Given the various players, partnerships and agreements involved in the pursuit of CAR T-cell research and therapy with the ultimate goals and objectives of bringing approved treatments/products to the marketplace, I find it necessary for me to get a macro view of what’s going on, who are the players, what’s their progress in research and what are the targeted cancers for research and clinical trials, etc. before I can make any sense and determination as to what, who and when to make any investment. I thought I’d share what I’ve found so far that might be helpful and useful for those here interested in this sector. So, here goes a long post.
THE INITIAL DECADES OF CAR T-CELL DEVELOPMENT (1980 to 2010)
A widely recognized pioneer developer of the chimeric antigen receptors (CAR) T-cells is Zelig Eshhar, a chemist and immunologist at the Weizmann Institute of Science and the Tel Aviv Sourasky Medical Center in Israel, whose efforts began in the 1980s. From the start, there have been lots of naysayers and doubters about such a concept, that is, development of a cancer immunotherapy, involving genetic modifications of T lymphocytes extracted from a cancer patient to produce chimeric antigen receptor (CAR) T-Cells, which are then injected back into the patient in a process called adoptive cell transfer.
Also at the forefront in the U.S. was another dedicated pioneer, Steven Rosenberg, a surgeon and biophysicist. In 1968, as a young surgeon, Rosenberg was performing a routine gallbladder operation on a patient, who 12 years earlier had a fist-sized tumor removed from his stomach by doctors, who had not been able to cut out many smaller growths in the patient’s liver. Rosenthal was mystified when he examined the patient’s abdominal cavity and could find no trace of cancer, after sifting the liver in his fingers and feeling no hard, dense tumors. His hunch was that the patient’s immune system had vanquished cancer. Hoping an “elixir” might exist in the patient’s blood, he got permission to transfuse some of it into another patient dying of stomach cancer. This notion failed, but lit Dr. Rosenberg’s lifelong workaholic quest to find answers.
In 1974, Steven Rosenberg joined the National Cancer Institute and, after failing a number of attempts at immunotherapy, it wasn’t until late 1984, when a patient with melanoma was given interleukin-2, or IL-2, a protein made by the body that spurs T-cells to proliferate, was cured and survives today. This case and others catapulted Dr. Rosenberg and IL-2 onto the cover of Newsweek and the front pages of newspapers. This success, however, was short-lived as IL-2’s vaunted prowess fizzled, helping only a few percent of patients with melanoma or kidney cancer.
In 1990, Zelig Eshhar took a year-long sabbatical to join Steven Rosenberg at the National Institute of Health, where they prepared CARs that targeted human melanoma. Eshhar and Rosenberg constructed the CAR T-cells with a modular design that included a specific cancer-targeting antibody, and later added a costimulatory signaling domain that amplifies the activation of the cells, giving them a stronger signal to multiply and kill cancer cells. Since that early work, researchers in both academia and industry have developed and tweaked each section of the modular design.
Readers here might be asking, why the long spiel on Eshhar and Rosenberg? Well, today, Kite Pharma has these two prominent pioneers in their corner. Eshhar is a member of Kite Pharma’s scientific advisory board and continues to collaborate with Rosenberg, who serves as a special advisor to the company.
Another prominent early pioneer was Dr. Carl June, a U.S. Naval Academy graduate, who was sent to medical school by the Navy for training in bone-marrow transplantation in order to treat people irradiated by nuclear weapons. In the mid-1980s, June switched to working with T-cells at the Naval Medical Research Institute and working with colleague, Dr. Bruce Levine, discovered a way to multiply T-cells in huge numbers outside the body, a method still used today. In the mid-1990s, working with a gene therapy company Cell Genesys, he attempted to genetically modify patients’ T-cells to kill HIV, the virus that caused AIDS. In 1996, tragedy hit the June family, when his wife developed ovarian cancer. Dr. June’s research then became personal as he tried various therapies on his wife to no avail; the cancer took her life in 2001. He stopped treating patients, moved to the University of Pennsylvania, where he devoted himself to creating cell therapies for cancer. In August 2012, the University of Pennsylvania entered an agreement with Novartis to pursue CAR-T research and therapy with Carl June, director of translational research at the Abramson Cancer Center at the University of Pennsylvania.
