title: Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy.
abstract: Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly downregulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8(+):Treg and CD4(+):Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8(+) T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor.
authors: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Peter S
authors: PS
authors: Kim
authors: Caroline
authors: C
authors: Jochems
authors: Italia
authors: I
authors: Grenga
authors: Renee N
authors: RN
authors: Donahue
authors: Kwong Y
authors: KY
authors: Tsang
authors: James L
authors: JL
authors: Gulley
authors: Jeffrey
authors: J
authors: Schlom
authors: Benedetto
authors: B
authors: Farsaci
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007211:Indoles; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D010051:Ovarian Neoplasms / Q000097:blood / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; C520962:obatoclax