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Combination Immunotherapy Lymphocytes Pan-Bcl-2 Inhibitor, GX15-070 (Obatoclax), Decreases Human T Regulatory Lymphocytes while Preserving Effector T Lymphocytes: A Rationale for Its Use in This information is current as Combination Immunotherapy of September 29, 2021. Peter S. Kim, Caroline Jochems, Italia Grenga, Renee N. Donahue, Kwong Y. Tsang, James L. Gulley, Jeffrey Schlom and Benedetto Farsaci J Immunol published online 10 February 2014 Downloaded from http://www.jimmunol.org/content/early/2014/02/07/jimmun ol.1301369 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 10, 2014, doi:10.4049/jimmunol.1301369 The Journal of Immunology 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 Peter S. Kim, Caroline Jochems, Italia Grenga, Renee N. Donahue, Kwong Y. Tsang, James L. Gulley, Jeffrey Schlom,1 and Benedetto Farsaci1 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 Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2014, 192: 000–000. X15-070 (GX15; obatoclax), a pan-Bcl-2 inhibitor, has bers (most notably, not to Mcl-1) (10, 11). Therefore, tumor cells been widely tested in clinical trials ever since the U.S. may become resistant to ABT-737 and ABT-263 by overexpression Food and Drug Administration granted it orphan drug of Mcl-1, which GX15 has been shown to inhibit (12). G by guest on September 29, 2021 status for the treatment of chronic lymphocytic leukemia. GX15 In preclinical studies, a wide range of GX15 concentrations was has also been tested preclinically and clinically for efficacy in acute used depending on the targets to be assayed. For instance, IC50sof myelogenous leukemia (1), mantle cell lymphoma (2), multiple GX15 in human lung cancer cell lines ranged from 1.33 to 15.4 myeloma (3), myelofibrosis (4), and solid tumors such as small- mM (8). In clinical studies, Cmax of GX15 was reported to be in cell lung cancer (5–9). the range of 0.03–0.36 mM (11). In a phase I dose-escalation study GX15 is a synthetic derivative of bacterial prodiginines be- of GX15 in patients with advanced solid tumors or lymphoma, the longing to the polypyrrole class of molecules. GX15 mimics the maximum tolerated dose using a 3-h i.v. infusion schedule in 27 2 BH3 domain of the antiapoptotic family members of Bcl-2 but patients was 20 mg/m , with Cmax of 0.28 mM and area under the differs from other Bcl-2 inhibitors by having consistent binding curve of 0.95 mM (5). On the basis of in vitro concentrations properties across all antiapoptotic Bcl-2 family members, includ- of GX15 and pharmacokinetic data derived from a search of the ing Bcl-2, Bcl-xL, Bcl-w, myeloid-cell leukemia differentiation literature, we used GX15 in concentrations ranging from 0.1 to 5 protein-1 (Mcl-1), and Bak, and is thus classified as a pan-Bcl-2 mM. As a single agent, GX15 has thus far shown modest clinical inhibitor. For instance, other Bcl-2 inhibitors such as ABT-737 activity (10, 11), leading some investigators to combine GX15 and ABT-263 have higher binding affinity to Bcl-2 and Bcl-xL with other anticancer agents such as bortezomib (a proteasome than does GX15, but they do not bind to all Bcl-2 family mem- inhibitor) (13, 14) and SNDX-275 (a histone deacetylase inhibitor) (15–17). These combinations have had an enhanced antitumor effect against hematologic malignancies. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, Na- In a preclinical model, we previously investigated the potential tional Cancer Institute, National Institutes of Health, Bethesda, MD 20892 1 of GX15 to synergize with vaccine-based immunotherapy using J.S. and B.F. contributed equally. a recombinant vaccine (recombinant vaccinia [rV] and recombi- Received for publication May 22, 2013. Accepted for publication January 7, 2014. nant fowlpox [rF]) encoding the tumor-associated carcinoem- This work was supported by the Intramural Research Program of the Center for Cancer bryonic Ag (CEA) and a triad of costimulatory molecules (rV/F- Research, National Cancer Institute, National Institutes of Health. CEA-TRICOM) in CEA-transgenic mice (18). We determined Address correspondence and reprint requests to Jeffrey Schlom, Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, that the sensitivity of murine lymphocytes to GX15 was dependent – National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892. on their activation status, as mature-activated CD69 lymphocytes E-mail address: [email protected] were more resistant to GX15 than early-activated CD69+ lym- Abbreviations used in this article: CEA, carcinoembryonic Ag; CTV, CellTrace Vi- phocytes in vitro (18). This finding suggested that GX15 should olet; Mcl-1, myeloid-cell leukemia differentiation protein-1; MFI, mean fluorescence intensity; PARP, poly(ADP-ribose) polymerase; Teff, effector T cell; Treg, regulatory ideally be administered after lymphocytes have undergone full T cell; TRICOM, triad of costimulatory molecule. maturation postvaccination (18). In addition, GX15 impaired the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301369 2 EFFECT OF GX15-070 ON HUMAN IMMUNE CELLS suppressive function of murine regulatory T cells (Tregs) isolated CD28 MACSi Beads (Miltenyi Biotec) for 1 d, then supplemented with IL-2 from GX15-treated mice (18). Finally, sequential combination (PeproTech) at 500 U/ml during the 14-d expansion period. therapy with rV/F-CEA-TRICOM vaccine followed by GX15 Treg suppression assay effectively reduced orthotopic pulmonary tumors (18), providing Tregs were first pretreated with GX15 at 1 mM for 24 h. CD4+CD25– a rationale for designing similar combination protocols for clinical 4 effector T (Teff) cells (1 3 10 cells/ml) were cultured alone or cocultured trials. with Tregs (1 3 104,53 103,or13 103 cells/ml) with 1 mg/ml plate- In this study, we evaluated the effect of GX15 on specific subsets bound anti-CD3 (clone OKT3; eBioscience, San Diego, CA) and irradiated of human T lymphocytes. Using PBMCs from healthy donors and (3500 rad) T cell–depleted PBMCs (1 3 105 cells/ml) in a 96-well flat- ovarian cancer patients, GX15 toxicity depended on the activation bottom plate at 37˚C and 5% CO2. On day 4, T cell proliferation was measured by [3H]thymidine (PerkinElmer, Waltham, MA) incorporation at status of human T lymphocytes, as indicated by CD69 expression. 1 mCi (0.037 MBq)/well and quantified 16 h later using a Wizard 2 gamma Furthermore, GX15 downregulated expression levels of both counter. Proliferation of CD4+CD25– T cells without Tregs was defined as FOXP3 and CTLA-4 in human Tregs and decreased their sup- 100% proliferation. Percent suppression was calculated using the follow- pressive function. The data obtained from this study provide a further ing formula: (cpm of Teff cells alone 2 cpm of Teff cells treated with rationale for the clinical translation of the combination of active Treg)/cpm of Teff cells alone. immunotherapy agents in a temporal regimen with the Bcl-2 In vitro treatment with GX15 inhibitor GX15. GX15 at a concentration of 5 mM was used for early and prolonged ac- tivation studies of PBMCs from healthy donors (n = 3). GX15 at a con- Materials and Methods centration of 1 mM was used for Treg suppression assay. GX15 at concentrations of 0.1, 1.0, and 5.0 mM was used to treat expanded Tregs and Downloaded from Drug preparation PBMCs taken from stage IIIc or IV ovarian cancer patients (n = 4) who had GX15 (obatoclax) was obtained through an agreement between the Cancer progressed on chemotherapy.
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