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475 Anti-TIGIT antibody tiragolumab leverages myeloid cells and regulatory T cells to improve PD-L1 checkpoint blockade
  1. Namrata Patil1,
  2. Raymond Meng1,
  3. Robert Johnston1,
  4. Patrick Chang1,
  5. Shyam Srivats1,
  6. Yoonha Choi1,
  7. Xiangnan Guan1,
  8. Barzin Nabet1,
  9. Lisa McGinnis1,
  10. Eugene Chiang1,
  11. Thinh Pham1,
  12. Alexis Dunkle1,
  13. Bill O’Gorman1,
  14. Ira Mellman1,
  15. Ruozhen Hu1,
  16. John Silva1,
  17. Joy Han1,
  18. Amelia Au-Yeung1,
  19. Chikara Takahashi1,
  20. Nandini Molden1,
  21. Pallavi Daggumati1,
  22. Wendy Connolly1,
  23. Melissa Johnson2,
  24. Delvys Rodriguez Abreu3,
  25. Byoung Chul Cho4,
  26. Antoine Italiano5,
  27. Ignacio Gil Bazo6,
  28. Enriqueta Felip7,
  29. Sanjeev Mariathasan1,
  30. Carlos Bais1 and
  31. David Shames1
  1. 1Genentech Inc., South San Francisco, CA, United States
  2. 2Sarah Cannon Research Institute, Nashville, TN, United States
  3. 3Hospital Universitario Insular, Las Palmas, Spain
  4. 4Yonsei University College of Medicine, Seoul, Korea, Republic of
  5. 5Institut Bergonie CLCC Bordeaux, Bordeaux, France
  6. 6Clínica Universidad de Navarra, Pamplona, Spain
  7. 7Vall d’Hebron Institute of Oncology, Barcelona, Spain


Background TIGIT is a co-inhibitory receptor and immune checkpoint associated with T cell and natural killer (NK) cell dysfunction in cancer. Tiragolumab is an anti-TIGIT antibody with an active, IgG1/kappa Fc. In a randomized double-blind phase 2 clinical trial in non-small cell lung cancer (NSCLC), tiragolumab + atezolizumab (anti-PD-L1) combination treatment demonstrated significant improvement relative to atezolizumab alone. However, the mechanisms underlying efficacy of this combination are not well understood.

Results Here, we show that tiragolumab functions as both a conventional checkpoint inhibitor and, via Fc gamma receptor (FcgR) engagement, as a modulator of immunosuppressive myeloid cells and T regulatory (Treg) cells. High levels of these cell subsets, which often mediate resistance to immunotherapy, were associated with treatment benefit in the tiragolumab + atezolizumab arm but not atezolizumab arm. Patients receiving the combination treatment exhibited transient on-treatment increases in serum proteins suggestive of myeloid cell activation, and decreases in circulating Treg cells. In preclinical experiments, treatment with Fc-active anti-TIGIT led to effector T cell and NK cell activation, Treg reduction, and proinflammatory modulation of myeloid cells and neutrophils.

Conclusions These findings reveal distinct mechanisms by which tiragolumab unleashes antitumor immune responses, and inform further clinical development of anti-TIGIT therapies.

Trial Registration NCT03563716

Ethics Approval Protocol approval was obtained from independent ethics committees for each participating site for both studies and an independent data monitoring committee reviewed the safety data.

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