Transfusion | 2019
A monthly roundup of key articles in other journals
Abstract
Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Ghorashian S, Kramer AM, Onuoha S, et al., Nat Med 2019;25:1408-14. Decreasing the binding affinity of CD19 chimeric antigen receptor T cells (CAR T cells) improves persistence and antitumor activity in cell culture, in a mouse model, and in a clinical trial of advanced relapsed refractory pediatric B cell acute lymphoblastic leukemia. Enthusiasm for CAR T cells continues to rise, but their effectiveness has been limited by adverse events, poor persistence, and high rates of relapse. Efforts to address these limitations include tweaking structural design features to improve outcomes. Here, Ghorashian et al. explored the relationship between CAR T cell binding affinity to the CD19 target antigen and T cell responses. The authors designed a single-chain variable fragment CD19 CAR T (“CAT”) with 40-fold lower affinity than FMC63, a high-affinity CAR T cell commonly used in clinical studies. They then compared CAT to FMC63 in a CD19-expressing cell line and found that CAT demonstrated greater cytotoxicity, higher antigen-specific proliferation, and increased induction of TNF-α secretion. In a mouse model, CAT decreased cancerous cell growth, tumor size, and the number of cancer cells in the bone marrow more effectively than FMC63. CAT was also more effective at inducing TNF-α, Bcl-2, and CD127. In a small clinical trial of advanced relapsed refractory pediatric B cell acute lymphoblastic leukemia (CARPALL, NCT02443831), patients (n = 14) were treated with CAT. The target dose of 10 cells/kg body weight was achieved for 12 patients. Robust CAT expansion (Cmax > 50,000) was detected in the blood and bone marrow in 12 patients (86%) and expression persisted throughout the follow-up period in 11 patients (median 14.4 months). Maximum expansion occurred 14 days post-infusion at which point 41% of T cells were CAT+. By the third month post infusion, 12 patients (86%) had achieved complete molecular remission. Six patients relapsed, only one with CD19+ disease. One patient developed a cytotoxic response to CAT. At the 1-year mark, overall survival was 63% and event-free survival was 46%. Median duration of morphological remission was not reached; molecular remission median was 7.4 months. Five patients (36%) remained disease-free with persistent CAT expression at the last follow-up. Side-effects were generally mild: cytokine release syndrome was detected in 13 (93%) patients, however none required tocilizumab or were admitted to the ICU. Cytopenias were common, however the underlying drivers were unclear given the cohort’s history of chemotherapy treatments and lymphodepletion. Low-affinity CAT demonstrated durable in vitro and in vivo proliferation and antitumor activity. Amongst the hundreds of CAR T cell therapeutics currently in various stages of development, this is only the second (after tisagenlecleucel) shown to persist beyond 2 months. Moreover, CAT performed significantly better in measures of both expansion and accumulation than published results for tisagenlecleucel, without increasing expression of proinflammatory cytokines. The favorable safety profile is also promising, however patients in this study had low tumor burden. Next steps should include testing CAT in a broader range of patient subtypes.