The co-receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) is a central inhibitory regulator of T-cell proliferation and expansion. Its dampening effect on the activation process limits and terminates T-cell responses, and as such is important for regulating peripheral T-cell tolerance and autoimmunity. The anti-CTLA-4 blocking antibody ipilimumab was the first immune checkpoint inhibitor to be tested and approved for the treatment of cancer patients. CTLA-4 (CD152) is a B7/CD28 family member that inhibits T cell functions. It is constitutively expressed by Tregs but can also be upregulated by other T cell subsets, especially CD4+ T cells, upon activation. Exhausted T cells are also often characterized by the expression of CTLA-4 among other inhibitory receptors.
Recently, combination of CTLA-4 and PD-1 blockers was evaluated to increase the response rates in patients, and ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) combination was shown to significantly enhance efficacy in metastatic melanoma patients. Subsequently, ipilimumab plus nivolumab was approved for treatment of metastatic melanoma, advanced renal cell carcinoma and metastatic colorectal cancer with MMR/MSI-H aberrations. The success of combination encouraged multiple clinical studies in other cancer types. Efficacy of the combination has been shown in a number of published studies and is under evaluation in multiple ongoing studies.
Combination anti-CTLA-4 plus anti-PD-1 therapy differentially affects MC38 tumor-infiltrating T cell populations.
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