Most patients with CD19+ treatment-refractory acute lymphoblastic leukaemia (ALL) respond to anti-CD19 chimeric antigen receptor (CAR) T cells. Nonetheless, adverse events can limit the utility of this approach. Now, data from a phase I study indicate that CAR T cells with a novel single-chain variable fragment (scFv) with a lower affinity for CD19 might overcome these limitations.
Researchers generated novel anti-CD19 scFv fragments using a CAT131E10 hybridoma (CAT) and conducted initial in vitro comparisons of this scFv versus the FMC63 scFv, which is included in the FDA-approved CAR T cell therapy tisagenlecleucel. CAT scFvs were found to have a 40-fold lower affinity for CD19 than the FMC63 scFv, largely owing to a much faster rate of antigen dissociation. CAT-CAR T cells also had greater levels of in vitro antigen-specific toxicity and proliferation, and these findings were confirmed in vivo.
The safety and efficacy of CAT-CAR T cells was then investigated in 17 patients with high-risk treatment-refractory CD19+ ALL. Among 14 patients who received an infusion, 12 had a molecular complete response after 3 months (overall response rate 71%). The expansion of CAT-CAR T cells was approximately threefold higher than that reported for tisagenlecleucel at 28 days. The 1-year overall survival and event-free survival was 63% and 46%, respectively. CAT-CAR T cells were detectable at the latest follow-up appointment in 11 of 14 patients.
Notably, no patient required tocilizumab or intensive care for grade ≥3 cytokine-release syndrome (CRS), although 3 patients required symptom management for CRS-related hypotension. Similarly, only one patient had a grade ≥3 neurotoxicity (leukoencephalopathy) and this was attributed to use of fludarabine for lymphodepletion. Grade ≥3 haematological toxicities, however, were common, including neutropenia in six patients and thrombocytopenia in three.
These data suggest that a lower-affinity anti-CD19 CAR enables robust expansion, with fewer serious adverse events. These findings warrant further evaluation.
Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019)
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Sidaway, P. CD19 affinity — is lower also better?. Nat Rev Clin Oncol 16, 661 (2019). https://doi.org/10.1038/s41571-019-0278-1
International Journal of Hematology (2020)