Abstract
SummarySecond 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+CD3ζ) 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 with T cells that express traditional linear CARs.
Highlights
Chimeric antigen receptors (CARs) are modular synthetic units that re-direct lymphocyte specificity against cell surface targets
Conceived over 30 years ago,[1] CAR technology was transformed from academic curiosity into groundbreaking cancer therapy with the demonstration that T cell receptor (TCR) and co-stimulatory signaling could be efficiently delivered via a single CD28+CD3z (28z) or 41BB+CD3z (BBz) fusion.[2,3]
When these second generation (2G) CARs were evaluated in human T cells, anti-tumor activity proved markedly superior to first generation (1G) counterparts that provide TCR-like signaling alone.[4,5]
Summary
Chimeric antigen receptors (CARs) are modular synthetic units that re-direct lymphocyte specificity against cell surface targets. Effectiveness against solid tumors remains inadequate, in large part due to tumor-induced T cell dysfunction.[6]. Given these considerations, it was logical to test whether potency could be augmented by insertion of an additional co-stimulatory element within a 2G CAR framework.[7] Some studies reported increased efficacy of this third generation (3G) CAR approach in non-clinical testing.[7,8,9,10,11,12] this has not proven to be uniformly the case. When compared with 2G designs, some 3G CARs elicit borderline superiority,[13,14,15] or even
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