Zelig Eshhar: Putting Cancer in the Rear-View Mirror

                        Professor Zelig Eshhar

(Introductory Note) Back in early June when this blog moved to its present site, the subtitle also changed: from "Formerly 'Beating the Bushes'" to "Politics and a Whole Lot More."  Well, this week is mostly "A Whole Lot More" and a tiny bit of "Politics." The underlying basis for this week's piece comes from an aspect of my professional life which I have rarely, if ever, written about.

For nearly 2 dozen years, I have served as a "community member" of two different Institutional Review Boards; first, Cleveland Clinic Florida and, for going on five years, Schulman Associates IRB (Institutional Review Board).  It is our job to carefully screen, edit and approve medical research projects - some dealing with surgical procedures, some pharmaceuticals and yet others, visionary techniques.  Our "primary directive" is to help safeguard the rights of research subjects and to make sure that all research is carried out in an ethical manner.

Over these many years, I have read, digested (to the best of my lay ability) and edited easily more than 1,000 research protocols.  By this point in time, I guess you could say that I qualify, medically speaking, as either a "lay professional," or perhaps a "professional layperson."  For it is my job to translate medical and scientific terminology into understandable English at, say, an 8th or 10th-grade level.  

Having written this, let's enter enter the world of Zelig Eshhar, cancer research and CAR-T . . . 

There's a pretty good chance that few, if any who are reading this piece have ever read or heard of Zelig Eshhar, let alone be conversant with the medical acronym CAR-T.  Trust me when I tell you that shortly, that's going to change; that both Professor Eshhar, an Israeli immunologist at Israel's Weizmann Institute of Science and his breakthrough research will become as well known as penicillin, Viagra and joint replacement surgery.  

Professor Eshhar's breakthroughA is called CAR T Therapy, which stands for Chimeric Antigen Receptor T-cell Therapy.   T-cells are the white blood cells that fight foreign or abnormal cells, including cancerous ones. Under normal circumstances, T-cells try to fight cancerous cells – but because the body has been weakened by the cancer, the response is usually not strong enough to prevent the spread of cancer. In addition, cancer cells are genetically programmed to evade T-cells - essentially to see them as "the enemy." Dr. Eshhar figured out a way around this by extracting T-cells from the patients and then genetically modifying them to develop longer-lasting and more aggressive responses to the disease. As a result, research subjects experienced significant improvement – and even elimination of the disease altogether.  In a sense, what Dr. Eshhar's process does is retrain T-cells and put them back into the body. CAR T therapy represents a quantum change in both theory and practice.  Instead of using chemotherapy, which is essentially a poison used to kill various tumors or cancer cells, CAR T takes an immunological approach in which one's own body provides the "slaying" mechanism.

Chemo drugs are huge money-makers for the pharmaceutical industry.  Various companies - such as Roche, Novartis and Eli Lilly pour tons of money into researching what they hope will become the next blockbuster drug.  And if (and when) they come up with a drug that works on a particular type of cancer (breast, prostate, lung, pancreas, etc.), it can be worth billions of dollars in global sales. 

Currently, the biggest sellers are:

• Roche's Avastin (Bevacizumab) with global sales of $6.7 billion;  used to treat breast, colorectal , kidney and ovarian cancers. 
• Celgene's Revlimid (Lenalidimide) with global sales of $4.2 billion;  used to treat Multiple myeloma (a cancer of plasma cells)
• Roche's Retuxin (Rituximab), with sales of $7.5 billion; used to treat non-Hodgkin's lymphoma (a cancer that starts in white blood cells called lymphocytes)
• Roche's Herceptin (Trastuzumab) with sales of $6.5 billion (used to fight a type of breast cancer called HER 2+)
• Johnson & Johnson's Imbruvica (Iritunib capsules) with sales of $5.3 billion (used to treat certain kinds of leukemia - a blood cancer - and lymphoma.

(BTW: many chemotherapy drugs you see advertised on TV end in either mab or nib. The former stands for "Monoclonal Antibody," [a  type of protein made in the lab which can bind itself to substances in the body like cancer cells]; the latter stands for a small molecule Inhibitor. A nib drug blocks [inhibits] the cell's ability to divide and grow.)

