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Optimized delivery of dual co-stimulation and anti-tumor activity using parallel chimeric antigen receptors (pCARs)

ABSTRACT: Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T-cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity and specificity, pCAR T-cells consistently elicit superior anti-tumor activity both in vitro and in vivo, warranting clinical development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186557 | GEO | 2021/12/10

REPOSITORIES: GEO

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