Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor–modified T cells

A CD19 chimeric antigen receptor–modified T cell product with defined composition has potent antitumor activity. Standardizing the CAR assembly line Chimeric antigen receptor (CAR)–modified T cells are engineered to recognize specific tumor antigens. They have shown promising results in clinical trials, primarily in leukemia so far, but it has been difficult to predict therapeutic efficacy and toxicity for individual patients. To address this issue, Turtle et al. treated non-Hodgkin’s lymphoma patients with CAR-T cells prepared from strictly defined subsets. By carefully controlling the ratio of CD4 to CD8 T cells, the authors were able to identify some of the treatment characteristics that correlate with therapeutic response and toxicity, including the role of the drug regimen used for lymphodepletion before CAR-T cell treatment. CD19-specific chimeric antigen receptor (CAR)–modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4+/CD8+ ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin’s lymphoma after cyclophosphamide (Cy)–based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4+/CD8+ ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.