Frontiers in Cancer Immunotherapy: A Critical Evaluation & Meta-Analysis of CAR-T Cell Therapy

Abstract

For decades, immuno-oncology has sought to improve the landscape of cancer treatment without many tangible results. Chimeric antigen receptor T cell therapy (CAR-T), which redirects the cytotoxic capability of T lymphocytes towards a tumor target using a synthetic receptor, offers a promising new platform for cancer immunotherapy. The ability of CAR-T to induce sustained remissions in hematological malignancies has already been demonstrated in early clinical trials. However, results have been variable, and it remains unclear how best to implement this complex therapy. In this thesis, to better understand optimal approaches for design, delivery, and toxicity management, I undertook a meta-analysis of phase I/II clinical trials for CAR-T targeted against the B cell antigen CD19 in leukemias and lymphomas. In 23 trials from 2010 to 2017, the efficacy of this treatment was confirmed with an overall response rate of 0.70 (95% CI: 0.57 – 0.80). Patients who received CAR-T in combination with a preconditioning regimen of chemotherapy experienced nearly a 100% increase in efficacy. Cytokine release syndrome (CRS) was more prevalent in positive responders, suggesting a correlation between efficacy and toxicity. CRS also associated significantly with neurological toxicities, a side effect whose etiology has not yet been elucidated. This study represents the largest CAR-T meta-analysis to date, establishing associations between clinical parameters and outcomes that have not been previously examined in meta-analyses. As physician- scientists seek to develop this therapy for solid organ tumors, these findings could help shape the molecular design and clinical optimization in future iterations of CAR-T therapeutics.