Auslander N et al. Nat Med 2018; 24: 1545–1549.

Antibodies that target coinhibitory receptors on T cells  are promising therapies for a range of malignancies. This chapter provides an overview of checkpoint blockade and combination therapy strategies. Summary points Antibodies targeting coinhibitory receptors on T cells (‘checkpoint blockade’), including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1), and others, have emerged as some of the most promising therapies for a broad range of malignancies. Ipilimumab (anti-CTLA-4 antibody), pembrolizumab, and nivolumab (anti-PD-1 antibodies) are currently approved for patients with advanced melanoma. Single agent checkpoint blockade is associated with 20–40% objective response rates in advanced melanoma and improved overall survival, whilst combination of anti-CTLA-4 and anti-PD-1 antibodies leads to an increased durable response rate compared to either antibody alone. An important goal in the field is to combine checkpoint blockade with other immunotherapies (e.g., vaccines, T cell stimulatory agents, T cell transfer) and other types of therapy (e.g., radiation, targeted therapy, chemotherapy, surgery) to increase the fraction of patients that have responses, while maintaining the durability of response and minimizing the toxicity. However, a lack of understanding about the precise mechanisms of action means it is currently difficult to predict whether these combinations will be synergistic or redundant. Critical issues that need to be addressed in order to develop combination strategies include developing targeted delivery mechanisms to minimize adverse events associated with stimulating the immune system, and improving understanding of the mechanism of action of checkpoint blockade and the effects of non-immunotherapies on the immune response to tumors. Juneja VR, LaFleur MW, Manguso RT, & Sharpe AH. In:  Novel Immunotherapeutic Approaches to the Treatment of Cancer . Edited by Rennert PD. Springer International Publishing, 2016. doi:10.1007/978-3-319-29827-6_1

Nishino M et al.  Nat Rev Clin Oncol 2017; 14: 655–668. doi:10.1038/nrclinonc.2017.88

Cheng W et al. Oncogenesis 2018; 7: 2. doi:10.1038/s41389-017-0013-7

Results from this preclinical study indicate that blocking programmed death-1 (PD-1)/PD-1 ligand interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation. Summary points Multiple myeloma is generally considered to be an incurable disease and successful treatments will likely require multi-faceted approaches incorporating conventional drug therapies, immunotherapy and other novel treatments. Previously, a combination of transient lymphodepletion (sublethal whole body irradiation) and programmed death-1 (PD-1)/PD-1 ligand blockade generated anti-myeloma T cell reactivity capable of eliminating established disease and so it was hypothesized that blocking a combination of checkpoint receptors would boost anti-tumor immunity. Elevated percentages of PD-1, 2B4, lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) proteins were expressed on T cells of bone marrow from myeloma-bearing mice that had been treated with a low dose of whole body irradiation and combinations of blocking antibodies. When PD-L1 blockade was combined with blockage of antibodies to LAG-3, TIM-3 or cytotoxic T-lymphocyte antigen 4, synergistic or additive increases in survival were observed (from approximately 30% to >80%); this also correlated with increased frequencies of tumor-reactive CD8 and CD4 T cells. These data indicate that blocking PD-1/PD-L1 interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation and may be a promising combination strategy for myeloma and other hematologic malignancies. Jing W et al. J Immunotherapy Cancer 2015; 3: 2. doi:10.1186/s40425-014-0043-z

Evan J et al. J Immunotherapy Cancer 2017; 5: 23. doi:10.1186/s40425-017-0228-3