In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: A phase I/II study

Joshua D. Brody, Weiyun Z. Ai, Debra K. Czerwinski, James A. Torchia, Mia Levy, Ranjana H. Advani, Youn H. Kim, Richard T. Hoppe, Susan J. Knox, Lewis K. Shin, Irene Wapnir, Robert J. Tibshirani, Ronald Levy

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377 Scopus citations

Abstract

Purpose: Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors. Patients and Methods: We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and - at that same site - injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells. Results: This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response. Conclusion: In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

Original languageEnglish
Pages (from-to)4324-4332
Number of pages9
JournalJournal of Clinical Oncology
Volume28
Issue number28
DOIs
StatePublished - 1 Oct 2010

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