Another pioneer giant was Michel Sadelain, who had a pipe dream while studying immunology at the University of Alberta, that the technique putting new genes into cells of the body to treat disease could be used to supercharge T-cells to fight cancer. At the Whitehead Institute for Biomedical Research in Cambridge, Mass., he learned how to do gene therapy, using disabled viruses that could not cause disease to deliver genes into cells. By 1992, he had demonstrated that he could genetically engineer mouse T-cells.
He moved to Memorial Sloan Kettering, where in 2003, he and his colleagues showed that genetically engineered T-cells could eradicate certain cancers in mice. The following is an excerpt that best explains what became to be called a chimeric antigen receptor, or CAR:
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“To fight cancer, T-cells have to recognize cancerous cells.
Each T-cell in the body has unique receptors, sort of like claws that jut out from its surface. T-cells patrol the body looking for protein fragments that indicate a cell might be infected by a bacterium or virus. If one of its claws latches on to such a fragment, the T-cell destroys the cell displaying it.
But cancer cells are mutated versions of the body’s own cells, not outsiders. T-cells do not always recognize them as something to kill.
So scientists like Dr. Sadelain decided to put a new claw on the T-cells, one that could recognize cancer by latching on to a telltale protein on cancer cells.
The new claws came from another part of the immune system known as antibodies. Drug companies already knew how to make antibodies with claws that bind to specific proteins in the body.
But the claw was not enough. Once a claw binds to a target protein, it needs a molecule to signal the T-cell to go into killing mode. Yet another signal helps sustain the killing. The DNA instructions for all three components are inserted into the patient’s T-cells.
Since this concoction is part antibody and part T-cell, it is a chimera, like the monster of Greek mythology that is part lion, part goat and part serpent. The claw is called a receptor and the protein it binds to on the cancer cell, the target, is called an antigen. So the whole construct is called a chimeric antigen receptor, or CAR, and the use of it to treat cancer is called CAR T-cell therapy, or CAR-T.”
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Another early developer was Dario Campana at St. Jude Children’s Research Hospital. As scientists worked to perfect the formula in the 1990s and early 2000s, there was a lot of sharing. Cancer cell therapy was still mostly an academic exercise. It was highly uncertain whether it would ever really work. Carl June, after hearing a presentation by Campana at a conference in 2003, requested a sample of Campana’s CAR. Michel Sadelain shared his design with both June and Rosenberg. According to Rosenberg, the most prominent CAR developed at the National Cancer Institute owed a lot to Sadelain.
Another early developer was James P. Allison, an immunologist who today is a professor and chair of Immunology and executive director of immunotherapy platform at the University of Texas M. D. Anderson Cancer Center in Houston, Texas. His discoveries have led to new cancer treatments for the deadliest cancers. He has a longstanding interest in mechanisms of T-cell development and activation, the development of novel strategies for tumor immunotherapy, and is recognized as the first person to isolate the T-cell antigen receptor complex protein.
Not only was the science proving to be difficult, but money for research was scarce. Pharmaceutical companies showed little interest, preferring mass-produced drugs, one size fits all, rather than a treatment that would be made separately for each patient.
The CAR-T research effort got a significant boost forward in 2001, when, after the death of their daughter-in-law due to breast cancer, Edward Netter, a wealthy financial services entrepreneur, and his wife, Barbara, formed the nonprofit Alliance for Cancer Gene Therapy, which issued some of its first grants to June and Sadelain. June also got support from the Leukemia and Lymphoma Society. According to June, without that we would not have had a clinical trial.
