Abstract
Anti-CD19 CAR-T cells with human binding domains were safer in B-cell lymphoma in a phase I trial.
Major Finding: Anti-CD19 CAR-T cells with human binding domains were safer in B-cell lymphoma in a phase I trial.
Concept: Neurotoxicity of the novel CAR-T cells was reduced compared to conventional anti-CD19 CAR-T cells.
Impact: Anti-CD19 CAR-T cell activity may not always entail neurotoxicity; further optimization is feasible.
CAR-T cells targeting CD19 produce dramatic, durable responses in some patients with B-cell lymphoma; however, potentially life-threatening side effects, such as cytokine release syndrome and severe neurotoxicty, remain obstacles. In a phase I, first-in-human clinical trial, Brudno and colleagues evaluated the safety and efficacy of treatment with T cells expressing the novel anti-CD19 CAR Hu19-CD828Z, which is characterized by the human-CD19 origin of its single-chain variable fragment (scFv) and CD8α-derived hinge and transmembrane domains. The rationale was that a human scFv might be less immunogenic than a mouse scFv, as is typically used, and that the combination of the CD8α hinge and transmembrane domains with a CD28 costimulatory domain could reduce cytokine release. In the trial, which enrolled 20 patients with B-cell lymphoma who had undergone at least one (median four) round of prior therapy, the complete response (CR) rate was 55% (11 of 20 patients), and the duration of response in patients who experienced a CR ranged from 17 to 35 months, demonstrating the treatment's activity in B-cell lymphoma. Neurologic toxicity with Hu19-CD828Z CAR-T cell infusion was rare, becoming severe in only 5% (1 of 20) of patients, in stark contrast to the severe neurotoxicity seen in 50% (11 of 22) of patients in a trial of FMC63-28Z anti-CD19 CAR-T cells (which include murine binding domains) conducted at the same center by the same group using a similar protocol. Compared with patients treated with FMC63-28Z CAR-T cells, patients treated with Hu19-CD828Z CAR-T cells had lower serum levels of immunologic proteins, such as granzyme A, IL2, TNFα, and IFNγ, and the only patient in the Hu19-CD828Z–treated group who exhibited severe neurotoxicity had elevated serum levels of some immunologic proteins compared with the rest of the Hu19-CD828Z cohort. This work demonstrates that CD19-targeted CARs are not inherently highly neurotoxic and that incorporation of CD28 domains is also not necessarily linked to toxicity. Notably, clinical development of Hu19-CD828Z CAR is continuing, now in combination with an anti-CD20 CAR.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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