Chimeric antigen receptor (CAR) T cells have met success in the clinic led by Carl June's group at University of Pennsylvania, Michel Sadelein's team at Memorial Sloan-Kettering, Steven Rosenberg at the NCI, and Malcolm Brenner's group at Baylor College of Medicine, among others around the world. Partnerships have been formed between Novartis, Juno, Kite, and Celgene, respectively to translate technologies from academia to industry. While the therapy has significant benefits in achieving complete remission in the some patients, there are still two main draw backs outside of anti-tumor efficacy that could be solved and make for a better therapy:
1. Risk of cytokine storm following immediate infusion of cells into the patient via recognition of tumor cells
2. After clearance of tumor, on-going response against antigen on normal tissues resulting in chronic inflammation, and/or their complete removal in the case of B cells and CD19
Currently, the first problem is solved by supportive care in the ICU, which is not ideal since the toxicity carries significant risks from patient to patient, and indeed some patients have died in trials. In the CD19 trials, the administration of an IL-6 antibody was required to prevent symptoms of systemic shock. For the second problem, steroids have been shown to treat autoimmunity from CAR T cells in limited cases, but this situation could continue to become worse as CAR T cell persistence improves. In the CD19 trials, complete removal of normal B cells is observed. In order to treat this status, intravenous immunoglobulin (IVIG), pooled from healthy human donors, can be administered into patients to supplement their lost B cells producing antibodies. While many investigators think the B cell aplasia isn't a problem since we have a current treatment for the disease, I would argue that giving someone a costly disease, on the magnitude like having a lysosomal storage disorder, isn't the solution either. Obviously, chronic antibody replacement is a better problem to have than death due to cancer, but immunotherapy should still attempt to solve both problems.
Herein, I highlight an intriguing solution for the current CAR T cell problems that is on hand at Bellicum Pharmaceuticals. As a disclaimer, I have no knowledge of Bellicum's inner workings beyond their site, and am not a stock holder of the company. I merely think their technology is interesting and there is room for a potential collaboration between Bellicum and Novartis, Juno, Kite, or other CAR T cell players in biotech.
In general, chimeric antigen receptor signaling is broken down into two parts: 1) zeta chain signaling mimicking TCR activation and an essential first trigger 2) auxiliary costimulation domains (CD28, 41BB, OX40) that deliver cytokine secretion and proliferation signals
The heart of Bellicum's company is its inducible dimerization platform, which they have exploited for many uses. An unpublished use that I came across on their site is splitting about the CAR into two parts, which they name the "GoCAR-T Technology" (see image below). The first has an antibody targeting tumor antigen linked to zeta chain, like normal CARs. The second has no ectodomain, but instead is completely intracellular with the costimulatory domains linked to a drug regulated dimerization domain. The theory is that T cells could recognize and kill tumors through antibody recognition, but their potency, proliferation, and persistence would be regulated by an oral drug administered to the patient.
|Taken from Bellicum Pharmaceuticals website|
Why does this matter you ask and what is the advantage? Let us return back to the two central problems of the CAR T cell trials, applying Bellicum's technology to it. For example, one could administer CD19 CAR T cells, but regulate with a small molecule drug the degree of their cytokine secretion and proliferation, thereby preventing the cytokine storm scenario seen in many CAR T cell trials. A physician could add more drug gradually to increase efficacy over time. For the second problem, once the tumor is satisfactorily removed, complete withdrawal of drug would lead to T cells that just have zeta chain signaling only. They could still attack host B cells, but the lack of costimulation would greatly reduce their potency and in the experience of previous trials, the CAR T cell numbers would drop over time and the T cells perhaps become somewhat anergic. This would allow a steady state population of B cells to repopulate, or prevent tissue damage in the setting of other CAR targets. This differs greatly from June's data, where a large population of CAR T cells persist, permanently attack and removing any new B cells (one hypothesis is that this off-target killing actually sustains the anti-tumor response and T cell persistence). If a tumor relapse ever did happen, drug could be administered again to revive the remaining CAR T cells to join the fight again at the tumor.
Bellicum appears to be applying the GoCAR-T cell technology first to PSCA and prostate cancer, but there appears to be wide application to other immunotherapy targets. Of course, Bellicum is also pushing forward it's inducible Caspase-9 death switch for CAR T cell therapy, with a program targeting CD19. The death switch is able to avoid side effects, but has the downside of eliminating the cells, as opposed to temporarily attenuating them and later turning the cells back on, which is beneficial at multiple stages of therapy as mentioned above. Given the cost and expense of administering multiple cell products, it seems advantageous to have regulation of the initial cell product that doesn't cause cell death. Regardless, this technology seems ripe for a potential licensing deal with another player in the CAR industry to earn Bellicum more cash. The idea of pharmacological regulation of T cells could be a game changer in the burgeoning field.