CAR-T Cell Approval by the FDA

A year ago we wrote extensively about the developments in CAR-T cells. We have been following this work for several years and it has finally reached a clinical level with FDA approval today of a Novartis therapeutic.

The FDA notes:

Kymriah, a cell-based gene therapy, is approved in the United States for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. Kymriah is a genetically-modified autologous T-cell immunotherapy. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells. ALL is a cancer of the bone marrow and blood, in which the body makes abnormal lymphocytes. The disease progresses quickly and is the most common childhood cancer in the U.S. The National Cancer Institute estimates that approximately 3,100 patients aged 20 and younger are diagnosed with ALL each year. ALL can be of either T- or B-cell origin, with B-cell the most common. Kymriah is approved for use in pediatric and young adult patients with B-cell ALL and is intended for patients whose cancer has not responded to or has returned after initial treatment, which occurs in an estimated 15-20 percent of patients.

ALL is a deadly childhood cancer, most often, and  I recall see my first case in March 1968. Cold rainy day and a ten year old had a fever and malaise and we ran the blood work and it was a leukemia. Death was then a certainty. Now with this therapeutic survival is a viable option.

It should be interesting to see how this can be applied to other cancers. Cell markers must be available for the differing malignancies.

CAR-T Cells

Last year we wrote an extensive analysis of CAR-T cells. In Nature this week there is a piece on the FDA progress on approving them. They note:

External advisers to the US Food and Drug Administration (FDA) have thrown their support behind a therapy that genetically engineers a patient’s own immune cells to target and destroy cancers. In a unanimous vote on 12 July, the panel determined that the benefits of CAR-T therapy outweigh its risks. The vote comes as the agency considers whether to issue its first approval of a CAR-T therapy, for a drug called tisagenlecleucel, manufactured by Novartis of Basel, Switzerland. The FDA is not obligated to follow the recommendations of its advisers, but it often does...Studies have shown that CAR-T therapies can produce lasting remissions in such cases. In one key trial of tisagenlecleucel, which started in 2015, 52 out of 63 participants — 82.5% — experienced overall remissions. The unpublished trial had no control group, so investigators cannot yet say with certainty how much effect the treatment had. But many participants of such trials have remained cancer-free for months or years.

These are most likely the first of many therapeutics that are customized to attack specific individual cancer cells of an individual patient. Simply stated:

1. Immune System is Used to Attack

2. Targets on the cancer cells are identified

3. Chimeric cells are created to use the patients immune system but modified to attack the specific cancer cell

4. The cells are individually customized and then reinserted into the patient.

5. This is a very powerful approach! It may actually be akin to carpet bombing, turning the immune system against itself. There seems to be no way to turn it off.

However, ALL was a deadly disease. One of the first cases I saw was in 1967 when a classmate was sent home from Marine Corps training with a high and uncontrolled fever. It was ALL and he was dead in a couple of weeks. If this approach works it may very well stop this disease and more.

More on CAR-T Cells

We have been following the progress on CAR-T cells over the past few years. The recent result reported in Science Daily is of special import. Namely:

In an early clinical trial, 33 out of 35 (94 percent) patients had clinical remission of multiple myeloma upon receiving a new type of immunotherapy -- chimeric antigen receptor (CAR) T cells targeting B-cell maturation protein or BCMA. Most patients had only mild side effects. 

Namely, find a target on the desired cell and then create a "smart bomb" the CAR-T cell, and then set it loose. It seems to be working much more effectively now. It still has some "carpet bombing effects" but this may very well change the paradigm for cancer treatment.

Namely, find a surface target, then construct a patient specific attack element, then let the immune system loose. Very worth while to follow!

Mabs and CAR-T

Immunotherapy has become an explosive field. We have been focusing on Mabs, which have been around for quite a while, plus CAR-T cells which have been available for about five years. There is an interesting report by Research and Markets which sizes up the CAR=T cell market. They state:

As per report findings, the promise of CAR modified T cell therapy derives from its combined immunologic benefits and include the specificity of a targeted antibody, the ability to expand the T cell population and the potential for long term persistence to facilitate the ongoing tumor surveillance. The success in early phase trials, assess the feasibility of evaluating the treatment modality across the multiple centers and in larger patients. Currently, there are 99 CAR T Cell based therapies in clinical pipeline and most of them belong to Phase-I and Phase-I/II clinical trials. 

