Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations

Abstract

Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the “magic bullet” to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.

ESR1 mutations in breast cancer

“…65,66 In breast cancer, immunotherapy clinical trials have been mainly focused on metastatic TNBC, a genomically unstable subtype of breast cancer that is believed to be the most immunogenic. In recent years, antibodies to PD-L1, PD-1, or CTLA4 have been developed to target immune-suppressive pathways, allowing for cytotoxic T cells to infiltrate and kill tumor cells.…”

“…In recent years, antibodies to PD-L1, PD-1, or CTLA4 have been developed to target immune-suppressive pathways, allowing for cytotoxic T cells to infiltrate and kill tumor cells. 65,66 In breast cancer, immunotherapy clinical trials have been mainly focused on metastatic TNBC, a genomically unstable subtype of breast cancer that is believed to be the most immunogenic. 67,68 The multicenter I-SPY 2, phase 2 clinical trial is evaluating novel neoadjuvant therapies and comparing immune therapy in combination with chemotherapy.…”

Knowledge is power—Rational design of cancer immunotherapy

“…First encouraging results have been reported, even though more trials are needed to optimize dosing, timing of mono-or combination treatment, and the feasibility of repeated treatment cycles to achieve clinical efficacy with minimal side effects. 29,30 Overall, and without a doubt, immunotherapy constitutes a breakthrough in cancer treatment with major impact on patient survival and disease outcome. As our knowledge about immune cells, their differentiation, function, and regulation increases, and novel experimental tools enable us to dissect the specifics of distinct tumor environments in different tumor types, we should be optimistic about the future and our ability to design better, more targeted, and highly efficacious cancer therapies.…”

“…). First encouraging results have been reported, even though more trials are needed to optimize dosing, timing of mono‐ or combination treatment, and the feasibility of repeated treatment cycles to achieve clinical efficacy with minimal side effects …”

Partial absence of PD-1 expression by tumor-specific CD8+T cells in EBV-driven lymphoepithelioma-like carcinoma: a case report

“…Treatment of cancer patients with anti-PD-1 or anti-PD-L1 has succesfully induced tumor regression in some cases. However, anti-PD-1 efficacy is variable across patients and cancer types [25]. Recently, we showed that PD-1 can also be expressed by bystander T cells in the tumors [2], making this receptor not exclusively expressed by tumor-specific cells, and raising questions about the effect of anti-PD-1 treatment on these cells.…”