Combinatorial approach to cancer immunotherapy: strength in numbers

Abstract

Immune-checkpoint blockade therapy with antibodies targeting CTLA-4 and PD-1 has revolutionized melanoma treatment by eliciting responses that can be remarkably durable and is now advancing to other malignancies. However, not all patients respond to immune-checkpoint inhibitors. Extensive preclinical evidence suggests that combining immune-checkpoint inhibitors with other anti-cancer treatments can greatly improve the therapeutic benefit. The first clinical success of the combinatorial approach to cancer immunotherapy was demonstrated using a dual-checkpoint blockade with CTLA-4 and PD-1 inhibitors, which resulted in accelerated FDA approval of this therapeutic regimen. In this review, we discuss the combinations of current and emerging immunotherapeutic agents in clinical and preclinical development and summarize the insights into potential mechanisms of synergistic anti-tumor activity gained from animal studies. These promising combinatorial partners for the immune-checkpoint blockade include therapeutics targeting additional inhibitory receptors of T cells, such as TIM-3, LAG-3, TIGIT, and BTLA, and agonists of T cell costimulatory receptors 4-1BB, OX40, and GITR, as well as agents that promote cancer cell recognition by the immune system, such as tumor vaccines, IDO inhibitors, and agonists of the CD40 receptor of APCs. We also review the therapeutic potential of regimens combining the immune-checkpoint blockade with therapeutic interventions that have been shown to enhance immunogenicity of cancer cells, including oncolytic viruses, RT, epigenetic therapy, and senescence-inducing therapy.

Keywords: immune checkpoints; immunogenic cell death; melanoma; senescence.

Figure 1

Current and emerging targets for therapeutic modulation of anti‐tumor immune response. Inhibition of immune checkpoints with antibodies targeting PD‐1 and CTLA‐4 inhibitory receptors of T cells produces durable responses in patients with many deadly malignancies. Several strategies are use to improve further the success rate of immunotherapies. These strategies include the following: 1) combining PD‐1 and CTLA‐4 blockers with each other or with antagonists of other inhibitory receptors on T cells, such as TIM‐3, LAG‐3, TIGIT, and BTLA; 2) combining the immune‐checkpoint blockade with agonists of costimulatory receptors of T cells, including CD27, 4‐1BB, OX40, and GITR; and 3) blocking immune checkpoints in conjunction with stimulation of TA recognition using vaccines and dendritic cell activation by CD40 agonists. An alternative approach involves combining the immune‐checkpoint blockade with therapy that enhances immunogenicity of tumors as a result of ICD (radiation, oncolytic viruses). Immunogenic death of tumor cells promotes immune cell recruitment and presentation of TAs. Enhancement of anti‐tumor immune responses can also be achieved by epigenetic therapies that restore silenced expression of molecules targeted by NK cells, TAs, and antigen‐presenting molecules (MHC I). In addition, therapy‐induced senescence can promote recruitment of anti‐tumor immune cells via the increased production of chemokines. *Molecules that can be modulated by therapeutic antibodies currently used in clinics or undergoing clinical development. DAMPs can include calreticulin, heat‐shock proteins, type I IFNs, ATP, and HMGB1. GITRL, OX40L, and 4‐1BBL, GITR, OX40, and 4‐1BB ligand.