CAR T-cell Therapy is a horse of a different color. As Professor Eshhar explains it, "T-cells and antibodies in patients and animals are part of the immune system, capable of distinguishing tumor cells from normal cells. These cells, however, are not enough to fight the cancer cells, which manage to “evade and avoid them. The end result is cancer and an immune system that is not efficient enough to thwart it."  Stumped by this reality, Eshhar decided to combine the antibodies with the T-cells, figuring, in his words that "Two are better than one."

What he did was extract the T-cells and genetically engineered  them to include a molecule that has the cancer recognition skills of both the antibodies and the T-cells. The modified T-cells were then injected into patients. As Eshhar explained it, these T-cells “now recognize the cancer and will now be efficient because I engineered them so they will attack the cancer."  This is the simple essence of Chimeric Antigen Receptors.  To date, this process has shown spectacular success; so much so that the company which began experiments with CAR-T - Kite Pharma - was just bought out by Gilead Sciences, Inc. for a whopping $12 billion.  Not bad for a company (Kite) which has never turned a profit.

And so, cancer care has taken a gigantic, formative step; away from medicines on the chemical level and towards therapy on the genetic.  The growth and acceptance of Eshhar's technique is moving as a geometric rate.  Just 4 days ago, the Food and Drug Administration (FDA) approved Novartis' CAR T-cell therapy for young people up to age 25 with a form of leukemia called "acute lymphoblastic leukemia" - a type of cancer of the blood and bone marrow that affects white blood cells.  And just last month, the online Genetic Engineering and Biotechnology News reported the first successful use of CAR-T in  therapy for Glioblastoma Multiforme (GBM), a virulent, fast-growing type of central nervous system tumor that forms from supportive  tissue of the brain and spinal cord.  (This, by the way, is the type of cancer that Arizona Senator John McCain recently had surgery for. The average survival for malignant glioblastoma is around 14 months.)

Various research projects involving CAR-T have shown startling results ranging from total remission of certain types of cancer to its total disappearance.  More time, more dollars and more research will be needed before it can be declared "the silver bullet" in cancer treatment. But for now, it is terribly exciting, extremely hopeful and awesomely imaginative.  When asked how much money he could make off the sale of KITE Pharma (on whose Scientific Advisory Board Professor Eshhar serves), the good doctor responded "I am not a banker and I don’t know the laws. I don’t know how much we will get. I prefer not to relate to this. Research is what interests me, to improve the treatment and make it more effective.”

So what is this potential miracle cure going to cost?  No one knows for sure, but Novartis has pegged the price of its newly-approved CAR-T drug Kymriah at $475,000 for a single infusion, an amount that is within the range anticipated by oncologists and that Novartis characterized as "well below a price level that could be justified on cost."  As time goes by and new CAR-T medicines become available, the price will likely come down. But make no mistake: for the foreseeable future, it's going to be a highly expensive therapy.  But in an article published just a couple of days ago the online Life Science Washington experts anticipate that "Through further collaboration between academic groups and industry, and with a greatly improved local infrastructure, and an increased understanding and predictability of therapy resistance, there is great hope that CAR-T will become an efficient and affordable therapy – for the benefit of everyone."

In my introductory remarks I noted that this week's piece was "mostly 'a Whole Lot More' and a tiny bit of 'Politics.'"  So where does politics enter the realm of CAR-T?  In this one closing thought:

The progress that can and should be made in this ground-breaking therapy will require a staggering investment - both on the part of big pharma, foundations and the federal government.  Regrettably, this is all happening at the very moment in which the administration has proposed cutting funds for the National Institutes of Health (NIH)  from $31.8 billion to $26 billion. They are also seeking a $1 billion cut in funds for the National Cancer Institute.  It doesn't take a genius to realize that this is bad, bad timing. Hopefully Senator McCain, who is one of the most widely respected voices on Capitol Hill, will be able to convince his colleagues to stem this heartless tide.

Then too, it is indeed highly ironic that a world class Israeli immunologist working at an Israeli institute, (and assisted by scientists named Kohn, Levy and Rosenberg) should be getting his most deserved moment in the sun at  precisely the same time that neo-Nazis and white supremists are airing their diabolic dreams and desires in front of every camera and microphone pointed their way.  God forbid any of them should wind up needing CAR-T therapy.  Will they turn it down because its "parents" are Jewish . . . ?

Copyright©2017 Kurt F. Stone