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98 Orca-T Results in High Gvhd-Free and Relapse-Free Survival Following Myeloablative Conditioning for Hematological Malignancies: Results of a Single Center Phase 2 and a Multicenter Phase 1b Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Prevention of graft vs. host disease after allogeneic hematopoietic cell transplantation
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Saturday, December 11, 2021: 9:45 AM

Rasmus T. Hoeg, MD1*, Anna Moroz, MD, PhD2*, Arpita Gandhi, MD3, Lori Muffly, MD4, Parveen Shiraz, MD5, Caspian Oliai, MD6, Rohtesh S. Mehta, MD, MPH, MS7, Samer A Srour8, Joseph P. McGuirk, DO9, Edmund K. Waller, PhD, MD10, Sally Arai, MD, MS11, Laura J. Johnston, MD11, Robert Lowsky, MD11, Andrew R. Rezvani, MD11, Wen-Kai Weng, MD, PhD12, David B. Miklos, MD, PhD11, Matthew J. Frank, MD, PhD13*, John Tamaresis14*, Ying Lu, PhD15*, Vaibhav Agrawal14*, Nathaniel B Fernhoff, PhD16*, Gerhard Bauer17*, Amy Putnam16*, J Scott McClellan, MD, PhD18, Bronwen E. Shaw, MD, PhD19, Mehrdad Abedi, MD20, Robert S. Negrin, MD14 and Everett H Meyer, MD, PhD14*

1UC Davis, Sacramento, CA
2Blood and Marrow Transplantation, Stanford University, Sanford, CA
3Division of Hematology/Oncology, OHSU, Portland, OR
4Division of BMT and Cellular Therapy, Assistant Professor of Medicine Bone & Marrow Transplantation Stanford University Medical Center, Stanford, CA
5Division of BMT and Cellular Therapy, Stanford University, Stanford, CA
6Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA
7Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
8Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX
9Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Cancer Center, Westwoon, KS
10Winship Cancer Institute, Emory University, Atlanta, GA
11Division of BMT and Cellular Therapy, Stanford University School of Medicine, Stanford, CA
12Stanford Univ. School of Med., Stanford, CA
13Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University Hospital, Stanford, CA
14Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA
15Dept of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA
16Orca Bio, Menlo Park, CA
17Institute For Regenerative Cures (IRC), University of California Davis, Sacramento, CA
18Orca Bio, Belmont, CA
19Medical College of Wisconsin, Milwaukee, WI
20Univerity of California Davis Comprehensive Cancer Center, Sacramento, CA

BACKGROUND

GVHD and non-relapse mortality (NRM) remain frequent complications of HLA-matched HSCT despite the use of standard immunosuppression like tacrolimus and methotrexate. Alternative GVHD prophylaxis (PPX) strategies like T-cell depletion and post-transplant cyclophosphamide negatively impact relapse, infection, and organ toxicity, and no strategy has yet demonstrated a clear benefit for GVHD-free survival. Orca-T is an investigational cellular product comprising stem and immune cells that leverages highly purified donor regulatory T cells to control alloreactive immune responses. Unlike point-of-care graft engineering approaches, Orca-T is produced in a central GMP laboratory and has been successfully distributed to multiple centers across in the U.S. Early clinical trials using Orca-T showed a good safety profile, promising GVHD control, and potentially improved immune reconstitution. Here, we present trial results from both a single-institution Phase 1/2 trial that has completed enrollment and an ongoing multicenter Phase 1b trial.

METHODS

As of 28 July 2021, 113 patients aged 18-72 have received Orca-T for AML, ALL, MDS, lymphoma, or myelofibrosis. We present here data from 80 patients that have ≥90 days follow-up. 28 and 52 patients, respectively, received Orca-T followed by single-agent GVHD prophylaxis on a single-center Phase 2 study (NCT01660607) and a multicenter Phase Ib (NCT04013685). Orca-T products were derived from HLA-matched related (n=46) or unrelated (n=34) donors. Patients received a variety of myeloablative conditioning regimens (e.g., non-TBI, n=66; TBI-based, n=14) followed by single-agent PPX with either tacrolimus (n=73) or sirolimus (n=7). Median follow-up for these patients is 541 days (single-center) and 248 days (multicenter).

