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Clin Cancer Res. 2018 Aug 9. doi: 10.1158/1078-0432.CCR-18-0469. [Epub ahead of print]

Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma.

Author information

1
Department of Medicine, University of Washington Medical Center, Seattle, Washington. sbhatia@uw.edu.
2
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Department of Medicine, University of Washington Medical Center, Seattle, Washington.
4
Division of Dermatology, University of Washington Medical Center, Seattle, Washington.
5
Immune Design, Seattle, Washington, and South San Francisco, California.
6
Department of Surgery, University of Washington Medical Center, Seattle, Washington.
7
Department of Radiation Oncology, University of Washington Medical Center, Seattle, Washington.
8
Department of Global Health, University of Washington Medical Center, Seattle, Washington.
9
Department of Laboratory Medicine, University of Washington Medical Center, Seattle, Washington.
10
Benaroya Research Institute, Seattle, Washington.

Abstract

Purpose: G100 is a toll-like receptor 4 (TLR4) agonist that triggers innate and adaptive antitumor immune responses in preclinical models. This pilot study assessed the safety, efficacy, and immunologic activity of intratumoral (IT) administration of G100 in patients with Merkel cell carcinoma (MCC).Experimental Design: Patients with locoregional MCC (n = 3; cohort A) received neoadjuvant IT G100 (2 weekly doses at 5 μg/dose) followed by surgery and radiotherapy; patients with metastatic MCC (n = 7; cohort B) received 3 doses in a 6-week cycle and could receive additional cycles with/without radiotherapy.Results: IT G100 was safe and feasible in both neoadjuvant and metastatic settings. Treatment-related adverse events were mostly grade 1 or 2 injection-site reactions. IT G100 led to increased inflammation in the injected tumors with infiltration of CD8+ and CD4+ T cells and activation of immune-related genes. These proinflammatory changes were associated with local tumor regression and appeared to promote systemic immunity. All 3 cohort A patients successfully completed therapy; 2 patients remain recurrence free at 44+ and 41+ months, including 1 with a pathologic complete response after G100 alone. In cohort B, 2 patients achieved sustained partial responses, both lasting 33+ months after 2 cycles of therapy.Conclusions: In this first-in-human study, IT G100 induced antitumor immune responses, demonstrated acceptable safety, and showed encouraging clinical activity. Clin Cancer Res; 1-11. ©2018 AACR.

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