| Autor: |
Jean S. Campbell, Renata Hermiz, Alain Algazi, Donna Bannavong, Michael Rosenblum, Lawrence Fong, Sharron Gargosky, Erica Browning, Christopher Garris, Scot Ebbinhaus, Christopher G. Twitty, Mikael J. Pittet, Adam B. Olshen, Lauren P. Levine, Robert H.I. Andtbacka, Robert H. Pierce, Bernard A. Fox, Ari Oglesby, Shailender Bhatia, Murray Franco, Sean P. Arlaukas, Katy K. Tsai, Mai Le, Dave Canton, Daud Adlil |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| Popis: |
Non-response to anti-PD-1 antibodies is characterized by a “cold” tumor microenvironment lacking “exhausted” CD8+ T cells. We report on the first prospective Phase 2 trial of intratumoral plasmid IL-12 and pembrolizumab in advanced melanoma with “exhausted” T-cell (peCTL) poor tumors that had a low pre-test probability of response to anti-PD-1 Ab monotherapy. Patients had a 43% objective response rate (n=23, RECIST 1.1) with 38% complete responses. Interrogation of samples demonstrated that, while intratumoral IL-12 triggered a rapid increase in immune signaling and licensing of the tumor microenvironment, the compensatory adaptive resistance blunted clinical responses. However, by disrupting the PD-1/PD-L1 axis with pembrolizumab, the IL-12/IFN-γ feed-forward cycle was sustained, driving intratumoral cross-presenting DC subsets with increased TIL and TCR clonality and, ultimately, systemic cellular immune responses. Thus, combination of intratumoral plasmid IL-12 with pembrolizumab transformed poorly immunogenic lesions into effective in situ vaccines, attaining clinical activity in low peCTL tumors. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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