We have examined this approach over the past few years and it does present potential. They also note the following players:

12.1 Autolus
12.2 Bellicum
12.3 Bluebird
12.4 Celgene
12.5 Cellectis
12.6 Celyad
12.7 Eureka Therapeutics
12.8 Fortress Biotech
12.9 Immune Therapeutics
12.10 Juno Therapeutics
12.11 Kite Pharma
12.12 Novartis
12.13 Sorrento therapeutics
12.14 TILT Biotherapeutics
12.15 Ziopharm  

It is well worth watching this landscape evolve.

Carpet Bombing Cancer

The immune system is a powerful attack system. Take the simple example of the common cold. You touch something, or someone coughs and sends particle towards you. The virus enters your nose. Then what? The immune system recognizes this new adversary, the virus, and it sends out warning signals, recruits immediate responders, and at the same time the virus multiplies the immediate immune system releases a volume of cytokines, killer proteins to carpet bomb everything in the path of the virus. The nose starts running, the throat gets sore, the lungs get congested as the battle between the growing virus load is slowly overcome by the ever faster growing immune response. So what makes us feel so bad with a common cold? It may very well be the immune system response rather than the attack.

Now consider working in the garden. Peaceful. Relaxing, at least for some. Then as you dig up weeds, you notice you just unearthed roots that attache to that shiny three leaves plant. Poison Ivy! But no immediate response, you go in and wash your hands, and thinks all is well. No luck. Slowly you start itching and have wheals all over your hands and arms. Again the near immediate response. Your immune system is after that interloper.

These two examples show how this protector of our lives can makes us worse off. It carpet bombs any attacker.

The NY Times notes[1]:

Another recent paper found that 30 percent of patients experienced “interesting, rare or unexpected side effects,” with a quarter of the reactions described as severe, life-threatening or requiring hospitalization. Some patients have died, including five in recent months in clinical trials of a new immunotherapy drug being tested by Juno Therapeutics Inc. The upshot, oncologists and immunologists say, is that the medical field must be more vigilant as these drugs soar in popularity. And they say more research is needed into who is likely to have reactions and how to treat them. “We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient to side effects. The woman’s immunotherapy drugs had successfully “melted away” her cancer, he said, but some weeks later, she got cold and flulike symptoms and died in the emergency room from an inflammatory response that Dr. Timmerman described as “a mass riot, an uprising” of her immune system. “We’ve heard about immunotherapy as God’s gift, the chosen elixir, the cure for cancer,” he said. “We haven’t heard much about the collateral damage.”

 

Unlike chemotherapy, immunotherapy can be long lasting. For example, the CAR-T cells which we have discussed are the patient's cells genetically engineered to recognize cell surface markers and when seen destroy the cancer cell. That would be fine if and only if the cells destroyed are cancer cells. However, there may be unintended consequences. First, there may be other cells which we do not yet fully understand that express the same or similar surface marker. They then also become targets. Second, and this is an issue, is that the process of destruction may have a lot of surrounding cells getting mascaraed, due to the released cytokines. This is collateral damage. Third, the collateral damage must be gotten rid of and this is part of the function of the immune system and this may be some positive feedback loop resulting in a set of catastrophic systemic failures.

Unlike chemotherapy, which is some chemical which kills certain types of cells, say rapidly reproducing ones, thus killing cancers as well as say hair. Immunotherapy may be long lasting if not permanent. You just can't stop administering it. Once started it may last forever, or at least until the patient dies. However, some recent work demonstrates that T cells do get "exhausted".[2]  The authors note:

During cancer or chronic infection, T cells become dysfunctional, eventually acquiring an “exhausted” phenotype. Immunotherapies aim to reverse this state. Using a mouse model of chronic infection, two studies now show that the epigenetic profile of exhausted T cells differs substantially from those of effector and memory T cells, suggesting that exhausted T cells are a distinct lineage (see the Perspective by Turner and Russ). Sen et al. defined specific functional modules of enhancers that are also conserved in exhausted human T cells. Pauken et al. examined the epigenetic profile of exhausted T cells after immunotherapy. Although there was transcriptional rewiring, the cells never acquired a memory T cell phenotype. Thus, epigenetic regulation may limit the success of immunotherapies.

