The Experts below are selected from a list of 392451 Experts worldwide ranked by ideXlab platform
Thomas A. Waldmann - One of the best experts on this subject based on the ideXlab platform.
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bench to bedside translation of Interleukin 15 for immunotherapy principles and challenges
Expert Opinion on Drug Delivery, 2020Co-Authors: Chalet Tan, Thomas A. WaldmannAbstract:Since its discovery 25 years ago by our group and Grabstein et al. [1–3], Interleukin-15 (IL-15) has attracted much attention in terms of its biological activities, mechanism of action and therapeutic modulations under various physiological and pathological conditions. In particular, the stimulatory effects of IL-15 on the proliferation and effector functions of natural killer (NK) cells and CD8+ T cells make it a promising component for immunotherapy in the treatment of malignancies and infectious diseases [4,5]. Here, we present a brief summary on the biological principles of how IL-15 exerts immunostimulatory effects on cells, the clinical investigations on IL-15-based therapeutic agents, and the challenges for safe and efficacious delivery of IL-15 in patients.
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abstract 1332 Interleukin 15 enhances rituximab dependent cytotoxicity ex vivo and in vivo against a mouse lymphoma expressing human cd20
Cancer Research, 2015Co-Authors: Bernard Wen, Meili Zhang, David Dilillo, Jeffrey V Ravetch, Thomas A. WaldmannAbstract:Rituximab (RTX), an anti-CD20 antibody, revolutionized treatment for B-cell malignancies, but it is not without its own shortcomings, most notably tumor relapse. Recent research has provided evidence supporting the increased efficacy of RTX when combined with Interleukin-15 (IL-15). IL-15 enhances antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of RTX, by increasing the proliferation and activation of natural killer (NK) cells, as well as monocytes and macrophages. However, the majority of this evidence has been obtained through in vitro experiments and in vivo models using xenografts in immuno-deficient mice. Given the complexity of the immune system, we used an immuno-competent, syngeneic mouse model of human B-cell lymphoma to further investigate the effect of combining IL-15 with RTX to enhance ADCC. Wild-type (WT) C57BL/6 mice (n = 40) were distributed into treatment groups of 10 mice each, and inoculated intravenously with EL4-CD20 cells, a mouse lymphoma line transfected with human CD20. IL-15 was given five times per week for 4 weeks (5μg/mouse), starting on day 3 after tumor inoculation, and RTX was given once per week for 4 weeks (100 μg/mouse), starting on day 5. While IL-15 and RTX individually prolonged survival of the mice when compared with the control (p Citation Format: Bernard Wen, Meili Zhang, David Dilillo, Jeffrey V. Ravetch, Thomas A. Waldmann. Interleukin-15 enhances rituximab-dependent cytotoxicity ex vivo and in vivo against a mouse lymphoma expressing human CD20. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1332. doi:10.1158/1538-7445.AM2015-1332
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Interleukin 15 in the treatment of cancer
Expert Review of Clinical Immunology, 2014Co-Authors: Thomas A. WaldmannAbstract:IL-15 is a 14-15 kDa member of the four α-helix bundle of cytokines that acts through a heterotrimeric receptor involving IL-2/IL-15R β, γc and the IL-15 specific receptor subunit IL-15R α. IL-15 stimulates the proliferation of T, B and NK cells, and induces stem, central and effector memory CD8 T cells. In rhesus macaques, continuous infusion of recombinant human IL-15 at 20 μg/kg/day was associated with approximately a 10-fold increase in the numbers of circulating NK, γ/δ cells and monocytes, and an 80- to 100-fold increase in the numbers of effector memory CD8 T cells. IL-15 has shown efficacy in murine models of malignancy. Clinical trials involving recombinant human IL-15 given by bolus infusions have been completed and by subcutaneous and continuous intravenous infusions are underway in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL-15 with IL-15R α(+/-) IgFc.
