Using Our Own Immune System as a Weapon Against Cancer – Highlights of the Talk with CAR T Cell Therapy Pioneer Dr. Carl June Discussing the New in Cancer Breakthrough
FDA approved the first gene therapy treatment in the US recently in August this year. This new therapy called the CAR T cell therapy, uses body’s genetically engineered immune system to hunt and kill cancer cells. Named “Kymriah” by Novartis, this therapy was approved for treatment of an aggressive type of Leukemia (specifically Acute Lymphoblastic Leukemia) in children and young adults up to 25 years of age who did not respond to other treatments.
Dr Carl June of University of Pennsylvania, the pioneer of this breakthrough, shared with us at CureTalks, about how this #newincancer therapy is going to change the way we fight cancer. CLICK HERE TO LISTEN TO THE TALK .
Dr. June started his career as a Navy Oncologist. Sharing some eureka moments from his CAR T journey, he told us, he began to work in 1980s around graft vs host disease which occurs after bone marrow transplants, and ended up researching on how “could we have the same benefits of a bone marrow transplant, but not have to do the transplant, and actually use your own immune system as the weapon.”
He rejoices, “And over about 25 or 30 years that has now culminated in FDA approved therapy called CAR-T cells.”
Here are the highlights of his talk on CAR T cell Therapy
- Immune therapy is precisely targeted at just the cancer cells. It does not cause off-target effects that standard chemotherapy and radiation cause. Off target effects are effects seen when the therapy is killing cells but not helping a patient get better. Examples include nausea, vomiting, to very severe issues like liver failure, heart failure, bloody diarrhea etc. On target effect is – side effects related to actually when the therapy is killing the tumor, and when the patient is actually benefitting from it. For example, high fever is an on target side effect of CAR T cell therapy.
- There are many different antigens or molecules on tumor cells. T cells evolved to kill cells that have new DNA in them. For example a virally infected cell gets killed by T cells because it has new viral DNA in it. A tumor, is a mutation which changes the DNA in the patient’s tumor cell. T cells can sense that and can kill the tumor cells, because it is in a way very similar to an infection. But, since the tumor cell remain very much like a normal cell from the immune system’s point of view, T cell does not attack it rigorously enough. CAR T cell technology is used to make a very strong recognition or binding of the T cell to the tumor cell, so that T cells can kill without fail.
- It is possible to make T cells, that ask before killing. The CAR T cells we have right now are always in an “on” state and kills all cells that express the target antigen, say CD19, on them. In the future it is possible to make T cells using transistor logic, or Boolean gates logic so that these cells can act on – AND, OR, NOT algorithms. So these T cells would first check if a cell expresses unique combinations of antigens on their surface. For example two antigens A and B, or just expresses one antigen A, and then can chose to kill only those cells which express both antigens. This technology can make the T cells tumor specific killers.
- Use of HIV and CRISPR technology is going to be used in a complementary way. Using Lenti viral vectors or HIV is a method to bring in new genes in to a cell. CRISPR is another technology, which can change target genes, by cutting desired DNA sequences precisely, to achieve a benefit in the patient.
- Myeloma patients do not express CD19 on their myeloma cells. However myeloma cells may be like a “chameleon”, and change the molecules on their surface at different times during their lifespan. This could be the reason why CD19 targeted CAR T cells may be effective in some myeloma patients.
- CAR T cell booster? Some early stage trials are in process, testing if boosting CAR T cells, either by re-infusing and maybe by giving maintenance infusions may benefit patients. There is an ongoing trial in Seattle where they are vaccinating patients to boost up the CAR T cells. So they are vaccinating with CD19 antigen, and then that would be a way then, without having to re-infuse the CAR T cells where potentially, one could maintain the effect in those patients who lose effective CAR T cell engraftment.
- Possibility of off-the-shelf CAR T cells? CAR cell therapy is a form of transfusion medicine, where instead of red cells or platelets, T cells are transfused. Off the shelf, CAR T cell would happen when it won’t be the patient’s own T cells, and if that could happen, it would make the process much simpler. Some hospitals are now testing these off the shelf cells in very early stage trials, and a few pharma and biotech companies are working on making off the shelf T cells for patients with leukemia.
- CAR T technology is very different from Sipuleucel T approved for prostate cancer treatment. Sipuleucel T is a vaccine made of dendritic cells. In case of vaccines, it takes time for the immune response to occur. The patient has to develop an immune response, and then later they are protected. With CAR T cells it is called active immunotherapy. They start working the minute they are infused. And you do not have to wait. Moreover, T cells live for years and years, they have a half-life of more than 10 years. Dendritic cells only live 3-4 days, and then what they need is to then trigger a long lasting immune response in the patient. So they are complementary therapies, and are very different approaches – one being a vaccine approach using dendritic cells, and one being active therapy using T cells that has long life.
- There are ongoing CAR T cell therapy trials in AML. There is one beginning at the National Cancer Institute in Bethesda, in 2018, to where the CAR T cell trial targeting CD33. There is another one targeting CD123 for AML, which has opened in City of Hope in Los Angeles, and will be open at University of Pennsylvania. Another one targeting CD33 for AML will start in 2018 at the University of Pennsylvania.
Dr. June says “immunotherapy had been an idea for more than a 100 years, to try to treat cancers. So the ideas are not new…, but we did not have initially the tools that were good enough to make it work. Now we have through all years and years of basic research on the immune system and ways to modify genes. In fact, in the entire human genome sequencing effort has had a major benefit in this cancer immunotherapy…..all this can be done now because we have better tools to get the job done.”
We wish Dr. June and his team success in their future research on CAR T cell therapy in treatment of diseases other than leukemia.