Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy

Abstract

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a membrane glycoprotein expressed by activated effector T cells (Teffs) and participates in the repression of T cell proliferation, cell cycle progression and cytokine production. Currently, antibodies targeting CTLA-4, ipilimumab and tremelimumab are widely used as a therapeutic approach in a variety of human malignancies. However, their detailed mechanism remains unclear. Therefore, in this review, we focused specifically on recent findings concerning the role of CTLA-4 in immune response and also discussed clinical studies of targeting CTLA-4, alone or in combination with other therapies for the treatment of cancers. CTLA-4 blockade is used as a therapeutic approach for the treatment of cancer through competing with CD28-positive costimulation for binding to their shared B7 ligands or exhibiting direct inhibitory effect on signaling molecules in the cytoplasmic tail. At present, antibodies for targeting CTLA-4 or in combination with other therapies significantly reinforced the anti-tumor effect and improved the prognosis of malignant disease. In addition, severe adverse events of targeting CTLA-4 therapy could be a challenge for the development of this therapeutic strategy. This review may provide some new insights for clinical studies of targeting CTLA-4.

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…CTLA‐4 monotherapy can produce meaningful and durable responses in melanoma, with the first clinical trials showing 22% 3‐year overall survival (OS) and durable responses extending beyond 10 years . Durable responses to CTLA‐4 monotherapy are rare (<10%) but occasionally reported in other solid tumors including pancreatic adenocarcinoma, renal cell carcinoma, B‐cell lymphoma, prostate cancer, refractory colorectal cancer, hepatocellular carcinoma, and malignant mesothelioma, reviewed in . We observed a dramatic response in a patient with refractory cutaneous angiosarcoma treated on a Phase I clinical trial with AGEN1884, a monoclonal antibody to CTLA‐4, at 0.1 mg/kg, nearly 10‐fold less than standard ipilimumab dosing .…”

“…20 Durable responses to CTLA-4 monotherapy are rare (<10%) but occasionally reported in other solid tumors including pancreatic adenocarcinoma, renal cell carcinoma, B-cell lymphoma, prostate cancer, refractory colorectal cancer, hepatocellular carcinoma, and malignant mesothelioma, reviewed in. 21 We observed a dramatic response in a patient with refractory cutaneous angiosarcoma treated on a Phase I clinical trial with AGEN1884, a monoclonal antibody to CTLA-4, at 0.1 mg/kg, nearly 10-fold less than standard ipilimumab dosing. 22 Biomarkers associated with response to CTLA-4 monotherapy are an area much in need of further study and will be discussed later in this review.…”

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

“…1). In a normal situation this inhibitory signal dampens T cell responses thereby avoiding collateral damage to healthy tissues (Acuto and Michel 2003;Zhao et al 2018). So far several radiotracers for CTLA-4, CD80 and CD86 have been reported.…”

A good start of immunotherapy in esophageal cancer

“…When it binds to CD80 or CD86 the immune system is downregulated . Currently, antibodies targeting CTLA4 are widely used in many forms of tumors . Tremelimumab, a humanized monoclonal antibody against CTLA4, was tested in metastatic melanoma as the second‐line setting.…”