Session: 722. Clinical Allogeneic Transplantation: Acute and Chronic GvHD, Immune Reconstitution: Phase I and II Trials
Hematology Disease Topics & Pathways:
Leukemia, ALL, HSCs, Adult, Biological, AML, Diseases, bioengineering, bone marrow, Therapies, Adverse Events, MDS, Biological Processes, MPN, immune cells, Technology and Procedures, Cell Lineage, immunotherapy, Lymphoid Malignancies, Study Population, Clinically relevant, Myeloid Malignancies, hematopoiesis, flow cytometry, immune mechanism, transplantation, stem cells
GVHD remains a frequent and serious complication of HSCT despite the decades-long use of standard immunosuppression, such as tacrolimus and methotrexate, as prophylaxis against GVHD. Preclinical models have shown that the timed infusion of donor-derived high-purity CD4+CD25+FOXP3+ regulatory T cells (Treg) preceding adoptive transfer of conventional T cells (Tcon) prevents GVHD and maintains anti-cancer immunity without the need of pharmacologic agents. Early clinical trials using purified Treg-engineered graft showed safety and feasibility, but more extensive clinical studies are needed to test scalability and efficacy. Orca-T is an industry-manufactured, precision-engineered CD34-selected, Treg-engineered graft made in a central GMP laboratory and distributed to multiple centers in the U.S. We present our early patient experience with Orca-T in an ongoing single center phase 2 trial and a multicenter Phase Ib trial and report a pre-planned evaluation of patients randomized to receive Orca-T plus single-agent GVHD prophylaxis (PPX) or Orca-T and no PPX.
51 patients with high risk or active hematologic malignancies undergoing myeloablative conditioning were enrolled on two trials: a single-center Phase I/II (n=40, NCT01660607) and a multicenter Phase Ib (n=11; NCT04013685) study. Patients received CD34-selected cells infused with highly purified Treg (target dose: 3.0 x 106 cells/kg) followed 2 days later by the infusion of Tcon (3.0 x 106 cells/kg). Initial GMP manufacturing was demonstrated at Stanford (n=9 grafts; 2016 – 2019) and then transferred to Orca Bio in 2019 for scaled production.
We evaluated the 34 patients beyond dose escalation since July 2016 who received Orca-T grafts from either matched related (n=25) or unrelated (n=9) donors and single agent GVHD PPX with either tacrolimus (n=28) or sirolimus (n=6). For comparative analysis, we identified a contemporaneous SOC cohort at Stanford (n=138) with both matched related (n=79) and unrelated (n=59) transplant recipients who received unmanipulated PBSC products (median f/u 546 days) and methotrexate plus tacrolimus.
In April 2019, enrollment on a phase 2, stage 1 pre-planned subgroup of 24 patients were randomized to test whether all GVHD PPX could be removed: Orca-T plus either single-agent PPX (Arm 1, n=12) or no PPX (Arm2, n=12).
The Orca-T drug products were manufactured reliably with high Treg purity (93.8% +/- 3.1%) and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between arms and trials). Central lab turn-around times were 25.3 +/- 3.0 hours and all vein-to-vein times were less than 72 hrs (Table 1). For trial participants, there were no manufacturing failures, engraftment failures or treatment related mortality. Orca-T patients vs. SOC showed earlier neutrophil (median of 11 days vs. 14 days, p<0.0001 by Mann-Whitney U) and platelet engraftment (11 vs 17 days, p<0.0001) and a shorter hospital stay (15 vs 19 days, p=0.0002).
Patients across 4 clinical sites received Orca-T plus single agent GVHD PPX (n=34; median f/u 261 days) had an acute GVHD grade 2-4 incidence of 0% as compared to 33% in the SoC cohort (n=138, p=0.0018 by Log-rank Mantel-Cox test, Fig. 1). The rate of moderate to severe chronic GVHD for Orca-T patients was 4% vs. 44% in the SoC cohort (p=0.016).
In a preliminary subset of evaluable Orca- T patients, GVHD & relapse free survival (GRFS) at one year was higher for Orca-T patients vs SoC (69% versus 33%, p=0.006) while relapse and overall survival did not appear to differ. We observed no differences in infectious complications.
In patients randomized to PPX vs. no PPX, the incidence of aGVHD grade 2-4 was 0% in Arm 1 and 58% in Arm 2 (p <0.0001, Log-rank Mantel-Cox test), with 17% of these events being Grade 3-4. All GVHD in Arm 2 responded to steroids with no GVHD-related deaths.
Manufacture of high precision Orca-T Treg-engineered donor products were successfully scaled in a central GMP with reliable distribution to centers. Patients who received Orca-T and single agent PPX had no grade 2 or greater acute GVHD acute and very little chronic GVHD when compared to SOC. Patients randomized to Orca-T and no PPX showed an increased incidence of acute GVHD vs. those with Orca-T and single agent PPX. Engineered Treg grafts show promise to improve GFRS and other transplant outcomes. Orca-T has been granted RMAT status by the FDA and evaluation continues in an ongoing multicenter clinical trial.
Disclosures: Meyer: Orca Bio: Research Funding. Moroz: Orca Bio: Research Funding. Miklos: Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding. Shiraz: Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Muffly: Adaptive: Research Funding; Servier: Research Funding; Amgen: Consultancy. Rezvani: Pharmacyclics: Research Funding. Shizuru: Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Fernhoff: Orca Bio: Current Employment, Current equity holder in private company. Putnam: Orca Bio: Current Employment, Current equity holder in private company. McClellan: Orca Bio: Current Employment, Current equity holder in private company. Shaw: Orca Bio: Consultancy. McGuirk: Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Bellicum Pharmaceutical: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding. Abedi: BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Negrin: Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; UpToDate: Honoraria; Amgen: Consultancy; BioEclipse Therapeutics: Current equity holder in private company.
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