Blocking VISTA as a Target for Cancer Immunotherapy in Triple-Negative Breast Cancer
Kristen Downey
Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options due to its lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2.1 The average survival rate of TNBC is around ten months with a 65% five-year survival rate in cases of regional tumors and 11% for those with metastatic cancer.2 Currently, the primary immunotherapy for TNBC is the PD-L1 inhibitor, atezolizumab.1 However, due to resistance, there is a lower than 30% positive response rate, resulting in shorter overall survival rates and severe adverse side effects.1 V-domain Ig suppressor of T cell activation (VISTA) is a newly discovered myeloid immune checkpoint regulator of T cell function that suppresses antitumor responses.3 In recent research, the role of VISTA has been identified in promoting tumorigenesis, blocking T-cell function, and modulating the activity of macrophages and myeloid-derived suppressor cells.3 VISTA inhibition may be a potential therapeutic solution for anti-PD-L1-resistant patients.
Objective: In this narrative review, we explored the mechanism of an anti-VISTA targeting antibody, named HMBD-002, that acts to suppress the antitumor response in TNBC tumors.
Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using the following keywords: “Triple-negative breast cancer”, ” VISTA”, and “Immunotherapy resistance”.
Results: In a study that evaluated the tumor composition in 254 patients with untreated TNBC, VISTA expression was found in 87.8% of immune cells and 18.5% of tumor cells.1 VISTA expression was shown to have increased after undergoing treatment with a PD-L1 inhibitor, suggesting that VISTA may play an important role in PD-L1 immunotherapy resistance.1 A VISTA inhibitor, HMBD-002, was created using an AI-developed approach designed to bind the functional epitope within the C-C loop of VISTA.3 HMBD-002 neutralized VISTA activity by inhibiting the binding of VISTA to its binding partner, VSIG3, causing over a 2-fold increase in interferon-gamma released from activated T cells.3 This resulted in significantly inhibited tumor growth through activation of M1 proinflammatory macrophages, inhibition of angiogenesis, and initiation of apoptosis in tumor cells.3 Mice were implanted with colon and breast cancer solid tumor models that overexpressed VISTA and treated biweekly with HMBD-002.3 HMBD-002 demonstrated significant single-agent efficacy with 84% and 53% tumor growth inhibition in colon and breast cancers, respectively.3 To confirm these effects were not limited to murine cancers, HMBD-002 was tested in humanized mice engrafted with CD24+ blood hematopoietic stem cells from multiple human cell lineages.3 HMBD-002 showed significant single-agent efficacy of 65% and 62% tumor growth inhibition in colorectal and lung cancers, respectively.3
Conclusions:
VISTA inhibitor HMBD-002 successfully shifted the tumor microenvironment to a pro-inflammatory, antitumor state in murine models by increasing interferon-gamma release, decreasing neutrophil chemotaxis, and upregulating Th1/Th17 responses.3 Based on its significant antitumor efficacy and safety profile, HMBD-002 is a promising immunotherapy for PD-L1-resistant TNBC patients and is currently in Phase I/II clinical trials as of 2023.
Works CIted:
- Cao X, Ren X, Zhou Y, et al. VISTA Expression on Immune Cells Correlates With Favorable Prognosis in Patients With Triple-Negative Breast Cancer. Front Oncol. 2021;10:583966. Published 2021 Jan 11. doi:10.3389/fonc.2020.583966
- Almansour NM. Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci. 2022;9:836417. Published 2022 Jan 25. doi:10.3389/fmolb.2022.836417
- Thakkar D, Paliwal S, Dharmadhikari B, et al. Rationally targeted anti-VISTA antibody that blockades the C-C’ loop region can reverse VISTA immune suppression and remodel the immune microenvironment to potently inhibit tumor growth in an Fc independent manner [published correction appears in J Immunother Cancer. 2022 Feb;10(2):]. J Immunother Cancer. 2022;10(2):e003382. doi:10.1136/jitc-2021-003382