2seventy bio, Inc. will present preclinical data on bbT369, an investigational novel CD79a/CD20 dual-targeting CBLB gene edited CAR T cell therapy at the American Association for Cancer Research (AACR) Annual Meeting 2022 in New Orleans, LA. These data will be presented in a poster session (poster #581) on April 10, 1:30-5:30 PM CT. bbT369 is an innovative therapeutic approach designed to address known limitations of anti-CD19 CAR T cell therapy: Emerging data suggests several failure modes for anti-CD19 CAR T cell therapies, including loss or down-regulation of CD19 antigen, loss of co-stimulatory ligands on tumor cells, exhaustion of CAR T cells, and immunosuppressive microenvironments. bbT369 was purposely designed with three layers of innovation to address the potential mechanisms of anti-CD19 CAR T cell therapy failure: First, bbT369 targets a novel combination of antigens highly expressed in B cell lymphomas, CD79a and CD20. CD79a, a novel target, is a critical signaling component of the B cell receptor and CD20 is a known clinical target for lymphoma. The dual targeting of bbT369 may limit antigen escape as a mechanism of lymphoma relapse. Second, bbT369 is designed with a combination of a traditional 2nd generation CAR and an investigative “chimeric co-stimulatory” architecture (CCR-CAR), a split co-stimulation signaling technology intended to drive more robust T cell activation in response to either antigen compared with dual CAR designs. Third, cells are gene-edited with megaTAL™ technology to remove the function of CBLB, a known negative regulator of T cells. Removal of CBLB function may enable robust antigen-dependent CAR T cell expansion and allow cells to resist anergy and maintain activity in sub-optimal conditions for T cell activation. bbT369 demonstrates increased anti-lymphoma activity and duration of response in preclinical models: Increased tumor control was seen with bbT369’s CCR-CAR design compared to dual CAR designs, and cell killing was observed when bbT369 encountered either antigen. Compared with non-gene edited cells in different in vitro model systems, bbT369 demonstrated a lower threshold for stimulation, retained activity in the presence of the immunosuppressive factor TGFß, reduced reliance on tumor cell co-stimulation, and exhibited increased capacity for multiple rounds of tumor cell killing. bbT369 resulted in three-fold increased cell expansion and prevention of late relapses in B-NHL mouse models compared with a non-gene edited control. bbT369 outperformed CD19 CAR T cells in cell-based and mouse models, with increased IL-2 secretion and prolonged duration of tumor remission, suggesting bbT369 may have enhanced functionality compared with the other constructs. Infusion of first patients in Phase 1/2 study of bbT369 in B-NHL is anticipated in 2022: CRC-403 (NCT05169489), an open-label, multi-site Phase 1/2 dose-escalation study, is currently enrolling patients, and will assess the safety and potential efficacy of bbT369 in patients with relapsed and/or refractory B-NHL, including patients who relapsed after CD19 CAR T cell therapy as well as patients who are CAR-naïve. Initial assessment of feasibility of bbT369 drug product manufacturing and patient safety is expected in 2H 2022. The study will also serve as a proof-of-concept assessment of 2seventy bio’s proprietary megaTAL™ gene editing platform, dual-targeting strategies and split co-stimulation signaling technology.
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