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Effect of a small molecule BCL‐2 inhibitor on immune function and use with a recombinant vaccine
Author(s) -
Farsaci Benedetto,
Sabzevari Helen,
Higgins Jack P.,
Di Bari Maria Giovanna,
Takai Shinji,
Schlom Jeffrey,
Hodge James W.
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25177
Subject(s) - immune system , in vivo , cd8 , cancer research , biology , immunology , vaccination , immunotherapy , pharmacology , microbiology and biotechnology
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.