Session: 703. Adoptive Immunotherapy: Poster I
Hematology Disease Topics & Pathways:
Biological, Lymphoma (any), Animal models, Diseases, bioengineering, Therapies, Technology and Procedures, Lymphoid Malignancies, Study Population
To facilitate selective ex vivo and in vivo expansion of engineered T cells we have developed a human orthogonal (ortho) ligand/receptor system consisting of a pegylated, IL-2 mutein (STK- 009) that does not significantly activate the wild type receptor and a mutated IL-2 Receptor Beta (orthoIL-2Rβ) that does not significantly respond to its native ligand, wild type IL-2. This system enables in vivo IL-2 signaling in engineered cells that express the orthoIL-2Rβ while avoiding signaling in bystander T cells and NK cells. Here, we demonstrate the ability of the STK-009/orthoIL-2Rb ligand/receptor pair to selectively potentiate human orthoIL-2Rb (hoRb) expressing CD19 CAR T cells (CD19 orthoCAR T cells) in vitro and in vivo. We also demonstrate that STK-009 is selective for the orthogonal IL-2Rb and in a non-human primate model does not potentiate wild type T or NK cells and shows no evidence of toxicity.
The STK-009/CD19 orthoCAR T platform was evaluated in a disseminated Raji mouse model of aggressive lymphoma. Subcutaneous administration of STK-009 dramatically expanded the CD19 orthoCAR T cells possessing a clinically favorable TSCM and TEMRA immunophenotype and significant antitumor efficacy was observed even at doses of CAR T cells typically regarded as sub-efficacious. When STK-009 dosing was stopped after complete tumor responses, CD19 orthoCAR T cells contracted as expected. Subsequent redosing of STK-009 in these tumor free mice re-expanded CD19 orthoCAR T cell levels demonstrating the on-demand control of the STK-009/orthoCAR T cell platform.
Given the deep and durable responses we observed in the disseminated Raji model, we subsequently invested investigated the efficacy of the STK-009/orthoCAR T cell platform in a subcutaneous Raji model of lymphoma characteristically resistant to CAR T cell therapy. No significant anti-tumor effect was observed in mice treated with either CAR T cells alone or the combination of high dose wild-type IL-2 and CAR T cells. The subcutaneous administration of STK-009 in combination with a sub-efficacious dose of CD19 orthoCAR T cells demonstrated significant expansion of the CD19 orthoCAR T cells with the clinically favorable TSCM and TEMRA immunophenotype and potent anti-tumor efficacy in this subcutaneous lymphoma model, demonstrating the selective potentiation of the CD19 orthoCAR T cells in response to STK-009.
The toxicity of STK-009 was evaluated in a non-human primate dose-escalation study. Subcutaneous administration STK-009 at anticipated therapeutic doses showed no evidence of toxicity or biological effect on immune cells expressing the wild-type IL-2 receptor. Pharmacokinetic analysis of STK-009 in this study showed stable exposure with minimal clearance, demonstrating the selectivity of STK-009.
These findings validate an orthogonal platform that selectively drives potent T cell effector functions of engineered cells without the toxicities mediated by NK cells or non-tumor specific T cells associated with high dose IL-2 therapy. These results demonstrate the ability of this orthogonal platform to improve the efficacy and durability of CAR T cell therapies.
Disclosures: Aspuria: Synthekine: Current Employment. Bauer: Synthekine: Current Employment. vivona: Synthekine: Current Employment. de Waal Malefyt: Synthekine: Current Employment. Kastelein: Synthekine: Current Employment. Oft: Synthekine: Current Employment. Emmerich: Synthekine: Current Employment. Rokkam: Synthekine: Current Employment. Kauder: Synthekine: Current Employment. McCauley: Synthekine: Current Employment. Riener: Synthekine: Current Employment. Verma: Synthekine: Current Employment.
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