Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities; Novel Conditioning Approaches.
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Antibody Therapy, Translational Research, Clinical Research, Immunodeficiency, Pediatric, Diseases, Immune Disorders, Therapies, Young Adults, Study Population, Transplantation
We previously reported the initial safety, tolerability, and proof-of-concept of JSP191 as a safe and effective conditioning agent for SCID patients in whom an initial HCT failed to engraft HSC. Here, we present data supporting a recommended phase 2 dose (RP2D) of JSP191 that achieves donor HSC engraftment predictive of clinically meaningful lymphocyte reconstitution. Study endpoints include 1) donor chimerism of stringently flow-sorted CD15+ blood granulocytes ≥3% (18–24 wks post-HCT) as a measure of HSC engraftment, 2) lymphocyte reconstitution of donor-derived naïve CD4+CD45RA+ T cells >85/μL (36–104 wks post HCT), and 3) improved clinical outcomes, including reduced Ig dependence. Twelve patients with prior HCT (3 to 38 years old) of different genotypes (Table 1) were dosed in the initial dose escalation (0.1, 0.3 and 1.0 mg/kg JSP191) and at the RP2D 0.6 mg/kg. At study entry all patients lacked donor HSC engraftment evidenced by 0% donor CD15+ granulocyte chimerism. JSP191 was infused as a single IV dose and serum pharmacokinetics (PK) measured in real-time. CD34+-selected cells obtained from the original donors were infused when the estimated JSP191 serum level fell below 500 ng/mL. JSP191 clearance displayed saturable non-linear kinetics, which was prolonged at the highest dose cohort of 1.0 mg/kg dose. JSP191 and HSPC infusions were uniformly well tolerated. Pre-and post-infusion marrow analyses in 7 evaluable patients showed a dose-dependent decline in CD117+HSPC following JSP191 treatment (range 30–89%). Table 1a shows that 6 of 9 non-IL2RG SCID patients who are >24 wks post-HCT reached the predefined endpoint of HSC engraftment with >3% donor CD15+ blood granulocytes. This level of HSC chimerism correlated with the subsequent development of naïve donor derived T lymphocytes. Importantly, beyond HSC engraftment and naïve donor T lymphocyte production, patients who achieved HSC donor chimerism have demonstrated clinical improvement including resolution of chronic diarrhea, healthy weight gain, reduced Ig dependence, and antibody responses to vaccines.
Three non-IL2RG patients did not achieve the chimerism threshold (one at 0.3 mg/kg and two at 1.0 mg/kg), potentially due to insufficient dose or prolonged JSP191 clearance and time to HSC infusion, respectively. Hence, an intermediate dose of 0.6 mg/kg which displays a shorter, more favorable half-life and higher HSC engraftment compared to the other dose cohorts was selected as the RP2D. Two of 3 IL2RG patients did not reach the donor chimerism threshold (Table 1b) reflecting the fact that re-transplanted IL2RG patients can have higher immune-mediated resistance, that may necessitate additional immune ablation.
Conclusion: This study is the first to show the long-term benefit of HSC engraftment following targeted single-agent JSP191 conditioning. These results suggest JSP191 conditioning has the potential to provide benefit for HCT in a wide spectrum of disorders without the deleterious risks of genotoxic agents. This study is actively enrolling previously transplanted and newly diagnosed SCID patients.
Disclosures: Dvorak: Jazz Pharma: Consultancy; Alexion, Inc: Consultancy; Omeros Corp.: Consultancy. Prockop: Memorial Sloan Kettering Cancer Center: Other: S Prockop receives support for the conduct of sponsored clinical trials through MSK from Atara Biotherapeutics, Jasper and AlloVir. , Patents & Royalties: S Prockop is a co-inventor on intellectual property (IP) licensed to Atara. S Prockop has waived rights to this IP to MSK and has no personal financial interests in Atara. MSK has financial interests in Atara and IP interests relevant to this abstract. ; Atara Biotherapeutics: Other: support for the conduct of sponsored trials and Inventor; Jasper: Other: support for the conduct of sponsored trials; AlloVir: Other: support for the conduct of sponsored trials; Neovii: Consultancy; ADMA Biologics: Consultancy; MSK: Other: Inventor. Kwon: Jasper Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Long-Boyle: Jasper Therapeutics: Consultancy. Arulprakasam: Jasper Therapeutics: Current Employment. Harada: Jasper Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Prohaska: Jasper Therapeutics: Consultancy, Current holder of stock options in a privately-held company. Pang: Jasper Therapeutics: Current Employment, Current equity holder in publicly-traded company. Heller: NextCure: Consultancy, Current equity holder in publicly-traded company; Jasper Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Weissman: FortySeven: Patents & Royalties. Cowan: Homology Medicines, Inc: Consultancy, Current equity holder in publicly-traded company; Bluebird Bio, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leadiant, Inc: Consultancy; Ensoma Inc.: Consultancy; Rocket Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding. O'Reilly: Atara Biotherapeutics: Consultancy, Patents & Royalties: for EBV-specific T-Cell Bank, Research Funding. Parkman: Jasper Biotech: Consultancy. Shizuru: Jasper Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; FortySeven (Gilead): Patents & Royalties: Inventor listed on a patent, licensed by FortySeven.
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