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1439 OrthoCARs: Engineered human IL-2/IL-2Rb orthogonal pairs selectively enhance CAR T cell antitumorefficacy

Program: Oral and Poster Abstracts
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
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Paul-Joseph Aspuria1*, Michael A Bauer, PhD2, Sandro vivona1*, Rene de Waal Malefyt1*, Rob Kastelein1*, Martin Oft3*, Jan Emmerich1*, Deepti Rokkam1*, Steven E Kauder, PhD4*, Scott McCauley5*, Romina Riener1* and Rakesh Verma, PhD6

1Synthekine, Inc., Menlo Park, CA
2Department of Biomedical Informatics, University of Arkansas For Medical Sciences, Little Rock, AR
3ARMO Biosciences, Redwood City, CA
4Alexo Therapeutics, South San Francisco, CA
5Lilly, Redwood City, CA
6MMCRI, Maine Medical Center, New Haven, CT

CAR T cell therapy has demonstrated remarkable clinical efficacy against relapsed and refractory hematological malignancies, such as B cell non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL) (Neelapu et al. NEJM, 2017; Schuster et al. NEJM, 2018; Turtle et al. Sci Trans Med, 2016). Despite these advances, prominent barriers including poor T cell effector function, lack of proliferation, and limited CAR T cell persistence prevent CAR T cell therapies from reaching their full curative potential (Srivastava and Riddell, Journal of Immunology, 2019). Interleukin-2 (IL-2) is a potent stimulator of CD4 and CD8 T cell proliferation, survival, and cytotoxic function, thereby making it an attractive molecule to support CAR T cell therapy. However, therapeutic use of IL-2 is limited by systemic toxicity due its promiscuous activation of undesired immune cell populations, including non-tumor reactive T cells and NK cells (Rosenberg et al. Journal of Immunology, 2014).

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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