Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

Abstract

Immunostimulatory mAb as vaccine adjuvants for the treatment of cancer hold considerable potential for boosting weak responses when used against immunogenic tumours, or in combination with various other vaccines. We now show that when administered with OVA, the combination of anti-4-1BB mAb with anti-CD40, anti-OX40 or anti-CD25 resulted in a fourfold enhancement in the antigen-specific T-cell response compared with anti-4-1BB mAb alone, with a similar enhancement in memory responses following rechallenge with OVA. Although the number of antigen-specific T-cells generated after treatment with each of the combinations was similar, marked functional differences were detected. In particular, anti-4-1BB/anti-CD25 resulted in excellent expansion of specific CD81 T cells but produced fewer IFN-c-secreting effector cells than the other combinations. Anti-4-1BB/anti-OX40 proved to be the most potent, inducing the most effective T-cell responses in the RIPmOVA diabetes model with adoptively transferred OVA-specific T cells, and, when given with a peptide vaccine, protecting mice against the poorly immunogenic B16-F10 tumour. Overall the results suggest that although these combinations of mAb look promising in terms of their therapeutic potential, further functional assays are needed to compare their effects.

Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse Model

“…In these tumors antigen-specific CD8 þ immunity is downmodulated and tumors progress at a fast pace with T-cell tolerance representing the major hurdle (21). Triple combination of ISmAbs makes sense since synergistic effects of the combined treatment consisting of anti-CD137 plus anti-B7-H1 (34, 35) mAbs or anti-CD137 plus anti-OX40 mAbs (36) have been reported in mouse models of transplantable tumors. As expected from the mechanism of action of these three antibodies, we observe an increase in T-cell infiltrates in tumor tissue composed of both activated CD4 þ and CD8 þ T lymphoblasts.…”

Therapeutic Glucocorticoid-Induced TNF Receptor-Mediated Amplification of CD4+ T Cell Responses Enhances Antiparasitic Immunity

“…Many reports indicate that agonistic signaling through T cell costimulatory receptors can enhance immunity to cancer (5)(6)(7)(8)(9). Glucocorticoid-induced TNF receptor (GITR) family-related protein (10,11) is one such receptor that has received significant attention in recent years.…”

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

“…Subsequent studies by other groups and ourselves have confirmed and extended this finding that 'dual costimulation' is therapeutic in breast cancer [116], melanoma [117] and lymphoma models [118].…”