Intratumoral checkpoint subversion as a strategy for minimizing adverse effects

One of the most significant clinical advances in cancer immunotherapy to date has been the targeting of the immune “checkpoints” that inhibit effector T-cell function. Cytotoxic T lymphocyte-associated protein 4 (CTLA4), which was one among the first checkpoint regulators to be characterized, is transiently expressed by activated effector T cells and constitutively expressed on regulatory T cells (Tregs). CTLA4 inhibits T cells by at least 2 mechanisms: (1) by preferentially binding CD80 or CD86 on antigen-presenting cells (APCs), thereby antagonizing the co-stimulatory signals delivered to T cells via CD28; and (2) by sending an anergy-inducing signal via the intracellular kinases phosphoinositide-3-kinase (PI3K) and AKT1 (also known as protein kinase B, PKB). Systemic CTLA4 blockade confers antitumor immunity in murine models and improves the overall survival of melanoma patients, but is associated with dose-dependent and occasionally fatal autoimmune toxicities, including pneumonitis, enterocolitis, and hepatitis. An approach that maximizes the activation of antitumor T cells while keeping T lymphocytes specific for self structures at bay would increase the benefit-to-risk ratio of this form of immunotherapy and provide immediate advantage to cancer patients.