Immune checkpoint modulation: rational design of combination strategies

Immune recognition and elimination of malignant cells require a series of steps orchestrated by the innate and the adaptive arms of the immune system. The majority of tumors have evolved mechanisms that allow for successful evasion of these immune responses. Recognition of these evasive processes led to the development of immunotherapeutic antibodies targeting the co-stimulatory and co-inhibitory receptors on T cells, with the goal of enhancement of T cell activation or reversal of tumor-induced T cell inhibition. Several of these agents, such as antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) have already demonstrated significant promise in clinical trials. Clinical benefit of these antibodies as single agents, however, has been limited to a subset of patients and has not been observed in all tumor types. These limitations call for the development of rational combination strategies aiming to extend therapeutic benefit to a broader range of patients. These include: 1) modalities that enhance antigen presentation, such as radiation, cryotherapy, chemotherapy, targeted agents, vaccines, toll-like receptor (TLR) agonists, type I interferon, and oncolytic viruses; 2) additional agents aiming to reverse T cell dysfunction, such as other immune checkpoint inhibitors; and 3) agents targeting other immune inhibitory mechanisms, such as inhibitors of indoleamine dioxygenase (IDO), regulatory T cells, and myeloid-derived suppressor cells (MDSCs). It is becoming increasingly evident that the efficacy of specific combinations will likely not be universal and that the choice of a treatment modality may need to be tailored to fit the needs of each individual patient.