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1544 Human Orthogonal IL-2/IL-2Rβ As a Tunable Approach to Enhance CD19-Specific CAR-T Cell Antitumor Activity

Program: Oral and Poster Abstracts
Session: 801. Gene Editing, Therapy and Transfer: Poster I
Hematology Disease Topics & Pathways:
bioengineering, Diseases, Lymphoma (any), Technology and Procedures, T-Cell Lymphoma, gene editing, Lymphoid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Qian Zhang, MD PhD1*, Morgan Hresko2*, Michael Jacob Hollander3*, Lora Picton4*, Leon Su4, Selene Nunez-Cruz5*, Jonathan T Sockolosky3*, K.Christopher Garcia, PhD6* and Michael C. Milone7

1Pathology and Lab medicine, University of Pennsylvania, Philadelphia, PA
2University of Pennsylvania, Piladelphia, PA
3Stanford University School of Medicine, Stanford, CA
4Stanford University Medical School, Stanford, CA
5University of Pennsylvania, Philadelphia, PA
6Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA
7Center for Cellular Immunotherapies, Perelman School of Medicine At the Univ. of Pennsylvania, Philadelphia, PA

Immunotherapy using T cells engineered with a chimeric antigen receptors (CAR) can produce deep and durable control of B-cell malignancies that is associated with the engraftment and persistence of the CAR T cells following adoptive transfer. Interleukin-2 (IL-2) is a central T cell cytokine that promotes T cell proliferation and effector function with a potential to enhance CAR T cell immunotherapy; however, the use of recombinant IL-2 to support T cell immunotherapy is limited by the significant toxicity associated with IL-2 infusion. Previous work has demonstrated the feasibility of engineering murine IL-2 and it’s receptor to create an orthogonal (ortho) cytokine-receptor pair capable of delivering IL-2’s signal without the associated toxicity (Sockolosky JT et al. Science 2018). In order to translate this novel approach to humans, we engineered a human orthogonal IL-2 (ortho-hIL-2) and human orthogonal IL-2Rβ (ortho-hIL-2Rβ) pair based upon similar mutations to those required in the murine system. We show that hoIL-2 induces JAK-STAT signaling and supports proliferation of the IL-2 dependent cutaneous T-cell lymphoma (CTCL) line, SeAx, and primary human CD8+ primary T cells when hoIL-2Rb is expressed in these cells. HoIL-2 at concentrations 1000-fold higher than wild-type IL-2 failed to induce signaling in the absence of the orthogonal receptor illustrating the high selectivity of ortho-hIL-2 for the ortho-hIL-2Rβ. Using a CD19-specific, 4-1BB-costimulated CAR T cell (CART19), we show that ortho-hIL-2 induced a dose-dependent increase in ortho-hIL-2Rβ CAR-T cell expansion and serum cytokines in vivo by as much as 1000-fold at 2 weeks following adoptive transfer into NSG mice bearing CD19+ Nalm6 leukemia xenografts and daily ortho-hIL-2 treatment. We further demonstrate that hoIL-2 can rescue the anti-leukemic effect of an otherwise suboptimal CAR T cell dose. In addition to augmenting initial CAR T cell engraftment and efficacy, we also show that ortho-hIL-2 administration initiated at the time of leukemic relapse following CAR T cell therapy can rescue an otherwise failed anti-leukemic response. In aggregate, these data demonstrate the ability of the human orthogonal IL-2 cytokine-receptor system to support T cell expansion in vivo and the potential of combining this approach with CAR T cell immunotherapy to augment the anti-tumor efficacy of engineered T cells.

Disclosures: Sockolosky: Synthekine Therapeutics: Current equity holder in private company. Garcia: Synthekine: Current equity holder in private company, Other: founder. Milone: Novartis: Patents & Royalties.

*signifies non-member of ASH