title: Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells.
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 CD127lowKLRG1highshort-lived effector cells, preferentially expanding the CD127highKLRG1lowlong-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.
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710.
authors: Shu
authors: S
authors: Wang
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710.
authors: Jose
authors: J
authors: Campos
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710.
authors: Marilena
authors: M
authors: Gallotta
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710.
authors: Mei
authors: M
authors: Gong
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710.
authors: Chad
authors: C
authors: Crain
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710.
authors: Edwina
authors: E
authors: Naik
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710 cguiducci@dynavax.com RCoffman@dynavax.com.
authors: Robert L
authors: RL
authors: Coffman
authors: Discovery, Dynavax Technologies Corporation, Berkeley, CA 94710 cguiducci@dynavax.com RCoffman@dynavax.com.
authors: Cristiana
authors: C
authors: Guiducci
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015552:Injections, Intralesional; D007370:Interferon Type I / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D051217:Toll-Like Receptor 9 / Q000819:agonists; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: C408982:CPG-oligonucleotide; D007370:Interferon Type I; D009838:Oligodeoxyribonucleotides; D061026:Programmed Cell Death 1 Receptor; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9
keywords: PD-1 blockade; TLR9 agonist; multifunctional CD8+ T cells