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554 JSP191 As a Single-Agent Conditioning Regimen Results in Successful Engraftment, Donor Myeloid Chimerism, and Production of Donor Derived Naïve Lymphocytes in Patients with Severe Combined Immunodeficiency (SCID)

Program: Oral and Poster Abstracts
Type: Oral
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
Sunday, December 12, 2021: 4:45 PM

Rajni Agarwal, MD1, Christopher C. Dvorak, MD2, Susan Prockop, MD3, Hye-Sook Kwon, PhD4*, Janel R Long-Boyle, PharmD, PhD5*, Anne Le6*, Janice W Brown, MD6, Elisabeth Merkel, RN1*, Kenny Truong2*, Brenda Velasco6*, Kavitha Arulprakasam4*, Nicole Harada4*, Kirstin A Dougall1*, Susan S Prohaska4*, Wendy W Pang, MD, PhD4, Kevin N. Heller, MD4*, Irving L Weissman, MD7, Morton J Cowan, M.D.2, Aaron C. Logan, MD, PhD8, Richard J O'Reilly, MD3, Robertson Parkman, MD1*, Ken I. Weinberg, MD1, Maria Grazia Roncarolo, MD, PhD1 and Judith A Shizuru, MD6

1Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University Medical Center, Stanford, CA
2Division of Pediatric Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, Benioff Children's Hospital, San Francisco, CA
3Department of Pediatrics, Stem Cell Transplantation and Cellular Therapy, Memorial Sloan Kettering Cancer Center, New York, NY
4Jasper Therapeutics, Inc, Redwood City, CA
5UCSF, Department of Clinical Pharmacy, San Fransico, CA
6Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University Medical Center, Stanford, CA
7Institute for Stem Cell Biology and Regenerative Medicine, Stanford University Medical Center, Stanford, CA
8Division of Hematology and Blood and Marrow Transplantation, University of California, San Francisco, San Francisco, CA

Successful hematopoietic cell transplantation (HCT) relies on conditioning of recipients to deplete hematopoietic stem cells (HSC) from marrow niches to allow healthy HSC to engraft. Currently, only genotoxic chemotherapy and/or radiation are used to achieve such niche clearance. We have developed a targeted non-genotoxic approach to deplete HSC using a monoclonal antibody, JSP191, that binds human CD117 (c-Kit), a receptor tyrosine kinase expressed on HSC and progenitor cells (HSPC). We have opened a phase 1 dose escalation trial using JSP191 as the sole conditioning agent in patients with SCID (ClinicalTrials.gov: NCT02963064). HCT is the only definitive cure for SCID, a uniformly lethal genetic immune disorder. Because infants with SCID lack functional T cells which can mediate transplant rejection and because of toxicity concerns, SCID infants may receive HCT without conditioning. This approach is associated with presumed engraftment of donor lymphoid progenitors but not HSC, resulting in incomplete and poorly sustained immune reconstitution, evidenced by naïve T cell production that wane over time and absent functional B cells requiring life-long immunoglobulin (Ig) replacement. Second donor HSC transplants (“boosts”) without conditioning have not led to HSC engraftment and thus immune defects persist.

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.

*signifies non-member of ASH