Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity
Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19+ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to toxicity associated with tumor-cell lysis and cytokine storm. Clinical trials will now be addressing the targeting of minimal burdens of CD19+ malignancy as patients are enrolled earlier in their disease course and receive concomitant chemotherapy. It is likely that the existing populations of CAR T cells generated ex vivo to address relapsed disease may not be able to address minimal residual disease (MRD). Therefore, we have developed a clinically appealing approach to sustaining the persistence of CAR T cells independent of TAA by providing signaling through the common gamma chain receptor (gc). Administration of exogenous soluble recombinant cytokines that signal through the gc, such as interleukin (IL)-2, have been used clinically to sustain the persistence of adoptively transferred T cells. However, systemic high-dose administration has resulted in dose-limiting toxicities. Unlike IL-2, IL-15 possesses numerous attributes desirable for adoptive therapy and has been ranked among the most valuable immunotherapeutic agent for cancer treatment. It is a pro-survival cytokine that promotes the survival of long-lived T-cell memory subsets and in vivo antitumor activity. Unlike other gc family cytokines, IL-15 is transpresented to responding T cells in the context of IL-15 receptor alpha (IL-15Ra). Therefore, we hypothesized that a membrane-bound IL-15 fusion protein (mIL15) tethered to the cell surface would enhance T-cell costimulation to support persistence independent of CAR activation by preserving T-cell memory potential and maintain antitumor activity in the presence of low TAA. Using clinically compliant methods, the generated mIL15-CAR T cells mimicked the physiologic mechanism of transpresentation to sustain costimulation via phosphorylation of signal transducer and activator of transcription (pSTAT5). In contrast to conventional CD19-specific CAR T cells, mIL15-CAR T cells persisted in mice independent of the presence of TAA and mediated potent rejection of a systemically distributed CD19+ leukemia. The potential for sustained immunity against B-cell malignancies was shown as, in the absence of antigen, mIL15-CAR T cells were long-lived and adopted a desirable CD45ROnegCCR7+ “low-differentiation” state with a memory-like molecular profile and phenotype. These results have direct implications for the design of an adoptive immunotherapy clinical trial evaluating mIL15-CAR T cells in the setting of MRD and warrants further investigation of mIL15 to engineer T cells targeting other tumor cells that have sequestered or low levels of TAA.
","abstract_html":"<p><strong>Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity</strong></p> <p>Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19<sup>+</sup> leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to toxicity associated with tumor-cell lysis and cytokine storm. Clinical trials will now be addressing the targeting of minimal burdens of CD19<sup>+</sup> malignancy as patients are enrolled earlier in their disease course and receive concomitant chemotherapy. It is likely that the existing populations of CAR T cells generated <em>ex vivo</em> to address relapsed disease may not be able to address minimal residual disease (MRD). Therefore, we have developed a clinically appealing approach to sustaining the persistence of CAR T cells independent of TAA by providing signaling through the common gamma chain receptor (gc). Administration of exogenous soluble recombinant cytokines that signal through the gc, such as interleukin (IL)-2, have been used clinically to sustain the persistence of adoptively transferred T cells. However, systemic high-dose administration has resulted in dose-limiting toxicities. Unlike IL-2, IL-15 possesses numerous attributes desirable for adoptive therapy and has been ranked among the most valuable immunotherapeutic agent for cancer treatment. It is a pro-survival cytokine that promotes the survival of long-lived T-cell memory subsets and <em>in vivo</em> antitumor activity. Unlike other gc family cytokines, IL-15 is transpresented to responding T cells in the context of IL-15 receptor alpha (IL-15Ra). Therefore, we <em>hypothesized</em> that a membrane-bound IL-15 fusion protein (mIL15) tethered to the cell surface would enhance T-cell costimulation to support persistence independent of CAR activation by preserving T-cell memory potential and maintain antitumor activity in the presence of low TAA. Using clinically compliant methods, the generated mIL15-CAR T cells mimicked the physiologic mechanism of transpresentation to sustain costimulation via phosphorylation of signal transducer and activator of transcription (pSTAT5). In contrast to conventional CD19-specific CAR T cells, mIL15-CAR T cells persisted in mice independent of the presence of TAA and mediated potent rejection of a systemically distributed CD19<sup>+</sup> leukemia. The potential for sustained immunity against B-cell malignancies was shown as, in the absence of antigen, mIL15-CAR T cells were long-lived and adopted a desirable CD45RO<sup>neg</sup>CCR7<sup>+</sup> “low-differentiation” state with a memory-like molecular profile and phenotype. These results have direct implications for the design of an adoptive immunotherapy clinical trial evaluating mIL15-CAR T cells in the setting of MRD and warrants further investigation of mIL15 to engineer T cells targeting other tumor cells that have sequestered or low levels of TAA.</p>","abstract_has_math":false,"creators":["Hurton, Lenka"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Laurence J.N. Cooper, M.D., Ph.D.","Joya Chandra, Ph.D.","Gianpietro Dotti, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-05-01T07:00:00Z","date_published":"2014-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:30Z","subjects":["immunotherapy","cytokines","IL-15","chimeric antigen receptor","T-cell persistence","memory","memory stem cell","leukemia","B-ALL","Medical Biotechnology","Medical Immunology","Medicine and Health Sciences","Other Immunology and Infectious Disease"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Laurence J.N. 