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2860 Conditioning Impacts on Regulatory T-Cells (Tregs) in the Microenvironment of AML: Observations from the Phase 1 Cynk-001-AML-001 Trial

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Translational Research, Clinical Research, drug development, Diseases, immune mechanism, Therapies, Adverse Events, Myeloid Malignancies, Biological Processes, Minimal Residual Disease
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Eunice S Wang, MD1, Hongtao Liu, MD, PhD2, Daniel N. Egan, MD3, Adrian Kilcoyne, MD4*, Bhavani Stout, MSc4*, Natalia Ruggeri Barbaro, PhD5*, Cherie Daly6*, Siyara Kilcoyne5*, Robert Hariri, MD, PhD7* and James McCloskey, MD8

1Department of Medicine, Roswell Park Comprehensive Cancer Center, BUFFALO, NY
2University of Wisconsin-Madison, Madison, WI
3Swedish Center for Blood Disorders and Stem Cell Transplants, Seattle, WA
4Celularity, Florham Park, NJ
5Celularity, Florham Park
6Celularity Inc, Warren, NJ
7Celularity, florham park, NJ
8The John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ

Introduction: Evidence shows that NK cells can exhibit potent anti-tumor activity against acute myeloid leukemia (AML). CYNK-001 is a CD56+CD3- enriched, off-the-shelf, allogeneic natural killer (NK) cell therapy expanded from placental CD34 cells. The use of recombinant IL-2 (rhIL-2) therapy has induced regression of tumors by stimulating the activation and proliferation of NK cells. Low dose RhIL-2 has been shown to selectively expand and enhance the expression of maturation markers on the surface of NK cells, making them more potent killers in vitro and in vivo. CYNK-001-AML-001 is a Phase I multi-dose study evaluating the safety, tolerability, and persistence of CYNK-001 with or without rhIL-2 in adults with primary or secondary acute myeloid leukemia (AML) in morphologic complete remission (CR) with minimal residual disease (MRD) or relapsed/refractory (R/R) AML

Aim: To determine the safety and tolerability of rhIL-2 when added to CYNK-001 and assess the impact of rhIL-2 on CYNK-001 activity and persistence.

Methods This Phase I, single-arm, dose escalation clinical trial (NCT04310592) enrolled patients 18-80 years with R/R AML or MRD-positive CR. Escalating doses of CYNK-001 cells were administered following a standard 3+3 design, with 2 separate arms (MRD+ and R/R AML). Cohort 4a enrolled MRD+ AML subjects, while cohorts 4b and 5b enrolled R/R AML subjects. Cohort 4a and 4b utilized a dose of 1.8 billion CYNK-001 x 3 doses of CYNK-001 without rhIL-2. Cohort 5b utilized same dose of CYNK-001 along with rhIL-2. The decision to administer rhIL-2 in cohorts 6a, 6b, 7a and 7b would be based on review of safety, efficacy, and translational data in Cohorts 5b. In cohort 5b rhIL-2 was administered at a dose of 6M IU on days 0,2,4,7,9,11 and 14. Cohort 4b was used as a comparator.

Results Five patients in cohort 5b received rhIL-2. Treatment was well tolerated with no dose limiting toxicities (DLT’s) being observed. Ten adverse events ≥ grade 3 were experienced. The commonest grade 3 AE’s were raised AST (2/10) and ALT (2/10). Two grade 4 AE’s were reported including febrile neutropenia and a pre-existing GVHD. In cohort 4b, 3 out of 6 patients achieved an objective response (3x MLFS) at day 28. No patient in cohort 5b achieved a response. While there was an apparent higher baseline blast count in cohort 5b which may have contributed to the differences, translational data demonstrated a surge in Tregs without enhancement of T helper or cytotoxic cells or NK cell reconstitution. In cohort 4a, one subject who received rhIL-2 (6MIU/dose) in error showed an increase in Tregs similar to cohort 5b.

Conclusion Treatment with CYNK-001 in combination with rhIL-2 was well tolerated with no dose-limiting toxicities observed. However, this approach does not enhance CD4 helper T cells, CD8 cytotoxic cells or NK cell reconstitution, while stimulated proliferation of Tregs. CYNK-001 proliferation and persistence was not enhanced with rhIL-2 infusion. Based on these data, rIL-2 was excluded from subsequent cohorts in this study.

Disclosures: Wang: Sumitomo: Consultancy; Kite: Consultancy; Kura Oncology: Consultancy; Novartis: Consultancy, Speakers Bureau; NuProbe: Consultancy; Pfizer: Consultancy, Speakers Bureau; PharmaEssentia: Consultancy; Rigel: Consultancy; Sellas: Consultancy; Amgen: Consultancy; Johnson and Johnson: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Glaxo Smith Kline: Consultancy; Daiichi Sankyo: Consultancy; CTI Biopharma: Consultancy; Astellas: Consultancy, Speakers Bureau; Abbvie: Consultancy; Bristol Myers Squibb: Consultancy. Liu: Miltenyi Biotec: Research Funding; Rigel: Consultancy; Astellas: Research Funding; Nkarta: Research Funding; Pfizer: Consultancy; CTI Biopharm: Consultancy; Servier: Consultancy; Nkarta: Consultancy; Alexion: Research Funding; Agios: Consultancy. Kilcoyne: celularity: Current Employment, Current equity holder in publicly-traded company. Stout: celularity: Current Employment. Ruggeri Barbaro: celularity: Current Employment. Daly: celularity: Ended employment in the past 24 months. Hariri: celularity: Current Employment, Current equity holder in publicly-traded company. McCloskey: Amgen: Speakers Bureau; BluPrint Oncology: Honoraria; Takeda: Speakers Bureau; Bristol-Myers Squibb/Pfizer: Consultancy, Honoraria, Speakers Bureau; Blueprint Medicines: Consultancy; Stemline Therapeutics: Speakers Bureau; Novartis: Consultancy; Jazz Pharmaceuticals: Speakers Bureau; BluePrint Health: Speakers Bureau; Incyte: Speakers Bureau.

*signifies non-member of ASH