T-cell receptors (TCR) recognize intracellular and extracellular
cancer antigens, allowing T cells to target many
tumor antigens. To sustain proliferation and persistence, T cells require not only signaling through the TCR (signal 1), but also costimulatory (signal 2) and
cytokine (signal 3) signaling. Because most
cancer cells lack costimulatory molecules, TCR engagement at the
tumor site results in incomplete T-cell activation and transient antitumor effects. To overcome this lack of signal 2, we genetically modified
tumor-specific T cells with a costimulatory
chimeric antigen receptor (CoCAR). Like classical CARs, CoCARs combine the
antigen-binding domain of an antibody with costimulatory endodomains to trigger T-cell proliferation, but CoCARs lack the cytotoxic CD3ΞΆ chain to avoid toxicity to normal tissues. We first tested a CD19-targeting CoCAR in combination with an
HLA-A*02:01-restricted,
survivin-specific transgenic TCR (sTCR) in serial cocultures with
leukemia cells coexpressing the cognate
peptide-HLA complex (signal 1) and CD19 (signal 2). The CoCAR enabled sTCR+ T cells to kill
tumors over a median of four additional
tumor challenges. CoCAR activity depended on CD19 but was maintained in
tumors with heterogeneous CD19 expression. In a murine
tumor model, sTCR+CoCAR+ T cells improved
tumor control and prolonged survival compared with sTCR+ T cells. We further evaluated the CoCAR in Epstein-Barr virus-specific T cells (EBVST). CoCAR-expressing EBVSTs expanded more rapidly than nontransduced EBVSTs and delayed
tumor progression in an EBV+ murine
lymphoma model. Overall, we demonstrated that the CoCAR can increase the activity of T cells expressing both native and transgenic TCRs and enhance antitumor responses.