Bio4t2, San Diego, CA
Farzad Haerizadeh , Helena Jiang , Laurence Cooper
Background: CAR-T has shown promise in patients with a subset of solid tumors. Future development depends on identifying CAR-T that differentiate between normal and malignant cells. The PrismCore platform develops CAR-T targeting self-antigens using three principles: 1) identification of targets uniformly expressed on solid tumors, 2) over-expression on the surface of invasive cancers compared to healthy cells, and 3) elevated levels linked to tumor aggressiveness. PrismCore produces CAR-T for treating multiple solid tumor types by calibrating T-cell activity against self-antigens only when present at elevated densities. Methods: PrismCore generates CAR-T by combining computational biology with empirical observations to target over-expressed self-antigens. Proto-libraries of CARs are created using synthetic single-domain antibodies and structural/signaling components. Bio-screening is performed using combinatorial libraries generated through computational simulation. Lead CAR-T are identified through iterative in vitro and in vivo testing and evaluated for safety in non-human primates (NHP). Results: PrismCore platform has identified engineered T cells against several self-antigens, with the first CAR-T, termed B4t2-001, advanced to clinical testing against the target BT-001. Libraries (1E10 to 1E11) of camelid antibodies were designed, synthesized, and assessed. Selected antibody variants subsets were combinatorially assembled into CAR-Ts and rigorously screened against gradient of BT-001. Six candidates were advanced to further testing in mice to evaluate anti-tumor effect and sustained in vivo biological activity. B4t2-001 was evaluated in NHP that express basal levels of BT-001. No toxicity observed despite measurable circulating CAR-T and in vitro activity to NHP BT-001 when at high density. The turnaround from target selection to B4t2-001 for clinical evaluation was six months. Conclusions: We report pre-clinical data for B4t2-001 that safely and effectively targets BT-001 when overexpressed on tumors. This is a novel target for T-cell therapy and is at elevated levels on multiple different types of solid tumors. BT-001 participates in pathobiology, tumor invasion as well as metastasis, and level of expression inversely correlates with overall survival. B4t2-001 demonstrated target density-dependent response, potency, durability of effect and safety in preclinical models and is undergoing phase I clinical evaluation (NCT05621486) in patients with different types of solid tumors.
Annual Global Cases (Millions) (2022)* | |||
---|---|---|---|
Indication | New cases | Deaths | BT-001 |
Lung | 2.2 | 1.7 | >85% |
Colorectal | 1.9 | 0.93 | >55% |
Gastric | 1.1 | 0.76 | >85% |
Pancreatic | 0.5 | 0.46 | >90% |
Breast | 2.2 | 0.68 | >70% |
*WHO and International Agency for Research on Cancer.
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Abstract Disclosures
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