Breaking the "Right" Gene promotes response to CAR-T cell therapy
One of the main problems with immunotherapy is that some people respond better than others to treatments. A patient’s striking response to CAR (Chimeric Antigen Receptor)-T cell based therapy in a recent clinical trial has encouraged researchers to go into the reasons for this unexpected success. There is something “broken” in this patient, which allowed CAR-T cells to induce remission of leukaemia: a gene called TET2 does not do its job. How does it affect response to treatment?
CAR-T cells are the T-cells of the patient isolated from its bloodstream, engineered with a super receptor targeting cancer cells and re-infused back. One challenge in this strategy, though, is the limited expansion and persistence of the injected cells.
In this clinical trial, patients were treated with CAR-T bearing a receptor against CD19, expressed on the surface of B-lymphocytes: this is a marker for leukaemia diagnosis and a target for immunotherapies against neoplastic lymphocytes. The patient did not respond immediately to treatment, but only two months after the second infusion, when peak of CD19 CAR-T cells was detected in his bloodstream.
This was curious, because tumor regression usually occurs earlier in responders, within a month from the treatment. Researchers found that the cells at the peak concentration were a clonal population, which means that they all descended from a single cell that has demonstrated massive expansion.
What was so special in this cell?
To figure it out, we must step back to when the DNA sequence encoding the CAR against CD19 was introduced in the patient’s T cells. A common strategy is to use viral vectors to genetically modify immune cells, which can be retroviruses or lentiviruses. The gene of interest is first inserted in the viral genome; then cells are infected with the engineered virus, which integrates its own genome (and therefore the gene we put inside it) in the host cell DNA. The main issue is that the sequence can end up anywhere in the genome: there is no control over the site of insertion.
In this “fortunate” cell, the CAR sequence happened to insert in a gene called TET2, leading to its disruption. This is crucial as TET2 promotes an epigenetic modification that regulates the maintenance and proliferation of T cells and in fact, it is considered as a tumor suppressor, a brake to uncontrolled expansion of neoplastic T cells. Humans present two copies, or alleles, for each gene, including TET2, but this patient has a mutation on the other allele: so he ended up with no functional TET2 protein!
Further experiments showed that T cells lacking TET2 produced a larger amount of perforins and granzymes, responsible for tumor cell lysis, and entry a cellular state called “central memory”, which stops the cells from becoming dysfunctional or “exhausted”. Of course, because TET2 is a tumor suppressor gene, the patient was kept under careful observation.
Researchers conclude that there is an epigenetic pathway shaping immune response that can be targeted to improve the efficacy of immunotherapy and, more surprisingly, that the progeny of a single CAR T cell mediated a potent anti-tumor effect. Vitares is on the side of the scientists who work hard to elucidate the mechanisms of variability in patients’ response to immunotherapy, hoping to optimize the existing therapies and allow as many people as possible to benefit from them.
Fraietta, J.A., et al. (2018). Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312.