2010 AND BEYOND
By the end of 2009, the three leading pioneers, i.e., Rosenberg, June and Sadelain, were ready for testing treatments in patients and scrambled to be the first to announce peer-reviewed results. Although Rosenberg was the first to publish in 2010 that tumors of a single patient with lymphomas shrank after treatment, he was outshone by June who reported in 2011 that 2 of 3 patients with chronic lymphocytic leukemia went into complete remission. More significantly, publication of Dr. June’s results transformed the field. Novartis, the big Swiss pharmaceutical company, licensed the rights to the therapies created in June’s lab at the University of Pennsylvania, throwing aside concerns that treatments manufactured for individual patients would not be good business. That set off a commercial rush, flooding the field with cash after years of doubt.
What followed was a frenzy of companies going public, lots of dealmaking and formation of partnerships.
CAR-T BIOTECH
COMPANY IPO DATE VALUE
Intrexon August 2013 $ 1.5 billion
Kite Pharma June 2014 $ 134.1 million
Bellicum December 2014 $ 140.0 million
Juno December 2014 $ 264.6 million
Cellectis March 2015 $ 228.0 million
After going through numerous 10K filings, I’ve identified and assembled the latest partnerships with key (not all) participants in the following table. For me, it was a laborious, but well spent effort that revealed the business deals, agreements and financial arrangements.
CAR-T BIO-TECH
COMPANIES CAR-T PIONEERS KEY PARTNERS
Kite Pharma (KITE) Zelig Eshhar National Cancer Institute
Steven Rosenberg Amgen
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Novartis AG (NVS) Carl June Univ. of Pennsylvania
Abramson Cancer Center
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Juno Therapeutics(JUNO) Michel Sadelain Memorial Sloan Kettering
Fred Hutchinson Cancer Research Center
Seattle Children’s Hospital
Celgene Corp. (CELG)
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ZioPharma Oncology (ZIOP) James P. Allison University of Texas
M.D. Anderson Cancer Center
Intrexon Corp. (XON)
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Bellicum Pharma (BLCM) University of Leiden, Netherlands
National Cancer Institute
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Cellectis S.A. (CLLS) Pfizer
(France) Ohio State University
Les Laboratoires Servier SAS
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Celgene Corp. (CELG) Bluebird Bio, Inc. (BLUE)
Baylor College of Medicine
Juno Therapeutics
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Fortress Biotech (FBIO) City of Hope
Mustang Bio, Inc
Regulatory authorities began giving CAR T-cell treatments priority review for filling unmet medical needs. Many of these therapies have received orphan or breakthrough status from the U.S. Food and Drug Administration (FDA), bringing expedited regulatory review, which translate into earlier realization of financial benefits from more rapid market entry. Full details about the FDA Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review process are provided at this website https://www.fda.gov/forpatients/approvals/fast/ucm20041766.h… . In November 2014, for example, the FDA granted orphan status to Juno’s JCAR015. Kite’s KTE-C19 for refractory aggressive non-Hodgkin’s lymphoma also received the designation from both the FDA and the European Medicines Agency. Also, the University of Pennsylvania /Novartis’s CTL019 for ALL received breakthrough status. Most researchers optimistically expect that the FDA will approve CAR T-cell therapies by the end of 2017 for the treatment of blood cancers such as leukemia and lymphomas.
Like Juno, Houston, Texas–based Bellicum Pharmaceuticals is working on refinements for next-generation CAR T-cell treatments. To better control antigen activation by its CAR T cells, for example, Bellicum is separating its dual costimulatory domain from the antigen-recognition domain, moving it onto a separate molecular switch that can be controlled by the small-molecule drug rimiducid. These T cells, known as GoCAR-Ts, can only be fully activated when they are exposed to both cancer cells and the drug.