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the role of Interleukin 15 in inflammation and immune responses to infection implications for its therapeutic use
Microbes and Infection, 2012Co-Authors: Pinyu Perera, Thomas A. Waldmann, Jack H Lichy, Liyanage P PereraAbstract:Interleukin-15 (IL-15) is a pleiotropic cytokine with a broad range of biological functions in many diverse cell types. It plays a major role in the development of inflammatory and protective immune responses to microbial invaders and parasites by modulating immune cells of both the innate and adaptive immune systems. This review provides an overview of the mechanisms by which IL-15 modulates the host response to infectious agents and its utility as a cytokine adjuvant in vaccines against infectious pathogens.
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Interleukin 15 biology and its therapeutic implications in cancer
Trends in Pharmacological Sciences, 2012Co-Authors: Jason C Steel, Thomas A. Waldmann, John C MorrisAbstract:Cancer immunotherapy is designed to stimulate the immune system to reject and destroy tumors. Recently, Interleukin-15 (IL-15), a member of the four α-helix bundle family of cytokines, has emerged as a candidate immunomodulator for the treatment of cancer. IL-15 acts through its specific receptor, IL-15Rα, which is expressed on antigen-presenting dendritic cells, monocytes and macrophages. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. It also enhances the cytolytic activity of CD8 + T cells and induces long-lasting antigen-experienced CD8 + CD44 hi memory T cells. IL-15 stimulates differentiation and immunoglobulin synthesis by B cells and induces maturation of dendritic cells. It does not stimulate immunosuppressive T regulatory cells (Tregs). Thus, boosting IL-15 activity could enhance innate and specific immunity and fight tumors. Here we review aspects of IL-15 biology that make it a promising agent for anticancer therapy. We also discuss preclinical models in which IL-15 has demonstrated antitumor activity and highlight ongoing clinical trials of IL-15 in patients with cancer and HIV infection.
Cliona M Rooney - One of the best experts on this subject based on the ideXlab platform.
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engineering cd19 specific t lymphocytes with Interleukin 15 and a suicide gene to enhance their anti lymphoma leukemia effects and safety
Leukemia, 2010Co-Authors: Valentina Hoyos, Concetta Quintarelli, Aruna Mahendravada, Juan F Vera, Helen E Heslop, Barbara Savoldo, Ming Zhang, Cliona M RooneyAbstract:Engineering CD19-specific T lymphocytes with Interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety
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engineering cd19 specific t lymphocytes with Interleukin 15 and a suicide gene to enhance their anti lymphoma leukemia effects and safety
Leukemia, 2010Co-Authors: Valentina Hoyos, Concetta Quintarelli, Aruna Mahendravada, Juan F Vera, Helen E Heslop, Barbara Savoldo, Ming Zhang, Cliona M RooneyAbstract:T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the Interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells 40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies.
Barbara Savoldo - One of the best experts on this subject based on the ideXlab platform.
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engineering cd19 specific t lymphocytes with Interleukin 15 and a suicide gene to enhance their anti lymphoma leukemia effects and safety
Leukemia, 2010Co-Authors: Valentina Hoyos, Concetta Quintarelli, Aruna Mahendravada, Juan F Vera, Helen E Heslop, Barbara Savoldo, Ming Zhang, Cliona M RooneyAbstract:Engineering CD19-specific T lymphocytes with Interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety
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engineering cd19 specific t lymphocytes with Interleukin 15 and a suicide gene to enhance their anti lymphoma leukemia effects and safety
Leukemia, 2010Co-Authors: Valentina Hoyos, Concetta Quintarelli, Aruna Mahendravada, Juan F Vera, Helen E Heslop, Barbara Savoldo, Ming Zhang, Cliona M RooneyAbstract:T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the Interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells 40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies.
Helen E Heslop - One of the best experts on this subject based on the ideXlab platform.
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engineering cd19 specific t lymphocytes with Interleukin 15 and a suicide gene to enhance their anti lymphoma leukemia effects and safety
Leukemia, 2010Co-Authors: Valentina Hoyos, Concetta Quintarelli, Aruna Mahendravada, Juan F Vera, Helen E Heslop, Barbara Savoldo, Ming Zhang, Cliona M RooneyAbstract:Engineering CD19-specific T lymphocytes with Interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety
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engineering cd19 specific t lymphocytes with Interleukin 15 and a suicide gene to enhance their anti lymphoma leukemia effects and safety
Leukemia, 2010Co-Authors: Valentina Hoyos, Concetta Quintarelli, Aruna Mahendravada, Juan F Vera, Helen E Heslop, Barbara Savoldo, Ming Zhang, Cliona M RooneyAbstract:T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the Interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL-15). We found that compared with CAR.19(+) T cells, iC9/CAR.19/IL-15(+) T cells had: (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10+/-6% for iC9/CAR.19/IL-15(+) T cells and 32+/-19% for CAR.19(+) T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells 40% for CAR.19(+) T cells); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL-15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies.
