74 a-TIGIT mAb belrestotug in combination with anti-PD1 induces an immunocompetent tumor microenvironment (TME)

Background

T cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint inhibitor expressed mainly on NK and T cell populations. Antagonist a-TIGIT mAbs in combination with a-PD(L)-1 demonstrated clinical proof of concept in 1L NSCLC.^{1 2} Belrestotug (previously known as EOS-448 or GSK4428859A) is an antagonistic anti-TIGIT human immunoglobulin G1 (hIgG1) antibody, designed to prevent ligand binding and to engage Fc gamma receptors (FcγR), resulting in a multifaceted mode of action: (i) activate effector T cells and NK cells (ii) modulate antigen-presenting cells, and (iii) deplete suppressive regulatory T cells (Tregs) as well as terminally exhausted CD8 T cells that express the highest levels of TIGIT.^3–5 In a first-in-human trial, belrestotug demonstrated a good tolerability profile with early signs of efficacy⁶ and we reported for the first time intratumoral TIGIT target engagement in the patient tumors.⁵ Belrestotug is currently being tested in combination with anti-PD1 in solid tumors.

Results

Pharmacodynamic assessment made by flow cytometry in the blood of patients treated with belrestotug in monotherapy and in combination with anti-PD1 (pembrolizumab or dostarlimab) showed (i) increased proportion of proliferating memory CD8+ T and NK cells during the first treatment cycle, (ii) sustained depletion of immunosuppressive Tregs, and (iii) decreased proportion of TIGIT high CD8+ T cells. We demonstrated the terminally exhausted phenotype of the TIGIT high CD8+ T cells targeted by belrestotug by isolating peripheral blood mononuclear cells (PBMCs) from treatment naïve cancer patients. Tregs in the tumor microenvironment (TME) hinder effective tumor immune response and are mainly localized in the stromal area. Stromal Tregs co-expressing several immune checkpoint inhibitors, including TIGIT, have a high immunosuppressive profile and its density is associated with poor clinical outcome.⁷ We investigated the functional effect of belrestotug combined with anti-PD1 on the TME using a multiplex immunofluorescence (mIF) panel. We observed a decrease of immunosuppressive TIGIT+ Tregs and PD1+ Tregs in the stroma, as well as a spatial reorganization.

Conclusions

Overall, our data suggests a mechanism whereby belrestotug in combination with anti-PD1 induces a more immunocompetent TME driven by immunosuppressive Treg depletion. These data support the clinical development of the doublet therapy to enhance an anti-tumor immune response.

References

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