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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.
- Source :
-
Journal of Immunology . 3/15/2014, Vol. 192 Issue 6, p2622-2633. 12p. - Publication Year :
- 2014
-
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 dosedependent 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MONONUCLEAR leukocytes
*CLINICAL immunology
*IMMUNOTHERAPY
*LYMPHOCYTES
*LEUCOCYTES
Subjects
Details
- Language :
- English
- ISSN :
- 00221767
- Volume :
- 192
- Issue :
- 6
- Database :
- Academic Search Index
- Journal :
- Journal of Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 103555779
- Full Text :
- https://doi.org/10.4049/jimmunol.1301369