A Costimulatory CAR Improves TCR-based Cancer Immunotherapy

Abstract

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 CD3ζ 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.

CAR T cells targeting the ganglioside NGcGM3 control ovarian tumors in the absence of toxicity against healthy tissues

“…Because of the broad expression of NGcGM3 by both solid and liquid tumors via dietary uptake in humans, there is also the potential for coadministration of anti-NGcGM3 CAR T cells with CAR T cells targeting a second antigen as a means of mitigating escape (42). Or, one could develop anti-NGcGM3 costimulatory CARs to enhance T cell receptor (TCR) based immunotherapy (43), or in the context of a parallel (p)CAR design (44). Finally, in recent years, several remote-control designs including ON-CARs (45), STOP-CARs (22), and OFF-CARs (46, 47) have been developed that could provide the means to more safely explore the translation of NGcGM3 redirected T cells to the clinic.…”

Emerging Challenges to Cellular Therapy of Cancer

“…To overcome these barriers to effector cell entry, activation, expansion, and persistence, investigators have expressed molecules in T cells that may reverse these impediments to success. These include, but are not limited to, additional costimulatory signaling domains (like dual CD28 and 4-1BB, e.g., third-generation CAR T cells 47 ); direct overexpression of costimulatory molecules (e.g., CD28L or OX40L 46 ) to supply local “signal 2” in trans; and chemotactic factors and proinflammatory cytokines 65 to reduce the impact of inhibitory signals such as PDL1 50 or TGF-β 66 . Some of these approaches have now been tested clinically.…”

Joining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”

“…Furthermore, several studies demonstrated the beneficial effects of combining a transgenic TCR with a non-classical, modified CAR [ 205 , 206 , 207 ]. In vivo experiments, for example, displayed that expansion and efficacy of NY-ESO-1 TCR-transduced T cells can be enhanced through co-expression of scFv-lacking 4-1BBζ CAR [ 205 ].…”

“…In this regard, it was hypothesized that the CAR, albeit not engaging any target antigen, induced a certain trans co-stimulation, thereby enhancing transgenic TCR signaling. Another study demonstrated that the serial killing potential and in vivo anti-tumor response through both native or transgenic TCR was increased by co-expression of CD19 CARs with 4-1BB co-stimulation but lacking the CD3ζ signaling domain [ 207 ].…”