Immune checkpoints consist of stimulatory and inhibitory 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 checkpoints for cancer treatment. 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.
Immune checkpoint blockade has revolutionized the treatment of cancer with remarkable success. A number of studies have revealed that immune checkpoint blockade may also be highly relevant for treating several infectious diseases, including malaria, HIV infection, HBV infection, and tuberculosis. The up-regulation of PD-1 and CTLA-4 on immune cells occurs during both acute infections and chronic persistent viral infections.
Fig.1 Immune checkpoint protein expression in HIV/HBV infection. (Wykes, 2018)
While CTLA-4 and PD-1 blockade has proved successful in improving survival rates, many patients do not respond or develop resistance to these interventions. Researches into the combination of two different immune checkpoints as therapeutic targets have shown promise in pre-clinical and clinical studies, such as CTLA-4 and PD-1, LAG-3 and PD-1, TIM-3 and PD-1, and A2AR/PD-L1.
The therapeutic possibilities for many cancers have changed due to the development of targeted therapies that inhibit oncogenic signaling pathways as well as immune-modulating therapies that unleash the patient antitumor immunity.
An increasing number of studies in recent years focus on the development of the combination therapy of immune checkpoint inhibitors with small-molecule inhibitors that target various pathways. At present, with inhibitors targeting molecules such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), PI3K and MAPK pathway, STING, TLR, and anaplastic lymphoma kinase (ALK), selected patients can experience impressive tumor responses.
Fig.2 The biological rationale behind combining immune checkpoint blockade with targeted therapies in melanoma and NSCLC. (Karachaliou, 2017)
CAR T cells are a form of cellular immunotherapy, where T cells are genetically modified ex vivo to express a new surface antigen receptor. The most frequently used CAR constructs consist of a single-chain variable fragment (scFV) antigen-recognition domain of an antibody linked to a CD3-derived T cell activation domain and a costimulatory domain (CD28, 4-1BB, or both). This allows for major histocompatibility complex (MHC) independent tumor cell recognition and killing.
Fig.3 Mechanisms of the rescue of CAR T cell exhaustion with checkpoint blockade. (Grosser, 2019)
Considerable attention has also been paid to cancer vaccines owning to their unique advantages such as good safety profiles, antigen-specific immunological responses, and effective immune memories. A combination of checkpoint inhibitors and cancer vaccine could enhance the effectiveness of the immune system to destroy cancers.
Many tumor cells cannot adequately protect themselves against viral infection, making the development of oncolytic virus (OV) an attractive therapy option that may selectively infect tumor cells. By lysing tumor cells, OV treatment can lead to the release of tumor-associated antigens by the dying cells and efficient cross-presentation of antigens to DCs, thus enhancing anti-tumor responses. Studies have suggested the potential merit of combining OVs with checkpoint inhibitors such as PD-L1 and CTLA-4.
Given the dynamic nature of immune responses at the tumor sites and the complicated regulation of immune checkpoints with their ligands, it may be challenging to rely on a sole immune checkpoint inhibitor for cancer immunotherapy. Therefore, it is necessary to combine checkpoint inhibitors with other strategies such as chemotherapy, radiotherapy, and phototherapy. Many of these combination strategies have achieved synergistic therapeutic effects than a single treatment of CTLA-4 or PD-1/PD-L1 blockade.
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Wykes, M. N.; Lewin S R. Immune checkpoint blockade in infectious diseases. Nature Reviews Immunology. 2018, 18(2): 91.
Karachaliou, N.; et al. The combination of checkpoint immunotherapy and targeted therapy in cancer. Annals of translational medicine. 2017, 5(19).
Grosser, R.; et al. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell. 2019, 36(5): 471-482.
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