia (CHOP) was the first institution to investigate CTL019 in the treatment of pediatric patients and led the single site trial.

SOURCE

https://www.novartis.com/news/media-releases/novartis-car-t-cell-therapy-ctl019-unanimously-10-0-recommended-approval-fda

RISKS:

During the 2015 tisagenlecleucel trial, 47% of participants experienced an

  • extreme inflammatory reaction known as cytokine release syndrome, severe cases of which are called cytokine storms. The syndrome — characterized by symptoms such as high fevers and organ failure — can be life-threatening. But
  • Novartis says trial clinicians were able to manage the reaction successfully in all cases.
  • Neurological problems such as seizures and hallucinations were also relatively common but temporary,
  • the Novartis team reported. This is in stark contrast to some other CAR-T trials that have,
  • over the past year, reported the deaths of several participants from severe brain swelling.
  • Novartis’s therapy is not identical to the CAR-T cells used in those trials, which were administered in adults, but the deaths cast a pall over the entire field.

To generate a batch of tisagenlecleucel, white blood cells are purified from a sample of a patient’s blood and shipped to a central processing centre. There, staff use a virus to insert into the T cells genes that encode a cellular receptor — called a chimaeric antigen receptor — that will recognize leukaemia cells.

SOURCE

Engineered cell therapy for cancer gets thumbs up from FDA advisers

Treatment shows promise in young people with leukaemia, but safety risks abound.

Heidi Ledford, 12 July 2017

http://www.nature.com/news/engineered-cell-therapy-for-cancer-gets-thumbs-up-from-fda-advisers-1.22304?WT.ec_id=NEWSDAILY-20170713

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