Cancer Treatment in the Checkpoint Inhibitor Era

Cross talk between antigen presenting cells, effector T cells and immune regulatory cells through co-stimulatory and inhibitory signals orchestrates the anti-tumor immune response that eventuates in either the effective tumor directed immune activity leading to the tumor removal or an immune suppressed tumor microenvironment leading to the tumor progression and metastasis.

The co-stimulatory signals have been shown to be mediated by CD28 and members of the tumor necrosis factor receptor (TNFR) family, such as CD40, OX-40, 4-1BB, CD30, and CD27, while the regulatory signals are generally mediated through cytotoxic T lymphocyte activator-4 (CTLA-4) and programmed death -1 (PD-1) receptors that share structural homology with the CD28 co-stimulatory class and also bind to the B7 family members. Despite the observed similarities in their structure and receptors, CTLA-4 and PD-1 show the main regulatory role and considered as checkpoints. Targeting these co-stimulatory or inhibitory receptors with either stimulating or blocking antibodies may lead to the enhanced immune response within tumor microenvironment and clinical benefits.

Successful treatment of tumors with primary resistance to conventional chemotherapy and radiation, such as melanoma in advanced and metastatic setting with CTLA-4 and PD-1 targeted monoclonal antibodies and the encouraging results of checkpoint inhibitors in the treatment of non-small cell lung cancer and renal cell carcinoma have led to more than 2000 ongoing clinical studies addressing safety and efficacy of these classes of monoclonal antibodies in a wide range of solid tumors and hematologic malignancies either alone or combined with other therapeutic options from conventional chemotherapy and radiation to other members of the checkpoint inhibitor family, small molecule kinase inhibitors and even cancer vaccines. These combination treatment modalities may demonstrate synergic anti-tumor effect beyond their specific therapeutic effects.