Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body’s immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

The immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.

Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.