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2070 CD371-Targeted CAR T-Cells Secreting Interleukin-18 Exhibit Robust Expansion and Disease Clearance in Patients with Refractory Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase Clinical Trials and Toxicities: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Acute Myeloid Malignancies, AML, Adult, Clinical Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Treatment Considerations, Biological therapies, Young adult , Myeloid Malignancies, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Mark Blaine Geyer, MD1,2, Susan DeWolf, MD3*, Xiaoli Mi, MD1, Brian C. Shaffer, MD, MS4, Briana Cadzin, RN5*, Devin McAvoy6*, Kinga K. Hosszu, PhD6*, Kenyon Weis7*, Rachel Lorenc8*, Alexander M. Lewis7*, Narina N. Girotra7*, Erin R. Burns9*, Jasmine S. Um9*, Sarah Yoo9*, Zoe Katsamakis6*, Xiuyan Wang, PhD10*, Isabelle Riviere11*, Kevin J. Curran, MD12*, Jae H. Park, MD3,13, Marcel R.M. van den Brink, MD, PhD14, Omar Abdel-Wahab, MD2,7,8, Renier Brentjens, MD PhD15 and Anthony F. Daniyan, MD1,3*

1Department of Medicine, Cell Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY
2Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
4Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
5Department of Nursing, Memorial Sloan Kettering Cancer Center, New York, NY
6Department of Pediatrics, Immune Discovery and Modeling Service, Memorial Sloan Kettering Cancer Center, New York, NY
7Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY
8Weill Cornell Medical College, New York, NY
9Memorial Sloan Kettering Cancer Center, New York, NY
10Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
11Takeda Development Center Americas, Inc., Lexington, MA
12Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
13Cell Therapy Service and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
14Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
15Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY

Background: Patients (pts) with (w/) relapsed and refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T cell (CAR T) therapy for AML has been limited by lack of optimal surface antigen targets, myelosuppression, and hostile tumor microenvironment (TME). CD371 is expressed on myeloid blasts and leukemia-initiating cells in most pts w/ AML. We designed next generation CAR T cells w/ fully human CD371-specific scFv (CD371), modified CD28 costimulatory domain to limit T cell exhaustion (SAVVY), wildtype CD3z, and constitutive secretion of interleukin 18 (IL-18) to enhance CAR T cytotoxicity and induce host immune response (CD371-SAVVYz-IL18).

Methods: We initiated a phase I clinical trial of CD371-SAVVYz-IL18 in pts w/ R/R AML (NCT06017258). Pts underwent leukapheresis for T cell collection and received fludarabine/cyclophosphamide conditioning + CD371-SAVVYz-IL18 (3x105 CAR Ts/kg, pts 1-2; 3x104/kg, pts 3-5). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were defined by ASTCT consensus grading (G) and other toxicities by CTCAE v5.0. Responses were evaluated by ELN criteria. We performed spectral flow cytometry (FACS), 5’-based CITE-seq to detect RNA, TCRs, and surface proteins in single cells (n=26 samples, 251,642 cells) and measured 96 cytokines by Luminex FLEXMAP in serial samples to study CAR T products and their effect on AML and TME.

Results: 5 pts (4 F/1 M) were enrolled/treated in the pilot study w/ median (med) age 32 yrs (range [r] 16-45). All received prior high-dose cytarabine-containing therapy and venetoclax. Three relapsed post-allogeneic hematopoietic cell transplant (alloHCT). Med production time was 7 days (d). All had measurable AML pre-treatment w/ uniform (n=4) or partial (n=1) CD371.

CAR T expansion was seen in all pts w/ highest vector copy number (med: 23 k/mL, r: 15-1164 k/mL) and peak IL-18 levels (med: 28.4 k pg/mL, r: 1.3 k-58.2 k pg/mL) d7-14 post-CAR T, and not clearly correlated w/ AML burden. CRS was manageable (G1-2, n=3; G3-4, n=2) w/ med onset d2; only 1 experienced ICANS (G3). 3 dose-limiting toxicities observed overall, 2 at higher (3x105 CAR T/kg) dose (prolonged hypoplasia w/ cytopenias, #1; G4 CRS, #2) and 1 at lower dose (G3 reduced LV ejection fraction lasting 16d, #5).

