Development of Immunotherapy Combination Strategies in Cancer

Abstract

Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies. SIGNIFICANCE: Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies.

Figure 1:. Immune checkpoint blockade and ‘hot’ vs ‘cold’ tumor microenvironments.

Immune checkpoint blockade frees T cells in ‘hot’ tumor microenvironments (top panel), but fails in ‘cold’ tumors due to dominant, multi-model suppressive mechanisms (bottom panel).

Figure 2:. Different Classes of Immunotherapy Combination Strategies.

(1) Immunotherapy/Immunotherapy Combinations: Example: CTLA-4/PD-1 Blockade: 1) CTLA-4 and PD-1 can no longer suppress T cell activation, expansion and effector function; 2) Treg cell function and differentiation is dampened; 3) Phagocytosis of tumor increases from myeloid PD-1 blocakde; 4) B7–1/2 can now co-stimulate T cells through CD28. (2) Immunotherapy/Chemotherapy Combinations: Example: Gemcitabine/nab-paclitaxel/PD-1 blockade/CD40 agonist: 1) Gemcitabine and nab-paclitaxel kill tumor cells releasing tumor antigen; 2) Both drugs also selectively deplete myeloid-derived suppressor cells; 3) CD40 activation enhances DC and M1 macrophage activation and increases T cell priming; 4) Activated T cells are protected from attenuation by PD-1 blockade. (3) Immunotherapy/Adoptive Cell Therapy Combinations: Example: Anti-CD19 CAR T cells/PD-1 Blockade: 1)PD-1 blockade prevents CAR T cells from being rapidly exhausted in the tumor microenvironment; 2) T cell effector function and cytotoxicity are enhanced by PD-1 blockade; 3) PD-1 blockade allows higher levels and duration of IFN-γ secretion that maintains an inflamed tumor microenvironment. (4) Immunotherapy/Targeted Therapy Combinations: Example: VEGFR2/PD-1/CTLA-4 blockade: 1) Blockade of VEGFR2 normalizes tumor vessels allowing T cell back in; 2) VEGFR2 blockade relieves VEGF inhibition of DC maturation; 3) PD-1 and CTLA-4 blockade allow tumor infiltrating T cells to survive, expand and kill tumor; 4) T cell produced IFN-γ helps maintain normalized vessels.