On April 8, 2022 2seventy bio, Inc. (Nasdaq: TSVT), a leading immuno-oncology cell therapy company, reported that it 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) (Free AACR Whitepaper) Annual Meeting 2022 in New Orleans, LA (Press release, 2seventy bio, APR 8, 2022, View Source [SID1234611707]). These data will be presented in a poster session (poster #581) on Sunday, April 10, 1:30-5:30 PM CT.
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"While anti-CD19 CAR T cell therapies have improved outcomes for relapsed and/or refractory B cell non-Hodgkin lymphoma (B-NHL) patients, 60-70% of those treated with currently available CAR T cell therapies do not achieve a long-term remission, highlighting the need for more treatment options," said Philip Gregory, D.Phil., chief scientific officer at 2seventy bio. "bbT369 was purposefully designed to potentially address known mechanisms of anti-CD19 CAR T cell therapy failure. We are excited to present the results of preclinical studies that demonstrate the anti-lymphoma activity of bbT369 and suggest that bbT369 has the potential to overcome failure modes of anti-CD19 CAR therapies, supporting a first-in-human trial (CRC-403) to evaluate initial safety and efficacy in B-NHL patients."
bbT369 is an innovative therapeutic approach designed to address known limitations of anti-CD19 CAR T cell therapy
Emerging data1-2 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 TGFβ, 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.
Results are detailed in an E-Poster here, available to registered attendees on the AACR (Free AACR Whitepaper) website through Wednesday, July 13.
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.
About bbT369
bbT369 is an investigational dual-targeting CAR T cell therapy with a gene edit for patients with relapsed and/or refractory B-NHL.
bbT369 has three layers of innovation, purposely designed to address the potential mechanisms of anti-CD19 CAR T cell therapy failure: dual targeting (CD79a/CD20), split co-stimulation signaling technology, and a gene edit to remove the function of CBLB.
In December 2021, the FDA cleared the Investigational New Drug (IND) application for bbT369.
The clinical development program for bbT369 includes the Phase 1/2 CRC-403 study (NCT05169489). Safety and potential efficacy of bbT369 in patients with specific subtypes of relapsed and/or refractory B-NHL will be assessed, including patients who relapsed after CD19 CAR T cell therapy as well as patients who are CAR-naïve.
bbT369 is not approved for any indication in any geography.
About megaTAL technology
megaTALs are single-chain enzymes that combine the natural DNA recognition and cleavage processes of Homing Endonucleases (HEs) with the modular DNA binding properties of transcription activator-like (TAL) effectors. This protein fusion architecture allows the generation of highly specific and active nucleases in a compact format compatible with all current viral and non-viral cell delivery methods.