Abstract
Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11-PIK3R3, found in a CD4cutaneous T cell lymphoma, that augments CARD11-BCL10-MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.
Overview
- The study focuses on improving the efficacy of adoptive T cell therapies for cancer by identifying mutations from human T cell cancers that can enhance T cell signaling, cytokine production, and in vivo persistence in tumors. The hypothesis being tested is that these mutations can be co-opted to improve T cell therapies. The methodology used includes screening 71 mutations from T cell neoplasms and testing their effects on T cell signaling, cytokine production, and in vivo persistence in tumors. The primary objective of the study is to identify a gene fusion that can enhance the anti-tumor efficacy of therapeutic T cells in immunotherapy-refractory models in an antigen-dependent manner. The study aims to explore the extremes of T cell biology and discover how solutions derived from the evolution of malignant T cells can improve a broad range of T cell therapies.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions, specifically the effects of 71 mutations from T cell neoplasms on T cell signaling, cytokine production, and in vivo persistence in tumors. The results identify a gene fusion, CARD11-PIK3R3, found in a CD4cutaneous T cell lymphoma, that enhances CARD11-BCL10-MALT1 complex signaling and anti-tumor efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. The study finds that CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation, underscoring its potential to be deployed safely. The key findings of the study suggest that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from the evolution of malignant T cells can improve a broad range of T cell therapies.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice, as they suggest that exploiting naturally occurring mutations can improve the efficacy of adoptive T cell therapies for cancer. The study identifies a gene fusion, CARD11-PIK3R3, that enhances the anti-tumor efficacy of therapeutic T cells in immunotherapy-refractory models in an antigen-dependent manner. The study also highlights the potential of CARD11-PIK3R3 to be deployed safely, as CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. The study suggests future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches. For example, future studies could investigate the effects of other gene fusions or mutations on T cell signaling, cytokine production, and in vivo persistence in tumors, and explore their potential to improve T cell therapies for cancer.