title: Effect of a small molecule BCL-2 inhibitor on immune function and use with a recombinant vaccine.
abstract: Small molecule BCL-2 inhibitors are being examined as monotherapy in phase I/II clinical trials for several types of tumors. However, few data are available about the effect of BCL-2 inhibitors on immune function. The aims of our study were to investigate the effect of a small molecule BCL-2 inhibitor on immune function and determine the most effective way of combining this inhibitor with a recombinant vaccine to treat tumors. The in vitro effect of the pan-BCL-2 inhibitor GX15-070 was assessed in mouse CD8 T lymphocytes at 2 different stages of activation as well as regulatory T lymphocytes (Treg). The in vivo effect of GX15-070 after recombinant vaccinia/fowlpox CEA-TRICOM vaccination was analyzed in tumor-infiltrating lymphocytes, and in splenocytes of mice bearing subcutaneous tumors. The therapeutic efficacy of such sequential therapy was measured as a reduction of pulmonary tumor nodules. Activated mature CD8 T lymphocytes were more resistant to GX15-070 as compared to early-activated cells. Treg function was significantly decreased after treatment with the BCL-2 inhibitor. In vivo, GX15-070 was given after vaccination so as to not negatively impact the induction of vaccine-mediated immunity, resulting in increased intratumoral activated CD8:Treg ratio and significant reduction of pulmonary tumor nodules. Our study is the first to show the effect of a small molecule BCL-2 inhibitor on the immune system and following a vaccine. It is also the first to demonstrate the efficacy of this sequence in reducing tumors in mouse models, providing a rationale for the design of combinational clinical studies.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Farsaci
authors.forename: Helen
authors.initials: H
authors.lastname: Sabzevari
authors.forename: Jack P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Di Bari
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D002453:Cell Cycle; D005434:Flow Cytometry; D018960:Hyaluronan Receptors / Q000276:immunology; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; D018960:Hyaluronan Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D014614:Vaccines, Synthetic