Combination immunotherapy approaches

Abstract

Combination immunotherapy approaches involving radiation, chemotherapy, androgen manipulation and T-cell modulation have been studied extensively in animal models, setting the stage for clinical trials. Radiation therapy, in particular, is an interesting modality in this regard, leading to synergistic efficacy when used in combination with immunotherapies in several models. Chemotherapy, the foundation of treatment of metastatic disease, may also augment the immune response to cancer; however, the potential immunosuppressive effects of chemotherapy render issues of dosing and timing critical. Perhaps, the most exciting combinatorial approach may be the co-administration of multiple immunological treatments. For example, in preclinical investigations, combined blockade of programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), which have key roles in the negative regulation of T-cell activation, has been shown to enhance antitumour immune responses compared with either agent alone. Taken together, the available data provide a strong rationale for initiating combination clinical trials, but lend a note of caution in that issues of dosing and timing likely require careful exploration in a phase II setting.

Figure 1

Immune potentiating mechanisms of action of conventional chemotherapies and radiotherapy. Republished with permission of the American Society for Clinical Investigation, from ‘The anticancer immune response: indispensable for therapeutic success?’ by Zitvogel et al. [9]; permission conveyed through Copyright Clearance Center, Inc. 5-FU, 5-fluorouracil; ATRA, all-trans-retinoic acid; DC, dendritic cell; HDAC, histone deacetylases; HSP90, heat shock protein 90; MDSC, myeloid-derived suppressor cell; MHC-I, major histocompatibility complex class I; HMGB1, high mobility group box 1 protein; NK, natural killer cell; NKG2DL, NK cell group 2D ligands; T_conv, conventional effectors; T_reg, regulatory-T cell.

Figure 2

In an autochthonous, murine model of prostate cancer, the wet weight of the urogenital tract, a gross surrogate for tumour burden, was significantly decreased in the T-GVAX plus cyclophosphamide (CY) treatment group compared with either agent alone. As monotherapy, T-GVAX immunotherapy had no treatment effect, whereas cyclophosphamide showed a nonsignificant trend toward efficacy compared with untreated control animals. Reprinted by permission from the American Association for Cancer Research: Wada et al. [17].

Figure 3

Examples of molecular interactions and signalling at the antigen-presenting cell/T-cell immune synapse that inhibit T-cell activation and contribute to negative regulation of the immune response. CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; GITR, glucocorticoid-induced TNFR-related protein; HLA, human leukocyte antigen; ICOS, inducible T-cell costimulator; LAG-3, lymphocyte-activation gene-3; MHC-II, major histocompatibility complex class II; PD1, programmed death 1; PD-L1, programmed death ligand-1.

Figure 4

Combination blockade of the PD1, CTLA-4 and PD-L1 coinhibitory molecules coupled with Fvax vaccination increased survival of mice challenged with antigen-presenting melanoma cells. Lack of survival was defined as death or tumour size >1000 mm³. CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; PD1, programmed death 1; PDL-1, programmed death ligand-1.