Abstract
Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB costimulatory 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 costimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3z)
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 compared to T-cells that express traditional linear CARs.
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 compared to T-cells that express traditional linear CARs.
| Original language | English |
|---|---|
| Journal | Cell Reports Medicine |
| Publication status | Accepted/In press - 21 Dec 2021 |
Keywords
- Chimeric antigen receptor,
- CAR T-cells,
- co-stimulation
- cancer
- immunotherapy
- parallel CAR,
- chimeric co-stimulatory receptor
