In the phase 2 CITYSCAPE trial, patients treated with tiragolumab and atezolizumab (anti-TIGIT/anti-PD-L1 combination) had improved outcomes compared to anti-PD-L1 alone. In studying the MOA, Guan et al. unexpectedly found that high baseline levels of intratumoral macrophages and Treg cells, along with serum macrophage activation, correlated with better clinical outcomes. In murine tumor models, a functional Fc domain of anti-TIGIT was required to activate tumor and circulating myeloid cells synergistically with anti-PD-L1, driving antitumor CD8+ T cells from an exhausted state to a more memory-like state.
Contributed by Katherine Turner
ABSTRACT: Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
Author Info: (1) Genentech Inc., South San Francisco, CA, USA. (2) Genentech Inc., South San Francisco, CA, USA. (3) Genentech Inc., South San Francisco, CA, USA. (4) Genentech Inc., South San
Author Info: (1) Genentech Inc., South San Francisco, CA, USA. (2) Genentech Inc., South San Francisco, CA, USA. (3) Genentech Inc., South San Francisco, CA, USA. (4) Genentech Inc., South San Francisco, CA, USA. (5) Genentech Inc., South San Francisco, CA, USA. (6) Genentech Inc., South San Francisco, CA, USA. (7) Genentech Inc., South San Francisco, CA, USA. (8) Genentech Inc., South San Francisco, CA, USA. (9) Genentech Inc., South San Francisco, CA, USA. (10) Genentech Inc., South San Francisco, CA, USA. (11) Genentech Inc., South San Francisco, CA, USA. (12) Genentech Inc., South San Francisco, CA, USA. (13) Genentech Inc., South San Francisco, CA, USA. (14) Genentech Inc., South San Francisco, CA, USA. (15) Genentech Inc., South San Francisco, CA, USA. (16) Genentech Inc., South San Francisco, CA, USA. (17) Genentech Inc., South San Francisco, CA, USA. (18) Genentech Inc., South San Francisco, CA, USA. (19) Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA. (20) Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain. (21) Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South Korea. (22) Institut Bergonie CLCC Bordeaux, Bordeaux, France. Faculty of Medicine, University of Bordeaux, Bordeaux, France. (23) Clnica Universidad de Navarra, CIMA Universidad de Navarra Pamplona, Pamplona, Spain. (24) Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. (25) Genentech Inc., South San Francisco, CA, USA. (26) Genentech Inc., South San Francisco, CA, USA. (27) Genentech Inc., South San Francisco, CA, USA. (28) Genentech Inc., South San Francisco, CA, USA. (29) Genentech Inc., South San Francisco, CA, USA. (30) Genentech Inc., South San Francisco, CA, USA. johnston.robert@gene.com. (31) Genentech Inc., South San Francisco, CA, USA. patil.namrata@gene.com.
