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VISTA as a New Immunotherapy Target

PD-1 and PD-L1 have had a significant clinical impact as an immunotherapy target for patients with multiple genitourinary malignancies, including bladder and renal cancers. We continue to find new settings and novel combinations for the use of the antibodies that target these checkpoints for our patients with genitourinary cancers. For example, just a few weeks ago, at ASCO GU 2024, we saw the data release from the AMBASSADOR randomized phase 3 clinical trial, offering supportive data for the use of pembrolizumab for adjuvant therapy for those with high-risk features after radical cystectomy for muscle invasive urothelial bladder cancer.1 However, there is still an urgent need to identify new immunotherapy targets and develop new therapies to manipulate those targets.

Given that PD-L1 (B7-H1) and PD-L2 (B7-H3) are both in the B7 family of immune regulatory proteins, the V-domain Immunoglobulin Suppressor of T cell Activation (VISTA), is another reasonable target to explore. VISTA is most closely related to PD-L1 with 25% sequence similarity, but it contains a single IgV-like domain and no IgC domain, unlike other B7 family members. It also contains 10 beta strands in the binding domain, distinct from other family members, which more typically contain 9 beta strands.2 Functionally, it is thought that VISTA is involved in the control of immune cell populations that are implicated for their roles in antitumor immunity.

Although VISTA is expressed on many human cells, it is notably highly expressed on myeloid lineage cells and lesser on lymphoid cell populations.3-5 In the murine tumor microenvironment, VISTA expression is found at the highest level on tumor-infiltrating myeloid-derived suppressor cells (MDSCs), known to have suppressive effects on antitumor immune effectors.6 Many human tumors have high level expression of VISTA in the microenvironment, including gastric, lung squamous and adenocarcinoma, melanoma, ovarian, pancreatic, breast cancer, and even acute myelogenous leukemia. High levels of VISTA expression in the human tumor microenvironment tend to correlate with worse progression-free or overall survival.7-10 Therefore, the concept of inhibiting VISTA is to restore T cell activation and induce a pro-inflammatory response against a patient’s tumor.

VISTA inhibitors have been used both as monotherapy and combination therapy in various preclinical models. For example, blocking VISTA and PD-1 together had significant reduction in tumor growth and survival in both murine colon cancer and melanoma models.11 In prostate cancer specifically, there may be interesting rationale for inhibiting VISTA. The expression of both VISTA and PD-L1 increases with infiltration of immune cells with the M2 suppressive phenotype in the tumor microenvironment after treatment with ipilumumab.12 Blocking VISTA in combination with CTLA-4 and PD-1 had a synergistic effect and addressed a key mechanism of resistance to therapy.13

Although it is early in development, there are many ongoing preclinical and early clinical trials with VISTA-targeting antibodies and small molecules. Although monotherapy efforts are initially necessary for drug development, combination therapy with other potentially synergistic agents that address other components of the immune system is of particular interest. There is much precedence for the use of immunotherapy for patients with genitourinary malignancies, such as bladder and renal cell carcinoma, but prostate cancer has been tough for checkpoint inhibitors to break into. VISTA provides another node of attack for us to explore in clinical trials with novel agents. A few agents have recently completed accrual to phase 1 efforts, and we eagerly await the results to be presented. Below are some of the ongoing efforts, where we have the opportunity to accrue our genitourinary cancer patients, in hopes of establishing early evidence to support expansion cohorts specifically focused on these malignancies that we treat.

Highlighted Trials targeting VISTA that are Actively Accruing Patients with Genitourinary Cancers

All trials below include eligible patients with prostate, bladder, and kidney cancers:

  • • SNS-101 as monotherapy and with cemiplimab (NCT05864144)
  • • HMBD-002 as monotherapy and with pembrolizumab (NCT05082610)
  • • PMC-309 as monotherapy and with pembrolizumab (NCT05957081)
  • • KVA12123 as monotherapy and with pembrolizumab (NCT05708950)

Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Apolo AB, et al. AMBASSADOR Alliance A031501: Phase III randomized adjuvant study of pembrolizumab in muscle-invasive and locally advanced urothelial carcinoma (MIUC) vs observation. J Clin Oncol 42, 2024 (suppl 4; abstr LBA531).
  2. Mehta N, et al. Structure and Functional Binding Epitope of V-domain Ig Suppressor of T Cell Activation. Cell Rep 2019; 28:2509-16.e5.
  3. Uhlen M, et al. Proteomics. Tissue-based map of the human proteome. Science 2015; 347:1260419.
  4. Uhlen M, et al. A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science 2019; 366:eaax9198.
  5. Lines JL, et al. VISTA is an immune checkpoint molecule for human T cells. Cancer Res 2014; 74:1924-32.
  6. Le Mercier I, et al. VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res 2014; 74:1933-44.
  7. Choi JW, et al. The prognostic significance of VISTA and CD33-positive myeloid cells in cutaneous melanoma and their relationship with PD-1 expression. Sci Rep 2020; 10:14372.
  8. Blando J, et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci 2019; 11:1692-7.
  9. Deng J, et al. Hypoxia-Induced VISTA Promotes the Suppressive Function of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Cancer Immunol Res 2019; 7:1079-90.
  10. Wu L, et al. Expression of VISTA correlated with immunosuppression and synergized with CD8 to predict survival in human oral squamous cell carcinoma. Cancer Immunol Immunother 2017; 66:627-36.
  11. Liu Y, et al. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc Natl Acad Sci 2015; 112:6682-7.
  12. Gao J, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 2017; 23:551-5.
  13. Yum JI, Hong YK. Terminating Cancer by Blocking VISTA as a Novel Immunotherapy: Hasta la vista, baby. Front Oncol 2021; 11:658588. 
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