Cancer Immunotherapy: Beyond Checkpoint Blockade

Abstract

Blocking antibodies to the immune checkpoint receptors or their ligands have revolutionized the treatment of diverse malignancies. Many tumors are recognized by adaptive immunity, but these adaptive responses can be inhibited by immunosuppressive mechanisms within the tumor, often through pathways outside of the currently targeted checkpoints. For this reason, only a minority of cancer patients achieve durable responses to current immunotherapies. Multiple novel approaches strive to expand immunotherapy's reach. These may include targeting alternative immune checkpoints. However, many investigational strategies look beyond checkpoint blockade. These include cellular therapies to bypass endogenous immunity and efforts to stimulate new adaptive antitumor responses using vaccines, adjuvants, and combinations with cytotoxic therapy, as well as strategies to inhibit innate immune suppression and modulate metabolism within the tumor microenvironment. The challenge for immunotherapy going forward will be to select rational strategies for overcoming barriers to effective antitumor responses from the myriad possible targets.

Keywords: antitumor immunity; cancer; checkpoint blockade; combination therapy; immunotherapy; oncogenic inflammation; toxicity.

Figure 1

Moving beyond checkpoint blockade to enhance antitumor immunity. Building on the success of checkpoint blockade, multiple investigational strategies aim to overcome the immunosuppressive pathways that protect tumors from productive antitumor immunity. These strategies include both systemic and in situ vaccines to activate naïve T cells, prophylactic vaccines, and efforts to block oncogenic innate inflammation. The tumor microenvironment is being targeted through multiple mechanisms to reduce the number of regulatory adaptive and innate cells, block immunosuppressive metabolites and cytokines, and disrupt tumor vasculature. Several strategies seek to activate tumoricidal macrophages or NK cells. Tumors can be directly targeted by therapeutic antibodies, and adoptive cellular therapies endeavor to bypass endogenous responses either through ex vivo expansion of antitumor T cells or through infusion of gene-modified T cells, such as CAR T cells that directly recognize tumor-expressed targets. Abbreviations: ADAR, adenosine deaminase acting on RNA; BiTE, bispecific T cell engager; CAR, chimeric antigen receptor; DC, dendritic cell; HBV, hepatitis B virus; HPV, human papilloma virus; IDO1, indoleamine 2,3-dioxygenase 1; IFN, interferon; IL, interleukin; MICA, MHC class I chain–related protein A; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NK, natural killer; NSAID, nonsteroidal anti-inflammatory drug; STING, stimulator of interferon genes; TAM, tumor-associated macrophage; TIL, tumor-infiltrating lymphocyte; TLR, Toll-like receptor; Treg, regulatory T cell; VEGF, vascular endothelial growth factor.