Bispecific antibody does not induce T-cell death mediated by chimeric antigen receptor against disialoganglioside GD2

Abstract

Chimeric antigen receptors (CAR) and bispecific antibodies (BsAb) are two powerful immunotherapy approaches for retargeting lymphocytes toward cancer cells. Despite their success in lymphoblastic leukemia, solid tumors have been more recalcitrant. Identifying therapeutic barriers facing CAR-modified (CART) or BsAb-redirected T (BsAb-T) cells should facilitate their clinical translation to solid tumors. Novel lentiviral vectors containing low-affinity or high-affinity 4-1BB second-generation anti-GD2 (disialoganglioside) CARs were built to achieve efficient T cell transduction. The humanized anti-GD2 × CD3 BsAb using the IgG-scFv platform was described previously. CART and BsAb-engaged T cells were tested for viability, proliferation, and activation/exhaustion marker expression, and in vitro cytotoxicity against GD2(+) tumor cells. The antitumor effect of CAR-grafted and BsAb-T cells was compared in a human melanoma xenograft model. The majority of high CAR density T cells were depleted upon exposure to GD2(+) target cells while the BsAb-T cells survived. The in vitro cytotoxicity of the surviving CART cells was inferior to that of the BsAb-T cells. Using low-affinity CARs, inclusion of the 4-1BB co-stimulatory domain or exclusion of a co-stimulatory domain, or blocking PD1 did not prevent CART cell depletion. Both CART cells and BsAb-T cells penetrated established subcutaneous human melanoma xenografts; while both induced tumor regression, BsAb was more efficient. The fate of T cells activated by BsAb differs substantially from that by CAR, translating into a more robust antitumor effect both in vitro and in vivo.

Anti-GD2/4-1BB chimeric antigen receptor T cell therapy for the treatment of Chinese melanoma patients

“…Recent research has indicated that GD2-specific CAR-T cells undergo activation induced cell death following antigenic stimulation [ 26 , 27 ]. We performed a “stress test” assay with GD2.BBζ CAR-T cells under repeated stimulation onto GD2-cells (293T), and GD2 + melanoma cells (HMV-II, GAK, WM-266-4) every 24 h in vitro, as shown in Fig.…”

CARs versus BiTEs: A Comparison between T Cell–Redirection Strategies for Cancer Treatment

“…A few studies directly compared the functional efficacy of the two strategies in their antitumor effect (106). In an early study, Stone and colleagues compared the CAR and BiTE treatment antitumor response in vitro using the same anticancer scFv against a murine fibrosarcoma epitope, 237.…”

“…Although both strategies enhanced T cell-mediated antitumor effect, CAR T cells were more potent than the BiTE approach against cancers expressing lower levels of antigens (107). In a recent study, Hoseini and colleagues compared a bispecific antibody (specific for both CD3 and GD2), with a CAR that contained the same anti-GD2 scFv (106). Incubating GD2 + target cancer cells with anti-GD2 CAR T cells for 24 hours led to the depletion of the CAR hi T cells, and, in contrast, in the presence of BC119, the exposure of untransduced T cells to GD2 + target cancer cells did not deplete the T cells.…”

Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy

“…In particular, the safety and immunostimulatory activity of recombinant GM-CSF is being investigated: (1) in subjects with neuroblastoma receiving a ganglioside GD2-targeting mAb, [263][264][265][266][267] optionally in the context of multimodal chemotherapy (NCT02641782; NCT03033303; NCT03189706; NCT 03363373); (2) in patients with breast cancer, who receive recombinant GM-CSF as an adjuvant to peptide-based vaccination (NCT02636582; NCT03012100; NCT03014076); and (3) in individuals with a panel of other tumors, including biliary cancer (NCT02703714), colorectal carcinoma (NCT03222089), ependymoma (NCT02774421), follicular lymphoma (NCT02 677155), GBM (NCT02663440), head and neck cancer (NCT0 2873819), hepatocellular carcinoma (NCT02946138), lung cancer (NCT02976740; NCT02623595) melanoma (NCT0 3282188), multiple myeloma (NCT02728102) and ovarian carcinoma (NCT02978222) often in combination with standardof-care therapy, radiation therapy, or experimental immunotherapy ( Table 1).…”