HLA Shapes CAR-T Cancer Immunotherapy Response

Essentially, T cells are collected from cancer patients and in a laboratory setting re-engineered to express CARs. The re-engineered T cells that express these special CARs are then returned to the patient via infusion and recognize and bind to antigens on cancer cells. The essential steps involved in CAR-T action are illustrated in Figure 3.

Pinpointing cancer-specific antigens remains challenging. Ideally, the most optimal CAR would be a type of receptor protein that recognizes and binds to an antigen expressed ONLY on tumor cells but NOT on normal immune cells. It is, however, extremely challenging to identify tumor-ONLY antigens. So far, the FDA has approved 6 CAR-T therapies that engineer two types of chimeric receptor proteins that respectively target CD-19 molecules and BCMA (B-cell maturation antigens) on leukemia and lymphoma cells. (Note: CD19 is a protein-coding gene. CAR-T uses CD19 molecules or BCMA antigens as targets. BCMA is not a gene, but rather a protein that is encoded by the TNFRSF17 gene.) In light of the incompleteness of tumor-ONLY antigen by CD-19, for example, a portion of the patient’s normal B cells could also be destroyed by anti-CD-19 CAR T therapy. That said, this therapy has been found to have maximal tolerability in patients and has demonstrated great success in eliminating cancer cells. It is highly hoped that guided by artificial intelligence (AI), better CAR-T can be produced to benefit cancer patients.

There is not yet a clear-cut roadmap when it comes to how HLA shapes CAR-T therapeutic response. Aspects that lead to an ultimate roadmap are obtained through clinical observations. For example, in one of the NIH clinical trial studies patients with metastatic cancers were treated with their own T cells⁶ - cells engineered to express a cancer antigen (harboring a devastating mutation on a major oncogene called KRAS). In other words, the engineered T cells preferentially targeted cancer cells that expressed the KRAS mutation. One patient responded to the therapy and experienced tumor remission. However, the relapse of the tumor took place at a later time point. As mentioned in a previous topic section: Upon sequencing of the patient’s tumor DNA, it was revealed that in contrast to an intact HLA-C allele termed HLA-C*08:02 (as verified prior to the KRAS-targeting T cell therapy), the same allele was lost in the tumor. A plausible explanation of this allelic loss was attributed to the tumor’s remarkable capacity for genetic alteration in response to the treatment.