Introduction

V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint regulator that is present on tumor, myeloid, and other immune cells. Its role in enhancing tumor growth and creating an immunosuppressive microenvironment has been well documented, potentially leading to resistance against anti-CTLA-4 and anti-PD-1/PD-L1 therapies. Consequently, VISTA has emerged as a promising therapeutic target.

HMBD-002, a first-in-class, clinical-stage, non-depleting, high-affinity IgG4 monoclonal antibody targeting VISTA, has demonstrated significant inhibition of tumor growth in preclinical studies, both as monotherapy and in combination with anti-PD1. HMBD-002 acts by increasing T-cell activity and reprogramming the suppressive tumor microenvironment to a proinflammatory antitumor phenotype.

Notably, certain cancer types including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC), exhibit elevated levels of VISTA in the tumor microenvironment (TME). This high expression provides a solid rationale for investigating the potential benefits of HMBD-002 in clinical studies for these indications.

Methods

A phase 1/2, open-label, multi-center trial is being conducted in two parts aimed to evaluate the safety, pharmacokinetics, and antitumor activity of HMBD-002 both as a monotherapy and in combination with pembrolizumab.

In the dose-escalation stage (Part 1), a standard 3 + 3 study design is being employed, with weekly dosing and adaptive dose-escalation increments. The primary objective is to determine the recommended phase 2 dose (RP2D) for subsequent disease-directed studies.

The dose-expansion stage (Part 2) focuses on assessing the antitumor activity of HMBD-002 as a monotherapy treatment and in combination with pembrolizumab, in patients with triple-negative breast cancer, non-small cell lung cancer, and various other malignancies that express VISTA.

Exploratory analyses will be conducted in collaboration with the Immunotherapy Platform at MDACC to assess treatment-induced immunological changes both systemically and within the tumor microenvironment. To achieve this, longitudinal blood samples will be collected and analyzed using single-cell mass cytometry (CyTOF) and multiplex cytokine analysis.

Additionally, pre- and on-treatment tumor tissue samples will undergo immunohistochemistry (IHC) analysis to determine VISTA and PD-L1 expression within the tumor microenvironment. Multiplex immunofluorescence and gene-expression profiling of the tumor tissues will be conducted to gain deeper insights into the treatment associated changes within the tumor immune microenvironment.

Results

We have successfully completed and cleared five dose levels in the monotherapy treatment, and to the best of our knowledge, dosed higher than any other VISTA antibodies in the clinic. We have now commenced the dose escalation of combination cohorts.

Conclusion

VISTA represents a promising therapeutic target for enhancing antitumor immune responses. HMBD-002, a high-affinity monoclonal antibody targeting VISTA, has demonstrated significant inhibition of tumor growth in preclinical studies and is currently undergoing evaluation in a phase 1/2 clinical trial. The successful completion of five monotherapy cohorts and the initiation of combination cohorts pave the way for further exploration of HMBD-002's potential as a novel immunotherapeutic agent for cancer treatment.

Clinical trial information: NCT05082610