Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells

Contributed by Robert L. Coffman, September 30, 2016 (sent for review May 31, 2016; reviewed by Wolf Fridman and Miriam Merad)
October 31, 2016
113 (46) E7240-E7249

Significance

Recent data suggest that patients harboring immunologically incompetent tumors fail to respond to programmed death 1 (PD-1) blockade. We have developed a mouse tumor model that mimics resistance found in human tumors, and we show that intratumoral injections of a high IFN-inducing CpG oligonucleotide, SD-101, can rapidly lead to durable rejection of anti–PD-1 nonresponder tumors and generate systemic immunity to untreated distant-site tumors. The change in tumor microenvironment caused by SD-101 leads to rapid T-cell infiltration and generation of multifunctional CD8+ T cells. These studies provide significant insights into the synergy between PD-1 blockade and local TLR9 activation and provide the experimental support for clinical studies of combination therapy with PD-1 blockade and intratumoral SD-101.

Abstract

Despite the impressive rates of clinical response to programmed death 1 (PD-1) blockade in multiple cancers, the majority of patients still fail to respond to this therapy. The CT26 tumor in mice showed similar heterogeneity, with most tumors unaffected by anti–PD-1. As in humans, response of CT26 to anti–PD-1 correlated with increased T- and B-cell infiltration and IFN expression. We show that intratumoral injection of a highly interferogenic TLR9 agonist, SD-101, in anti–PD-1 nonresponders led to a complete, durable rejection of essentially all injected tumors and a majority of uninjected, distant-site tumors. Therapeutic efficacy of the combination was also observed with the TSA mammary adenocarcinoma and MCA38 colon carcinoma tumor models that show little response to PD-1 blockade alone. Intratumoral SD-101 substantially increased leukocyte infiltration and IFN-regulated gene expression, and its activity was dependent on CD8+ T cells and type I IFN signaling. Anti–PD-1 plus intratumoral SD-101 promoted infiltration of activated, proliferating CD8+ T cells and led to a synergistic increase in total and tumor antigen-specific CD8+ T cells expressing both IFN-γ and TNF-α. Additionally, PD-1 blockade could alter the CpG-mediated differentiation of tumor-specific CD8+ T cells into CD127lowKLRG1high short-lived effector cells, preferentially expanding the CD127highKLRG1low long-lived memory precursors. Tumor control and intratumoral T-cell proliferation in response to the combined treatment is independent of T-cell trafficking from secondary lymphoid organs. These findings suggest that a CpG oligonucleotide given intratumorally may increase the response of cancer patients to PD-1 blockade, increasing the quantity and the quality of tumor-specific CD8+ T cells.

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Acknowledgments

We thank the team at Murigenics for assistance with animal work and thank our colleagues at Dynavax for critical reading of the manuscript.

Supporting Information

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 113 | No. 46
November 15, 2016
PubMed: 27799536

Classifications

Submission history

Published online: October 31, 2016
Published in issue: November 15, 2016

Keywords

  1. PD-1 blockade
  2. TLR9 agonist
  3. multifunctional CD8+ T cells

Acknowledgments

We thank the team at Murigenics for assistance with animal work and thank our colleagues at Dynavax for critical reading of the manuscript.

Authors

Affiliations

Shu Wang1
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710
Jose Campos1
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710
Marilena Gallotta
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710
Mei Gong
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710
Chad Crain
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710
Edwina Naik
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710
Robert L. Coffman2 [email protected]
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710
Cristiana Guiducci2 [email protected]
Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710

Notes

2
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: S.W., R.L.C., and C.G. designed research; J.C., M. Gallotta, M. Gong, C.C., and E.N. performed research; S.W., J.C., R.L.C., and C.G. analyzed data; and S.W., J.C., R.L.C., and C.G. wrote the paper.
Reviewers: W.F., Immune Microenvironment and Tumours Laboratory, Cordeliers Research Center, INSERM UMRS872; and M.M., Mt. Sinai School of Medicine.
1
S.W. and J.C. contributed equally to this work.

Competing Interests

Conflict of interest statement: The authors are present or former employees of Dynavax Technologies, which supported this work and is conducting clinical trials of SD-101 for the treatment of lymphoma and melanoma.

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    Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells
    Proceedings of the National Academy of Sciences
    • Vol. 113
    • No. 46
    • pp. 12887-E7347

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