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Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19+ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to toxicity associated with tumor-cell lysis and cytokine storm. Clinical trials will now be addressing the targeting of minimal burdens of CD19+ malignancy as patients are enrolled earlier in their disease course and receive concomitant chemotherapy. It is likely that the existing populations of CAR T cells generated ex vivo to address relapsed disease may not be able to address minimal residual disease (MRD). Therefore, we have developed a clinically appealing approach to sustaining the persistence of CAR T cells independent of TAA by providing signaling through the common gamma chain receptor (gc). Administration of exogenous soluble recombinant cytokines that signal through the gc, such as interleukin (IL)-2, have been used clinically to sustain the persistence of adoptively transferred T cells. However, systemic high-dose administration has resulted in dose-limiting toxicities. Unlike IL-2, IL-15 possesses numerous attributes desirable for adoptive therapy and has been ranked among the most valuable immunotherapeutic agent for cancer treatment. It is a pro-survival cytokine that promotes the survival of long-lived T-cell memory subsets and in vivo antitumor activity. Unlike other gc family cytokines, IL-15 is transpresented to responding T cells in the context of IL-15 receptor alpha (IL-15Ra). Therefore, we hypothesized that a membrane-bound IL-15 fusion protein (mIL15) tethered to the cell surface would enhance T-cell costimulation to support persistence independent of CAR activation by preserving T-cell memory potential and maintain antitumor activity in the presence of low TAA. Using clinically compliant methods, the generated mIL15-CAR T cells mimicked the physiologic mechanism of transpresentation to sustain costimulation via phosphorylation of signal transducer and activator of transcription (pSTAT5). In contrast to conventional CD19-specific CAR T cells, mIL15-CAR T cells persisted in mice independent of the presence of TAA and mediated potent rejection of a systemically distributed CD19+ leukemia. The potential for sustained immunity against B-cell malignancies was shown as, in the absence of antigen, mIL15-CAR T cells were long-lived and adopted a desirable CD45ROnegCCR7+ “low-differentiation” state with a memory-like molecular profile and phenotype. These results have direct implications for the design of an adoptive immunotherapy clinical trial evaluating mIL15-CAR T cells in the setting of MRD and warrants further investigation of mIL15 to engineer T cells targeting other tumor cells that have sequestered or low levels of TAA.
"]},{"key":"dc:title","label":"Title","values":["Tethered Il-15 to Augment The Therapeutic Potential of T Cells Expressing Chimeric Antigen Receptor: Maintaining Memory Potential, Persistence, and Antitumor Activity"]}]}],"canonical_facts":{"dc:contributor":["Laurence J.N. Cooper, M.D., Ph.D.","Joya Chandra, Ph.D.","Gianpietro Dotti, Ph.D."],"dc:creator":["Hurton, Lenka"],"dc:date.available":["2015-02-28T08:00:00Z"],"dc:description.abstract":["Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity
Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19+ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to toxicity associated with tumor-cell lysis and cytokine storm. Clinical trials will now be addressing the targeting of minimal burdens of CD19+ malignancy as patients are enrolled earlier in their disease course and receive concomitant chemotherapy. It is likely that the existing populations of CAR T cells generated ex vivo to address relapsed disease may not be able to address minimal residual disease (MRD). Therefore, we have developed a clinically appealing approach to sustaining the persistence of CAR T cells independent of TAA by providing signaling through the common gamma chain receptor (gc). Administration of exogenous soluble recombinant cytokines that signal through the gc, such as interleukin (IL)-2, have been used clinically to sustain the persistence of adoptively transferred T cells. However, systemic high-dose administration has resulted in dose-limiting toxicities. Unlike IL-2, IL-15 possesses numerous attributes desirable for adoptive therapy and has been ranked among the most valuable immunotherapeutic agent for cancer treatment. It is a pro-survival cytokine that promotes the survival of long-lived T-cell memory subsets and in vivo antitumor activity. Unlike other gc family cytokines, IL-15 is transpresented to responding T cells in the context of IL-15 receptor alpha (IL-15Ra). Therefore, we hypothesized that a membrane-bound IL-15 fusion protein (mIL15) tethered to the cell surface would enhance T-cell costimulation to support persistence independent of CAR activation by preserving T-cell memory potential and maintain antitumor activity in the presence of low TAA. Using clinically compliant methods, the generated mIL15-CAR T cells mimicked the physiologic mechanism of transpresentation to sustain costimulation via phosphorylation of signal transducer and activator of transcription (pSTAT5). In contrast to conventional CD19-specific CAR T cells, mIL15-CAR T cells persisted in mice independent of the presence of TAA and mediated potent rejection of a systemically distributed CD19+ leukemia. The potential for sustained immunity against B-cell malignancies was shown as, in the absence of antigen, mIL15-CAR T cells were long-lived and adopted a desirable CD45ROnegCCR7+ “low-differentiation” state with a memory-like molecular profile and phenotype. These results have direct implications for the design of an adoptive immunotherapy clinical trial evaluating mIL15-CAR T cells in the setting of MRD and warrants further investigation of mIL15 to engineer T cells targeting other tumor cells that have sequestered or low levels of TAA.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/421"],"dc:subject":["immunotherapy","cytokines","IL-15","chimeric antigen receptor","T-cell persistence","memory","memory stem cell","leukemia","B-ALL","Medical Biotechnology","Medical Immunology","Medicine and Health Sciences","Other Immunology and Infectious Disease"],"dc:title":["Tethered Il-15 to Augment The Therapeutic Potential of T Cells Expressing Chimeric Antigen Receptor: Maintaining Memory Potential, Persistence, and Antitumor Activity"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:30Z"}