Three pts (all w/ prior alloHCT) achieved best response of morphologic leukemia free state (MLFS), minimal residual disease (MRD) negative by FACS, w/ first response at med d15, hypocellular in pt #1/#2 (<5%), normocellular in pt #5 (40-50%), w/ MLFS sustained at 4 weeks post-CAR T. Pt #1 received CD34-selected stem cell boost from her HLA-identical sibling on d36 due to ongoing cytopenias and disseminated Fusarium infection; she subsequently relapsed and died d73. Pt #2 proceeded to second alloHCT d45, but subsequently relapsed and died d219. Pt #5 experienced adenovirus reactivation (had prior CD34-selected alloHCT) and died d57 of multi-organ failure w/out evidence of AML. All pts w/ detectable AML post-CAR T (n=4) had CD371 expression.

CITE-seq and FACS showed CAR T products consisted predominantly of CD4 proliferating and central memory T cells. CD8 effector memory T cells became dominant CAR T population by d14 in the 3 responders. CD4 and CD8 CAR Ts were polyclonal based on TCRs and acquired cytotoxic profile post-infusion (↑ of GZMB, PRF1, IFN-γ, and GNLY) w/ gene set enrichment analyses revealing active IFN-γ and -α responses; CD8 CAR Ts also acquired NK-like features (CD56, CD16, and KIRs). Notably, all 3 responders were post-alloHCT; CAR Ts were of donor origin in the 2 pts w/ opposite sex donors based on X/Y mismatch. NK cells expanded in responders post-CAR T w/ differential expression of activation and cytotoxic markers, and enrichment of genes associated w/ IFN responses. Non-responders had limited CD8 CAR T and NK cell expansion.

Conclusions: CD371-SAVVYz-IL18 CAR T exhibits robust expansion and activity at low doses in pts w/ highly refractory AML, but w/ risk of CRS and prolonged cytopenias. We plan to treat next pts at the 3x104 cells/kg dose and intensify preventive CRS interventions. IL-18 secretion may provide autocrine stimulation for CAR T expansion, including expansion of low frequency cytotoxic CD8+ T cells, as well as activation of host NK cells to promote anti-leukemic activity. Prompt alloHCT post-CAR T may prevent complications of prolonged cytopenias and consolidate response.

Disclosures: Geyer: Tigen Pharma: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Takeda: Consultancy. Shaffer: Hansa Biopharma: Consultancy. Riviere: Takeda Development Center Americas, Inc.: Current Employment, Current equity holder in publicly-traded company. Park: Adaptive Biotechnologies, Affyimmune, Allogene, Amgen, Artiva Biotherapeutics, Autolus, Bright Pharmaceutical Services, BMS, Caribou Biosciences, Curocell, Galapagos, Gilead Sciences, Intellia, In8Bio, Kite, Novartis, Pfizer, Servier, Sobi, Synthekine: Consultancy; Takeda: Consultancy; Autolus, Fate Therapeutics, Genentech, InCyte, Servier, Sobi, Takeda (Institution): Research Funding; Curocell: Current equity holder in publicly-traded company. Abdel-Wahab: Codify Therapeutics: Consultancy, Current equity holder in private company, Research Funding; Nurix Therapeutics: Research Funding; Minovia Therapeutics: Consultancy, Research Funding. Brentjens: Triumvira, Cargo Tx, CoImmune: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BMS, Caribou, Sanofi: Other: licensed intellectual property to and collects royalties from; BMS, Atara Biotherapeutics Inc. and was a consultant for Triumvira, Cargo Tx, CoImmune: Consultancy. Daniyan: Caribou Biosciences, Inc: Patents & Royalties: Intellectual Property Rights; Promicell Therapeutics, Inc.: Consultancy, Current holder of stock options in a privately-held company; Shoreline Biosciences, Inc.: Consultancy; Tigen Pharma SA: Patents & Royalties: Intellectual Property Rights.

OffLabel Disclosure: CD371-SAVVYz-IL18 CAR T-cells are not FDA-approved for treatment of acute myeloid leukemia

*signifies non-member of ASH