We identified a contemporaneous SOC cohort, and we reported on their clinical outcomes at Stanford (n=95) with both matched related (n=52) and unrelated (n=43) transplant recipients who received unmanipulated PBSC products (median f/u 546) and methotrexate plus tacrolimus prophylaxis.

RESULTS

The Orca-T investigational cell therapy was manufactured reliably, delivered in less than 72 hours for all patients, and every patient enrolled received Orca-T. The Treg drug product was characterized by high Treg purity of 93.8% +/- 3.1% and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between trials). An Orca-T product was produced and infused for all patients, and there were no logistics failures or infusion reactions. All patients engrafted and Orca-T patients showed earlier neutrophil (median of 12 days vs. 14 days, p<0.0001 by Mann-Whitney U) and platelet engraftment (14 vs 17 days, p<0.0001) compared to SOC.

On the single-center, Phase 2 clinical trial study at Stanford there is evidence of improved 1-year GVHD and relapse-free survival (GRFS) which was 77% (CI 51-88%) for Orca-T patients vs 34% (CI 25-44%) with SOC (Figure 1A). We observed improved rates of >grade 2 acute GVHD at Day +180 (aGVHD, 14% versus 33%), moderate-to-severe chronic GVHD at 1 year (4% versus 42%) and NRM at 1 year (0% versus 13%). Relapse-free (RFS) and overall survival (OS) trended upwards for Orca-T. Severe infectious complications were rare.

Key clinical results from both Orca-T trials are summarized in Table 1; 23 of 80 patients had ≥1 year follow-up. Consistent with findings from the single-institution study, on the multicenter study, rates of moderate-to-severe cGVHD and non-relapse mortality were low at 1-year post-transplant at 3% and 4%, respectively.

For all patients who received Orca-T across both studies, we observed GRFS of 72% (Figure 1B), RFS of 78%, and OS of 91% at 1 year. These survival rates compare favorably to the contemporaneous SOC control (33%, 71% and 78%, respectively).

Immune reconstitution in Orca-T patients with single agent tacrolimus appears similar to SOC except for observable differences in the IL-2 pathway.

CONCLUSIONS

Manufacture of high precision Orca-T investigational cell therapy drug products was scaled in a central GMP with reliable distribution to centers. Patients that received Orca-T and single-agent PPX showed significantly reduced aGVHD, cGVHD and NRM. Orca-T shows promise to improve GRFS and other transplant outcomes. Orca-T has been granted Regenerative Medicine Advanced Therapy status by the FDA, and a phase 3 prospectively, randomized study is planned.

Disclosures: Gandhi: Gamida Cell: Consultancy, Membership on an entity's Board of Directors or advisory committees; CareDx Inc: Honoraria; Talaris: Membership on an entity's Board of Directors or advisory committees. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Mehta: Kadmon: Research Funding; Incyte: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding. McGuirk: Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; EcoR1 Capital: Consultancy; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Novartis: Research Funding; Astelllas Pharma: Research Funding. Waller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Arai: Magenta Therapeutics: Research Funding. Rezvani: US Department of Justice: Consultancy; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding; Kaleido: Other: One-time scientific advisory board. Weng: Kite Pharma: Research Funding. Miklos: Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Allogene Therapeutics: Research Funding. Fernhoff: Orca Bio: Current Employment. Putnam: Orca Bio: Current Employment. McClellan: Orca Bio: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Abedi: Seattle Genetics: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau. Meyer: Triursus Therapeutics: Current holder of stock options in a privately-held company; GigaImmune: Current holder of stock options in a privately-held company; Orca Biosystems: Research Funding; Indee, Jura: Consultancy.

*signifies non-member of ASH