However, there is an explosion of new markers and CAR-T cell targets. Juno Therapeutics lists some of the surface targets which their therapeutics address[3]. They are:

CD19… a cell surface marker for lymphocytes that is present on most B cell malignancies, including acute lymphoblastic leukemia and various subtypes of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma.

WT-1: …high-affinity TCR T cell product candidate targets WT-1, an intracellular protein that is overexpressed in a number of cancers, including adult myeloid leukemia, or AML, and non-small cell lung, breast, pancreatic, ovarian, and colorectal cancers.

CD22…Like CD19, CD22 is a cell surface marker for lymphocytes that is present on most B cell malignancies, including acute lymphoblastic leukemia and various subtypes of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma.  Importantly, CD22 expression has been shown to be maintained in acute lymphoblastic leukemia that has lost CD19, making anti-CD22 CAR T cells a potential combination or follow on therapy for CD19 CAR T cells.

L1-CAM…also known as CD171, is a cell-surface adhesion molecule that plays an important role in the development of a normal nervous system. It is overexpressed in neuroblastoma, and there is increasing evidence of aberrant expression in a variety of solid organ tumors, including glioblastoma and lung, pancreatic, and ovarian cancers. Our L1CAM product candidate was originally developed at SCRI.

MUC-16 / IL-12…a protein overexpressed in the majority of ovarian cancers, but not on the surface of normal ovary cells. CA-125 is a protein found in the blood of ovarian cancer patients that results from the cleavage of MUC-16. CA-125 levels in the blood are a common test for ovarian cancer progression because they correlate with cancer progression. Our MUC-16/IL-12 product candidate, which was originally developed at MSK, has a binding domain that recognizes an extracellular domain of MUC-16 that remains following cleavage of CA-125.  Our MUC-16/IL-12 product candidate is our first development candidate that uses our “armored” CAR technology.

ROR-1…a protein expressed in the formation of embryos, but in normal adult cells its surface expression is predominantly found at low levels on adipocytes, or fat cells, and briefly on precursors to B cells, or pre-B cells, during normal B cell maturation. ROR-1 is overexpressed on a wide variety of cancers including a subset of non-small cell lung cancer, triple negative breast cancer, pancreatic cancer, prostate cancer, and ALL. It is expressed universally on B cell chronic lymphocytic leukemia and mantle cell lymphoma. Our ROR-1 product candidate was originally developed at FHCRC.

One major concern is that of targeting the right cell. We assume that we can identify a specific cell by its unique surface marker. We design a specific immune targeting mechanism that goes after that cell. But if we believe in the stem cell theory of cancer, we more than likely have not targeted the stem cell. We have targeted some of it proliferations but not control elements. In fact, I would be willing to bet we have not targeted the stem cell. Thus, any immunotherapy may just make cancer a chronic illness but would not be curative. One then would be concerned by the continuing mutations.

Immunotherapy is a derived or indirect therapy. It is derived from examining how cancer cells are different, based upon surface markers. It is indirect because it deals with a secondary effect of the failing cell. It does not care what the problem is inside the cell but just that it has a different cell marker. In contrast the pathway methods whereby we know what pathway element is defective addresses a specific direct defect. This is a directed therapy.

Immunotherapy has a wealth of tools. T cells, NK cells, CAR-T cells Mabs, IL variations and the likes. To a degree, they are all a step up from chemotherapy but do not necessarily represent a panacea. There are two things we must do. First identify the stem cell and its characteristics. Second, eliminate the stem cell or fix the genetic fault. Until then we will always have the unintended consequences.

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[1] http://www.nytimes.com/2016/12/03/health/immunotherapy-cancer.html?hpw&rref=health&action=click&pgtype=Homepage&module=well-region&region=bottom-well&WT.nav=bottom-well

 

[2] http://science.sciencemag.org/content/354/6316/1165

[3] https://www.junotherapeutics.com/pipeline/clinical/