Introduction: Unlocking the Potential of CAR-T Therapy in Solid Tumors
Chimeric antigen receptor (CAR) T cells have successfully treated relapsed/refractory B-cell neoplasms and multiple myeloma but have limited efficacy in solid cancers. The main challenges in solid tumors are the absence of highly-specific cancer cell-surface targets, leading to on-target/off-tumor toxicity and issues with T cell expansion and persistence due to antigen inaccessibility and the immunosuppressive tumor microenvironment.
Messenger RNA (mRNA) vaccines, known for their success against infectious diseases, are now being explored in cancer research. These vaccines utilize mRNA technology to stimulate the immune system against cancer cells. In cancer immunotherapy, mRNA vaccines offer a novel approach, holding promise for more effective and targeted treatments.
Targeting Claudin 6 for Solid Tumor Treatment
The phase 1 BNT211-01 trial explored the use of Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells, along with an amplifying RNA vaccine (CARVac), in treating relapsed or refractory solid tumors. CLDN6, a primitive tight junction protein, is a promising target for immunotherapy due to its high and specific expression in many solid tumors. Yet, suppressed expression in healthy adult tissues makes it an ideal immunotherapy target.
The trial focused on the safety and feasibility of this approach. Manageable toxicity was observed, with some patients experiencing cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome. The efficacy of the treatment was also notable, with an unconfirmed objective response rate (ORR) of 33% and a disease control rate of 67% in the evaluable patients. Notably, patients with germ cell tumors (GCT) treated at higher dose levels showed a higher response rate.
The study highlighted the potential of CLDN6 expression as a predictive biomarker, suggesting that higher levels of CLDN6 expression predict better treatment outcomes. This is significant as it could guide selection of patients most likely to benefit from CLDN6-targeted therapies.
This trial represents a significant step in using CAR-T therapies for solid tumors, a field where these therapies have historically faced challenges such as lack of specific cell-surface targets and poor expansion and persistence in the tumor microenvironment.