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Table 2. Current status of VISTA therapeutics in preclinical and clinical development
Drug Type Target Company Stage Cancers
JNJ-61610588 IgG1 mAb VISTA Janssen/ImmuNext Phase I: [D] NCT02671955 Advanced solid tumors
CI-8993 IgG1 mAb VISTA Curis/ImmuNext Phase I: [IP] NCT04475523 Relapsed/refractory solid
tumors
CA-170 Small VISTA & PD- Curis/ImmuNext Phase I: [C] NCT02812875 Advanced solid tumors or
molecule L1 lymphomas
CA-170 Small VISTA & PD- Curis/Aurigene Phase II: [IP] Advanced solid tumors or
molecule L1 CTRI/2017/12011026 lymphomas
K01401-020 W0180 +/- mAb VISTA +/- Pierre Fabre Phase Ia, 1b: [ IP] Locally advance or metastatic
Pembrolizumab PD-1 NCT04564417 solid tumors
HMBD-002 IgG4 mAb VISTA Hummingbird Phase I/II: [IP] Advanced solid tumors
NCT05082610
KVA 12.1 IgG1 mAb VISTA Kineta Preclinical -
VTX-0811 mAb PSGL-1 Verseua Preclinical -
PMC-309 IgG1 mAb VISTA PharmAbcine Preclinical -
SNS-101 IgG1 mAb VISTA/PSGL-1 Sensei Preclinical -
Biotherapeutics
IMT-18 mAb VSIG-3 iOMx Preclinical -

VISTA: V-domain Ig Suppressor of T cell Activation; D: discontinued; IP: in progress; C: complete.

The first clinical trial (NCT02671955) studying a drug that targeted VISTA involved an antagonistic mAb
(JNJ-61610588) developed by ImmuNext in collaboration with Janssen Biotech . This phase I trial enrolled
[93]
twelve participants with advanced cancers but was terminated by Janssen. The asset was returned to
ImmuNext and licensed by Curis. Currently underway is a phase I clinical trial (NCT04475523) using
CI-8993, an anti-VISTA IgGk mAb in patients with relapsed or refractory solid tumors . Preclinical data
[94]
published in November 2021 demonstrated that CI-8993 specifically bound VISTA in human VISTA
knock-in mice, which is a promising indicator for use in solid tumor patients in the clinical trial .
[95]

CA-170 is a small molecule that targets both VISTA and PD-L1, potentially by involving binding to
[96]
VISTA’s histidine binding sites or forming a defective ternary PD-1/PD-L1 complex . The phase I trial
[96]
(NCT02812875) was successful , and the phase II trial (CTRI/2017/12/011026) demonstrated efficacy
[97]
but was discontinued. Another clinical trial is evaluating the VISTA mAb W0180 in patients with locally
advanced or metastatic solid tumors (NCT04564417) . This phase Ia trial, led by Pierre Fabre, will evaluate
[98]
the safety of W0180 as a monotherapy, and phase Ib will involve treatment with W0180 and/or
pembrolizumab (anti-PD-1). A monoclonal IgG4 anti-VISTA antibody (HMBD-002) is being developed by
Hummingbird, with the phase I/II trial ongoing (NCT05082610) . This antibody is cross-reactive to
[99]
murine VISTA and has been shown to be therapeutically effective in preclinical murine tumor models .
[100]
FUTURE PERSPECTIVES
Combination ICI therapy approaches have potential to improve cancer patient outcomes. Here, we will
discuss the potential for the use of anti-VISTA in conjunction with anti-PD-1 and anti-CTLA-4, based on
preclinical murine models, data from patient samples, and current clinical trials. In mice, blockade of PD-L1
and VISTA resulted in 80% tumor regression in the CT26 colon cancer model, which was superior to either
treatment alone . A murine RCC model demonstrated that co-blockade of VISTA and PD-1/PD-L1
[28]
resulted in a greater reduction of tumor growth relative to either treatment alone . Furthermore, survival is
[28]
significantly higher in the B16 melanoma model using co-blockade of PD-L1 and VISTA, as compared to
monotherapy, despite being a less immunogenic model than CT26. These data demonstrate that VISTA
antagonism may be beneficial even in cancers that are less likely to respond to immunotherapy. For