title: Immunosensitization with a Bcl-2 small molecule inhibitor.
abstract: Several tumor immunotherapy approaches result in a low percentage of durable responses in selected cancers. We hypothesized that the insensitivity of cancer cells to immunotherapy may be related to an anti-apoptotic cancer cell milieu, which could be pharmacologically reverted through the inhibition of antiapoptotic Bcl-2 family proteins in cancer cells. ABT-737, a small molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-w and Bcl-x(L), was tested for the ability to increase antitumor immune responses in two tumor immunotherapy animal models. The addition of systemic therapy with ABT-737 to the immunization of BALB/c mice with tumor antigen peptide-pulsed dendritic cells (DC) resulted in a significant delay in CT26 murine colon carcinoma tumor growth and improvement in survival. However, the addition of ABT-737 to either a vaccine strategy involving priming with TRP-2 melanoma antigen peptide-pulsed DC and boosting with recombinant Listeria monocytogenes expressing the same melanoma antigen, or the adoptive transfer of TCR transgenic cells, did not result in superior antitumor activity against B16 murine melanoma. In vitro studies failed to demonstrate increased cytotoxic lytic activity when testing the combination of ABT-737 with lymphokine activated killer (LAK) cells, or the death receptor agonists Fas, TRAIL-ligand or TNF-alpha against the CT26 and B16 cell lines. In conclusion, the Bcl-2 inhibitor ABT-737 sensitized cancer cells to the antitumor effect of antigen-specific immunotherapy in a vaccine model for the CT26 colon carcinoma in vivo but not in two immunotherapy strategies against B16 melanoma.
authors.affiliation: Department of Surgery, University of California at Los Angeles, UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095-1782, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Begley
authors.forename: Dan D
authors.initials: DD
authors.lastname: Vo
authors.forename: Lilah F
authors.initials: LF
authors.lastname: Morris
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bruhn
authors.forename: Robert M
authors.initials: RM
authors.lastname: Prins
authors.forename: Stephen
authors.initials: S
authors.lastname: Mok
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.forename: Hermes J
authors.initials: HJ
authors.lastname: Garban
authors.forename: Begonya
authors.initials: B
authors.lastname: Comin-Anduix
authors.forename: Noah
authors.initials: N
authors.lastname: Craft
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016219:Immunotherapy, Adoptive; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D015979:Killer Cells, Lymphokine-Activated / Q000637:transplantation; D008089:Listeria monocytogenes / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009596:Nitrophenols / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D053218:Receptors, Death Domain / Q000819:agonists; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D013449:Sulfonamides / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000494:pharmacology
chemical_list: C501332:ABT-737; D000951:Antigens, Neoplasm; D001713:Biphenyl Compounds; D019496:Cancer Vaccines; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D053218:Receptors, Death Domain; D011993:Recombinant Fusion Proteins; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase