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In Situ Transfection of Interleukin 12 Plasmid Enhances Anti-PD-1 Immune Response in Patients with Immunologically Quiescent Melanoma

37 Pages Posted: 5 Mar 2019 Sneak Peek Status: Review Complete

See all articles by Alain P. Algazi

Alain P. Algazi

University of California, San Francisco (UCSF) - Department of Medicine

Christopher G. Twitty

OncoSec Inc

Katy K. Tsai

University of California, San Francisco (UCSF) - Department of Medicine

Mai Le

Fred Hutchinson Cancer Research Center

Robert Pierce

Fred Hutchinson Cancer Research Center

Jean Campbell

Fred Hutchinson Cancer Research Center

Erica Browning

OncoSec Inc

Renata Hermiz

OncoSec Inc

Dave Canton

OncoSec Inc

Donna Bannavong

OncoSec Inc

Ari Oglesby

University of California, San Francisco (UCSF) - Department of Medicine

Murray Franco

OncoSec Inc

Lawrence Fong

University of California, San Francisco (UCSF) - Department of Medicine

Mikael J. Pittet

Massachusetts General Hospital - Center for Systems Biology

Sean P. Arlaukas

Massachusetts General Hospital - Center for Systems Biology

Christopher Garris

Massachusetts General Hospital - Center for Systems Biology

Sharron Gargosky

OncoSec Inc

Lauren P. Levine

University of California, San Francisco (UCSF) - Department of Medicine

Adam Olshen

University of California, San Francisco (UCSF) - Department of Medicine

Shailender Bhatia

Fred Hutchinson Cancer Research Center

Scot Ebbinhaus

Merck & Co., Inc.

Robert Andtbacka

Huntsman Cancer Institute

Bernard A. Fox

Providence Cancer Center - Earle A. Chiles Research Institute

Michael D. Rosenblum

University of California, San Francisco (UCSF) - Department of Dermatology

Daud Adlil

University of California, San Francisco (UCSF) - Department of Medicine; University of California, San Francisco (UCSF) - Department of Dermatology

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Abstract

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.

Suggested Citation

Algazi, Alain P. and Twitty, Christopher G. and Tsai, Katy K. and Le, Mai and Pierce, Robert and Campbell, Jean and Browning, Erica and Hermiz, Renata and Canton, Dave and Bannavong, Donna and Oglesby, Ari and Franco, Murray and Fong, Lawrence and Pittet, Mikael J. and Arlaukas, Sean P. and Garris, Christopher and Gargosky, Sharron and Levine, Lauren P. and Olshen, Adam and Bhatia, Shailender and Ebbinhaus, Scot and Andtbacka, Robert and Fox, Bernard A. and Rosenblum, Michael D. and Adlil, Daud, In Situ Transfection of Interleukin 12 Plasmid Enhances Anti-PD-1 Immune Response in Patients with Immunologically Quiescent Melanoma (March 5, 2019). Available at SSRN: https://ssrn.com/abstract=3346978 or http://dx.doi.org/10.2139/ssrn.3346978
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Alain P. Algazi

University of California, San Francisco (UCSF) - Department of Medicine

San Francisco, CA
United States

Christopher G. Twitty

OncoSec Inc

5820 Nany Ridge Drive
San Diego, 92121
United States

Katy K. Tsai

University of California, San Francisco (UCSF) - Department of Medicine

San Francisco, CA
United States

Mai Le

Fred Hutchinson Cancer Research Center

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Robert Pierce

Fred Hutchinson Cancer Research Center

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Jean Campbell

Fred Hutchinson Cancer Research Center

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Erica Browning

OncoSec Inc

5820 Nany Ridge Drive
San Diego, 92121
United States

Renata Hermiz

OncoSec Inc

5820 Nany Ridge Drive
San Diego, 92121
United States

Dave Canton

OncoSec Inc

5820 Nany Ridge Drive
San Diego, 92121
United States

Donna Bannavong

OncoSec Inc

5820 Nany Ridge Drive
San Diego, 92121
United States

Ari Oglesby

University of California, San Francisco (UCSF) - Department of Medicine

San Francisco, CA
United States

Murray Franco

OncoSec Inc

5820 Nany Ridge Drive
San Diego, 92121
United States

Lawrence Fong

University of California, San Francisco (UCSF) - Department of Medicine

San Francisco, CA
United States

Mikael J. Pittet

Massachusetts General Hospital - Center for Systems Biology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Sean P. Arlaukas

Massachusetts General Hospital - Center for Systems Biology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Christopher Garris

Massachusetts General Hospital - Center for Systems Biology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Sharron Gargosky

OncoSec Inc

5820 Nany Ridge Drive
San Diego, 92121
United States

Lauren P. Levine

University of California, San Francisco (UCSF) - Department of Medicine

San Francisco, CA
United States

Adam Olshen

University of California, San Francisco (UCSF) - Department of Medicine

San Francisco, CA
United States

Shailender Bhatia

Fred Hutchinson Cancer Research Center

1100 Fairview Avenue North
M2-C206
Seattle, WA 98109-1024
United States

Scot Ebbinhaus

Merck & Co., Inc.

2000 Galloping Hill Road
Kenilworth, NJ 07033
United States

Robert Andtbacka

Huntsman Cancer Institute

2000 Cir of Hope Dr
Salt Lake City, UT 84103
United States

Bernard A. Fox

Providence Cancer Center - Earle A. Chiles Research Institute

Providence, OR 97213
United States

Michael D. Rosenblum

University of California, San Francisco (UCSF) - Department of Dermatology

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Daud Adlil (Contact Author)

University of California, San Francisco (UCSF) - Department of Medicine ( email )

San Francisco, CA
United States

University of California, San Francisco (UCSF) - Department of Dermatology ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

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