In addition to altering the components of the CAR T cells themselves, researchers are also experimenting with different methods to introduce the receptors into the patients’ cells. At M.D. Anderson Cancer Center in Houston, Laurence Cooper and his colleagues are using a nonviral system called “Sleeping Beauty,” licensed from the University of Minnesota’s Perry Hackett, that relies on a transposon derived from fish to paste any desired gene into the genome. According to Cooper, this system employs electroporation [an electric current] to introduce elements of the Sleeping Beauty system into T cells; he hopes the system will be less complex and cheaper to use than viral vectors. As shown above, the University of Texas M.D. Anderson Cancer Center has partnered with ZioPharma, where Laurence Cooper became CEO in May 2015.
Tumor Cancers
This past week, I had a physical exam by my primary care physician who began his medical career as an oncologist, completing a fellowship in medical oncology at the National Cancer Institute and spending almost a decade there conducting cancer research not involving CAR-T. Long story short he transitioned to internal medicine and became one of the founders and partners of one of the largest medical groups in Southern California. At the end of my physical, I asked my doctor for his thoughts about the state of CAR-T research and therapy. After quickly rattling off the top types of common cancers that all have tumors, he said that CAR-T research and therapy to date has only scratched the surface and has a long way to go in spite of showing promising results treating blood cancers. He mentioned reading a recent article in the New England Journal of Medicine about the success of City of Hope researchers with remission results using CAR-T treatment for a patient with deadly brain cancer tumors. I asked if he thought the City of Hope was lagging behind Memorial Sloan Kettering, M.D. Anderson Cancer Center and Abramson Cancer Center in research and clinical trials. Showing a “are you kidding me” facial expression, he responded that the City of Hope is no small fry and he wouldn’t count them out. He said picking winners now is way too premature as currently it’s a wide open challenge, delivering viable treatments for tumor cancers to the marketplace. He wants all of them to succeed.
The National Cancer Institute provides a list of common cancer types with estimated annual incidence for 2017 (with at least 40,000 cases per cancer type) that I rearranged in rank order.
2017 ESTIMATED ESTIMATED
RANK CANCER TYPE NEW CASES DEATHS
1 Breast (female-male) 252,710 40,610
2 Lung (incl. Bronchus) 222,500 155,870
3 Prostate 161,360 26,730
4 Colon & Rectal (combined) 135,430 50,260
5 Melanoma 87,110 9,730
6 Bladder 79,030 16,870
7 Non-Hodgkin Lymphoma 72,240 20,140
8 Kidney (Renal Cell & Renal Pelvis) Cancer 63,990 14,400
9 Leukemia (All Types) 62,130 24,500
10 Endometrial 61,380 10,920
11 Thyroid 56,870 2,010
12 Pancreatic 53,670 43,090
13 Liver & Intrahepatic Bile Duct 40,710 28,920
SOURCE: NIH National Cancer Institute
My cursory search found that CAR-T therapy has so far been tested on hundreds of patients, mostly with blood cancers and that solid tumors pose a very difficult challenge. I’m searching for reasons why, given the list above where tumors prevail in the top four highest incidence of cancer, i.e., breast, lung, prostate and colon & rectal. Dr. Carl June, the CAR-T pioneer at the University of Pennsylvania, related at a November 2016 NIH Director’s Lecture that unfortunately, he has not had the same success in patients with solid tumors because “most tumors have targets on the surface essential for other normal cells,” and complex sugars found only on the surface of tumors, however, might be alternative targets for therapy. Bruce Levine, a gene therapy professor working with him and Novartis on CAR-T therapy, simply stated, “We’re in the Model T phase.”
Targeting Neoantigens
In pursuit of the “holy grail” of cancer immunotherapy, other researchers are targeting neoantigens, which might be the Achilles heel of cancer.
From Wikipedia sources:
“Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a high mutational burden. The level of transcripts associated with cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors.
Neoantigens are those that are entirely absent from the normal human genome. As compared with nonmutated self-antigens, neoantigens are of relevance to tumor control, as the quality of the T cell pool that is available for these antigens is not affected by central T cell tolerance. Technology to systematically analyze T cell reactivity against neoantigens became available only recently.”
