On May 17, 2023 2seventy bio, Inc. (Nasdaq: TSVT), a leading immuno-oncology cell therapy company, reported new data featuring novel approaches combining the company’s platform CAR T cell and T cell receptor technology and unique cell therapy engineering capabilities to potentially enhance treatment potency in a range of cancers (Press release, 2seventy bio, MAY 17, 2023, View Source [SID1234631801]). The data were shared in three presentations at this year’s American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting in Los Angeles, California.
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"We’re excited to present new data related to our programs in acute myeloid leukemia, non-Hodgkin lymphoma and solid tumors," said Philip Gregory, D.Phil., chief scientific officer, 2seventy bio. "These presentations provide further evidence of our focus on generating potent and targeted anti-tumor activity while limiting toxicity through innovative approaches to controlling T cell responses. With this approach, we believe we can augment the tremendous potential of cell-based immunotherapy, with the goal of advancing next-generation treatments targeting a broad range of cancer types."
bbT369, a dual-targeted and CBLB gene edited autologous CAR T product for non-Hodgkin lymphoma, showed edit-driven enhanced activity in preclinical in vitro and in vivo models
bbT369 is 2seventy’s novel investigational CD79a/CD20 dual-targeting CBLB gene edited CAR T cell therapy for the treatment of patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). This preclinical study evaluated the role of the CBLB edit across multiple aspects of CAR T cell function compared to unedited controls. In the study, in vitro assays were designed to model known challenges to maximal CAR T cell activity within the tumor, such as chronic activation, antigen downregulation, and immunosuppression.
The data demonstrated that the CBLB gene edit significantly enhanced the activity of the bbT369 CAR T cells across each of the in vitro model systems tested.
bbT369 T cells also drove greater T cell expansion and durable tumor control compared with unedited controls in vivo using a xenograft NSG mouse model.
RESET, a novel TCR coupled antigen receptor architecture, showed targeting sensitivity and pharmacologically- controlled anti-tumor activity in models of acute myeloid leukemia
For some tumors, available target antigens lack ideal expression, necessitating improvements in targeting sensitivity, potency, control, and/or exhaustion mitigation to achieve robust anti-tumor efficacy. While classical CAR T cells require high levels of target antigen for maximum activity, the endogenous T cell receptor (TCR) is significantly more sensitive to low target antigen abundance. To address this gap, a novel receptor architecture called RESET (rapamycin-enabled, switchable endogenous TCR) was developed to more closely mimic TCR activation, thus potentially improving T cell killing of low antigen expression tumor cells. RESET combines the antibody-based targeting of CARs, the drug-regulated activity of the DARIC (a rapamycin-regulated CAR) technology and the natural signaling proficiency and inherent sensitivity of TCRs. The RESET receptor comprises two functional units that are designed to enable toggling of RESET T cells between inert and activated states through rapamycin-induced dimerization:
When challenged with low antigen density tumor cells in vitro, CD33-targeted RESET T cells (RESET33) were more potently reactive to CD33+ tumor cells after rapamycin dimerization, secreting approximately three times more cytokine than CD33-targeted regulated CAR T cells.
This enhancement was also observed in preclinical NSG mouse models in vivo, where RESET33 T cells more deeply controlled systemic CD33+ AML tumor models, providing a significant survival benefit in comparison to DARIC33 T cells.
A novel TGFβ switch receptor drove robust MAGE-A4 TCR anti-tumor activity with a favorable safety profile
Solid tumors frequently secrete TGFβ, a pleiotropic cytokine that suppresses T cell responses. To counteract the immunosuppressive effects of TGFβ within engineered T cells, a synthetic receptor (CTBR12) was developed to leverage an immunosuppressive cytokine to convert TGFβ binding into pro-inflammatory signaling events that enhance anti-tumor function:
T cells co-expressing a pairing enhanced MAGE-A4 TCR with the CTBR12 switch receptor demonstrated robust antigen-dependent responses that were significantly enhanced upon exposure to TGFβ, whereas MAGE-A4 TCR controls lacking CTBR12 were suppressed by this anti-inflammatory cytokine.
CTBR12 co-expression did not alter the safety profile of the MAGE-A4 TCR.
In two murine xenograft tumor models with abundant TGFβ, T cells co-expressing the MAGE-A4 TCR and CTBR12 both controlled tumors at T cell doses that elicited only minimal responses without CTBR12 co-expression and exhibited superior durability of response overall.
About SC-DARIC33
SC-DARIC33 is an investigational CD33-specific cell therapy that utilizes 2seventy bio’s proprietary Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T cell platform. SC-DARIC33 is designed as a regulatable, potentially first-in-class autologous T cell therapy and is now being studied at Seattle Children’s in a Phase 1 trial, PLAT-08 (NCT05105152), as a first-in-human investigation of the DARIC T cell platform in relapsed/refractory pediatric and young adult AML.
DARIC separates the antigen binding and signaling functions of a CAR, with the intent that these two components are brought together by the small molecule rapamycin, resulting in a functional CAR construct. In preclinical studies, SC-DARIC33 has shown robust drug-dependent anti-tumor activity (similar to CD19 CAR T controls). Importantly, SC-DARIC33 has been shown to be activated by low non-immunosuppressive concentrations of rapamycin in the blood and, when rapamycin is removed, DARIC returns to an inactive state. SC-DARIC33 tests the hypothesis that a pharmacologically regulated CAR can enable potent AML targeting while limiting toxicities associated with normal myeloid and myeloid progenitor cell targeting.
The investigation of SC-DARIC33 in the Phase 1 PLAT-08 study of pediatric and young adult AML patients and the scientific translation of these data are intended to establish the safety profile of SC-DARIC33 and evaluate feasibility of the reversable modulation (OFF-ON-OFF) of SC-DARIC33.
SC-DARIC33 is not approved for any indication in any geography.
About bbT369
bbT369 is an investigational dual-targeting CAR T cell therapy with a gene edit being evaluated for the treatment of patients with relapsed and/or refractory B-NHL currently being evaluated in a first-in-human Phase 1/2 trial (CRC-403 NCT05169489). bbT369 was purposely designed with three layers of innovation to address the potential mechanisms of anti-CD19 CAR T cell therapy failure, including dual targeting of CD79a/CD20, which is a novel combination of antigens highly expressed in B cell lymphomas, a split co-stimulation signaling technology intended to drive more robust T cell activation, and a gene edit to remove the function of CBLB, a known negative regulator of T cells.
In the 3L+ relapsed and/or refractory B-NHL setting, 60-70% of patients treated with commercially available CAR T cell therapies do not achieve a long-term remission, highlighting a significant unmet clinical need.
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 the MAGE-A4 Program
MAGE-A4 is a member of the MAGE family of cancer-testis antigens expressed in a number of solid tumor types. The program employs a highly potent TCR discovered in our MediGene collaboration that recognizes HLA-presented MAGE-A4 peptides and further enhances the potency of these re-directed T cells using our CTBR12 TGFβ "flip" receptor technology — which converts the immunosuppressive effects of TGFβ into an activation signal for the T cells. Regeneron and 2seventy bio are co-developing the program under their collaboration entered into in 2018.