John C Morris - One of the best experts on this subject based on the ideXlab platform.
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abstract a52 vaccine cells derived from cancer stem cells expressing Interleukin 15 and its receptor inhibit tumor growth
Cancer immunology research, 2018Co-Authors: Donatien Kamdem Toukam, Jason C Steel, Christian Carwell, Ihab Eldessouki, John C MorrisAbstract:Background: Interleukin-15 (IL-15) is a powerful activator and inducer of NK cells and cytolytic CD8+ T cells. IL-15 also activates and expands CD8+ memory T cells without stimulating immunosuppressive CD4+CD25+ T regulatory cells. As such, IL-15 may be useful as an immunotherapy for cancer. In an effort to enhance antitumor activity and reduce systemic side effects, we studied an approach using a tumor vaccine enriched for cancer stem cells (CSCs) expressing murine (m) IL-15 and its receptor (mIL-15Rα). Methods: Lentiviral vectors expressing the wild type or optimized (opt) cDNA sequences for mIL-15 and/or mIL-15Rα under the control of the human EF-1 promoter were generated and used to transduce TC1 mouse lung cancer cells. The TC1 cells were cultured under low serum conditions to generate tumor spheroids enriched for CSCs. Results: The transduced TC1 cells demonstrated the expected mRNA transcripts. On flow cytometry only the cells transduced with mIL15Rα in combination with mIL-15 showed surface expression of mIL-15, while cells transduced with mIL-15 or mIL-15Rα constructs did not. When co-cultured with the transduced tumor spheroids or incubated with supernatants from these TC1 cells, CTLL-2 murine T cells demonstrated proliferation indicating that the cloned cDNAs expressed functional proteins. The vector demonstrating the greatest stimulation of CTLL-2 cells expressed both the mIL-15Rα and mIL-15opt sequences and demonstrated suppressed TC1 tumor growth in vivo. Conclusion: CSCs expressing mIL-15Rα and mIL-15 stimulated proliferation of T cells in vitro and demonstrated inhibited tumor growth in mice. In vivo tumor vaccination studies are in progress. Citation Format: Donatien Kamdem Toukam, Jason C. Steel, Christian Carwell, Ihab Eldessouki, John C. Morris. Vaccine cells derived from cancer stem cells expressing Interleukin-15 and its receptor inhibit tumor growth [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A52.
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redistribution hyperproliferation activation of natural killer cells and cd8 t cells and cytokine production during first in human clinical trial of recombinant human Interleukin 15 in patients with cancer
Journal of Clinical Oncology, 2015Co-Authors: Kevin C Conlon, Sigrid Dubois, John C Morris, Enrico Lugli, Hugh C Welles, Steven A Rosenberg, Antonio Tito Fojo, Thomas A Fleisher, Liyanage P PereraAbstract:Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fo...
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Interleukin 15 biology and its therapeutic implications in cancer
Trends in Pharmacological Sciences, 2012Co-Authors: Jason C Steel, Thomas A. Waldmann, John C MorrisAbstract:Cancer immunotherapy is designed to stimulate the immune system to reject and destroy tumors. Recently, Interleukin-15 (IL-15), a member of the four α-helix bundle family of cytokines, has emerged as a candidate immunomodulator for the treatment of cancer. IL-15 acts through its specific receptor, IL-15Rα, which is expressed on antigen-presenting dendritic cells, monocytes and macrophages. IL-15 exhibits broad activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. It also enhances the cytolytic activity of CD8 + T cells and induces long-lasting antigen-experienced CD8 + CD44 hi memory T cells. IL-15 stimulates differentiation and immunoglobulin synthesis by B cells and induces maturation of dendritic cells. It does not stimulate immunosuppressive T regulatory cells (Tregs). Thus, boosting IL-15 activity could enhance innate and specific immunity and fight tumors. Here we review aspects of IL-15 biology that make it a promising agent for anticancer therapy. We also discuss preclinical models in which IL-15 has demonstrated antitumor activity and highlight ongoing clinical trials of IL-15 in patients with cancer and HIV infection.