Recently, Johns Hopkins Kimmel Cancer Center scientists report data from a new study providing evidence that random, unpredictable DNA copying “mistakes” account for nearly two-thirds of the mutations that cause cancer. Their research is grounded on a novel mathematical model based on DNA sequencing and epidemiologic data from around the world.
https://www.sciencedaily.com/releases/2017/03/170323141403.h…
I found that Steven Rosenberg at the National Cancer Institute is targeting neoantigens in a recent 2/15/2017 online publication, “Final common pathway of human cancer immunotherapy: targeting random random somatic mutations” which states in the abstract: “Here we highlight evidence suggesting that T cells that target tumor neoantigens arising from cancer mutations are the main mediators of many effective cancer immunotherapies in humans.”
http://www.nature.com/ni/journal/v18/n3/full/ni.3682.html
Other Issues
There are also questions on how the one-time CAR-T therapy and treatment will be given to patients in the marketplace.
• KITE’s chief medical officer Dr. David Chang said, “I don’t think this is a treatment that we foresee will be limited to comprehensive cancer centers or specialized hospitals.”
• Dr. Renier Brentjens, director of cellular therapeutics at Memorial Sloan Kettering, who is working with Juno on its CAR-T treatment, said, "Whether this will be technology that’s specific to boutique, high-end academic centers, or technology that can be used in community hospitals if people learn how to infuse them in a safe manner — we just don’t know yet.”
•. At the November 2016 NIH Director’s Lecture, Dr. Carl June, professor of immunotherapy at the University of Pennsylvania, stated, “At first, CAR T-cell therapy will only be available at high-end “quaternary” cancer centers. Physicians practicing at community hospitals won’t be sufficiently trained in immunotherapy, so they can’t offer it to patients. How T cells are produced will also limit the availability of treatments. We need robotic and fully automatic cell culture. We have a system that still depends on academic-based manufacturing systems—basically requiring highly trained personnel.” Since CAR T-cell therapy is personalized, new T cells must be grown from a patient’s own cells. June said it isn’t clear yet whether cord blood or T cells from a healthy donor can be used.
Also, unknown is the patient’s cost for a one-time treatment in the marketplace. In another post here, I related that the costs for treating future patients could be enormous, with potential bills running hundreds of thousands of dollars. Juno CFO Harr has seen estimates as high as $500,000 to $750,000 — though said that doesn’t necessarily reflect how Juno will price its own CAR-T therapy.
Keep in mind, looking at the overall macro picture, CAR-T cell research and therapy is one of many types of cancer treatment. According to the NIH National Cancer Institute, the types of treatment that a patient receives will depend on the type of cancer the patient has and how advanced it is. The NCI lists the following 8 main types of cancer treatment:
• Surgery
• Radiation Therapy
• Chemotherapy
• Immunotherapy
• Targeted Therapy
• Hormone Therapy
• Stem Cell Transplant
• Precision Medicine
Some people with cancer will have only one treatment. But most people have a combination of treatments, such as surgery with chemotherapy and/or radiation therapy.
https://www.cancer.gov/about-cancer/treatment/types
While CAR T-cell therapy sells itself as a one-time treatment, this may not be the case for aggressive tumor cancers like glioblastoma and breast cancer that are known to reoccur after treatment.
Hope the above helps your understanding and assessment about the CAR T-cell research and therapy sector. I’m still in search/due diligence mode. If and when the FDA gives CAR T-cell therapy the green light for treatment of blood cancers, hooray it will be a several decades long battle won, but the big war on cancer remains and will be won (in whole or in part with more battle wins) if and when CAR T-cell therapies or other means and methods can be successfully applied to tumor cancers that unfortunately affect and kill a much larger population of victims.
As always, conduct your own due diligence and decision-making.
Regards,
Ray