Sindhoora Ponnam

Background: Cancer is a leading cause of mortality globally, killing approximately 10 million people in 2020.⁶ Immunotherapy is an emerging cancer therapeutic defined as the treatment of disease by activating or suppressing components of the patient’s immune system rather than directly targeting tumor cells, especially in terms of the treatment of melanoma.⁷ Advanced melanoma evades immune destruction through checkpoint-mediated suppression of T-cell activation and effector function, therefore limiting antitumor immunity.  CTLA-4 and PD-1 are core inhibitory pathways which regulate distinct stages of the antitumor T-cell immune response, making them major therapeutic targets in cancer immunotherapy.^1,2 Future therapeutic strategies could be aimed at the mechanisms enhancing checkpoint blockade efficacy as well as coordinating interactions between dual checkpoint signaling, Fc effector function, and tumor metabolic context.^3,4

Objective: This narrative review examines how CTLA-4 blockade promotes antitumor immunity in melanoma through the influences of CTLA-4 and PD-1 checkpoint inhibition mechanisms, the synergistic and clinical effects of dual checkpoint inhibition, Fc effector function, and tumor metabolic context.

Search Methods: A literature review was conducted from 2017 and onwards with search terms including “checkpoint immunotherapy,” “CTLA-4 blockade,” “tumor microenvironment,” “regulatory T-cells.”

Results: CTLA-4 blockade was associated with early immune activation and transcriptional programs related to cell-cycle regulation and proliferative expansion, while PD-1 blockade displayed impact on transcriptional and functional programs of pre-existing exhausted effector T-cells within the tumor microenvironment, specifically with regard to mitochondrial metabolism and oxidative phosphorylation in analyses of human melanoma samples and murine tumor models.¹ Combinational therapy altered phenotypically exhausted CD8+ T-cells and expanded activated effector CD8+ T-cells.² Combinationally treating patients noted to have previously untreated melanoma with ipilimumab (CTLA-4 inhibitor) with nivolumab (PD-1 inhibitor), resulted in longer progression-free survival and overall survival, with the sustained five-year survival of the patients.⁵ Anti-CTLA-4 antibodies engineered to preserve Fc receptor binding in murine melanoma models demonstrated significantly greater antitumor activity in comparison to Fc-silenced antibodies that retained CTLA-4 binding but lacked Fc effector function.³ In murine tumor models characterized by differing glycolytic activity, tumors with high intrinsic glycolytic activity sustained a tumor microenvironment in which metabolism was restricted and the suppressive nature of T-cells was maintained.⁴

Conclusions: CTLA-4 blockade enhances antitumor immunity by increasing CD28-mediated co-stimulatory signaling, leading to increased T-cell priming and clonal expansion of effector T-cell populations, while PD-1 blockade restores function in exhausted CD8+ T-cell populations within the tumor microenvironment.^1,2 Dual CTLA-4 and PD-1 blockade coordinates immune activation across distinct T-cell compartments, resulting in synergistic antitumor effects, which were evidenced by survival in melanoma patients.^2,5 Anti-CTLA-4 antibodies that engage Fc receptors led to the depletion of intratumoral regulatory T-cells, therefore reducing local immunosuppression.³ Glycolytic activity within the tumor microenvironment was shown to determine stability of regulatory T-cells as well as the therapeutic efficacy of the CTLA-4 blockade.⁴ Based on this, future therapeutic strategies could encompass the targeting of these mechanisms in combination to improve the magnitude and durability of antitumor immunity in melanoma.

Works Cited:

1. Wei SC, Levine JH, Cogdill AP, et al. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell. 2017;170(6):1120-1133.e17. doi:10.1016/j.cell.2017.07.024
2. Wei SC, Anang NAS, Sharma R, et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc Natl Acad Sci U S A. 2019;116(45):22699-22709. doi:10.1073/pnas.1821218116
3. Arce Vargas F, Furness AJS, Litchfield K, et al. Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer Cell. 2018;33(4):649-663.e4. doi:10.1016/j.ccell.2018.02.010
4. Zappasodi R, Serganova I, Cohen IJ, et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature. 2021;591(7851):652-658. doi:10.1038/s41586-021-03326-4
5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836
6. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a Cancer Journal for Clinicians. 2021;71(3):209-249. doi:https://doi.org/10.3322/caac.21660
7. Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069-1086. doi:10.1158/2159-8290.CD-18-0367