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simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by Interleukin 15 in a murine metastatic colon carcinoma model
Clinical Cancer Research, 2010Co-Authors: Jason C Steel, John C Morris, Meili Zhang, Thomas A. WaldmannAbstract:Purpose: Interleukin 15 (IL-15) is a promising cytokine for immunotherapy of cancer due to its ability to stimulate the immunity of natural killer, B, and T cells. Its effectiveness, however, may be limited by inhibitory checkpoints and pathways that can attenuate immune responses. Finding strategies to abrogate these negative regulators and enhance the efficacy of IL-15 is a critical challenge. Experimental Design: In a preclinical study, we evaluated IL-15 combined with antibodies to block the negative immune regulators cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in a metastatic murine CT26 colon carcinoma model. Results: IL-15 treatment resulted in a significant prolongation of survival in mice with metastatic tumor. Administration of IL-15, however, also increased expression of PD-1 on the surface of CD8 + T cells including CD8 + CD44 high memory phenotype T cells. Moreover, IL-15 also increased the secretion of the immunosuppressive cytokine, IL-10. Combining IL-15 with anti-PD-L1 and anti-CTLA-4 (multiple immune checkpoint blockade) exhibited greater CTL killing and IFNγ secretion. Moreover, this combination resulted in a significant reduction in surface expression of PD-1 on CD8 + T cells, a decrease in IL-10 secretion, and led to significantly longer survival of tumor-bearing animals compared with mice treated with IL-15 alone or combined singularly with anti-PD-L1 or anti-CTLA-4. Conclusions: Combining the immune stimulatory properties of IL-15 with the simultaneous removal of 2 critical immune system inhibitory checkpoints, we showed enhancement of immune responses leading to increased antitumor activity. Clin Cancer Res; 16(24); 6019–28. ©2010 AACR .
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Interleukin 15 and its receptor augment dendritic cell vaccination against the neu oncogene through the induction of antibodies partially independent of cd4 help
Cancer Research, 2010Co-Authors: Jason C Steel, Thomas A. Waldmann, Charmaine A Ramlogan, Yoshio Sakai, Guido Forni, John C MorrisAbstract:Interleukin-15 (IL-15) stimulates the diffrentiation and proliferation of T, B, and natural killer cells; enhances CD8+ cytolytic T-ceII activity; helps maintain CD44hiCD8+ memory T cells; and stimulates immunoglobulin synthesis by B cells. IL-15 is trans-presented to effector cells by its receptor, IL-15Rα, expressed on dendritic cells (DC) and monocytes. We examined the antitumor effect of adenoviral-mediated gene transfer of IL-15 and IL-15Rα to augment a DC vaccine directed against the NEU (ErbB2) oncoprotein. Transgenic BALB-neuT mice vaccinated in late-stage tumor development with a DC vaccine expressing a truncated NEU antigen, IL-I5, and its receptor (DCAd.Neu+Ad-mIL-15+Ad.mlL-15Rα) were protected from mammary carcinomas, with 70% of animals tumor-free at 30 weeks compared with none of the animals vaccinated with NEU alone (DC Ad.Neu). The combination of neu, IL-15, and IL-15Rα gene transfer leads to a significaintly greater anti-NEU antibody response compared with mice treated with DCAd.Neu or DCAd.Neu combined with either IL-15 (DCAd.Neu+Ad.mlL-15) or lL-15Rα (DC Ad.Neu+Ad.mlL-15Rα). The antitumor effect was antibody mediated and involved modulation of NEU expression and signaIing. Depletion of CD4 + cells did not abrogate the antitumor effect of the vaccine, nor did it inhibit the induction of anti-NEU aritibodies. Coexpression of IL-15 and IL-15Rα in an anticancer vaccine enhanced immune responses against the NEU antigen and may overcome impaired CD4+ T-helper function.