Allogeneic Hematopoietic Cell Transplant with Orca-T for the Treatment of Acute Myeloid Leukemia, Acute Lymphoid Leukemia, Mixed Phenotype Acute Leukemia and Myelodysplastic Syndrome, ACCESS-T Trial

Inclusion Criteria

• PARTICIPANT: Eligible diseases: * Acute myeloid, lymphoid or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi); with or without the presence of known minimal residual disease, or * Myelodysplasic syndrome (MDS) myelodysplastic syndromes eligible for allogeneic hematopoietic stem cell transplantation (alloHSCT) and/or treatment-related MDS < 10% blasts
• PARTICIPANT: Age ≥ 18 and ≤ 70 years at the time of enrollment
• PARTICIPANT: Eligible for myeloablative alloHCT including one of the myeloablative conditioning regimens
• PARTICIPANT: Has a related or unrelated donor available who is 7/8 match (single allele mismatched) at HLA-A, -B, -C, and -DRB1, all typed using deoxyribonucleic acid (DNA)-based high-resolution methods
• PARTICIPANT: Estimated glomerular filtration rate (eGFR) ≥ 50 mL/minute or creatinine < 2 mg/dL
• PARTICIPANT: Cardiac ejection fraction at rest ≥ 45% or shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA)
• PARTICIPANT: Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50%
• PARTICIPANT: Total bilirubin < 2 times upper limit of normal (ULN) (patients with Gilbert’s syndrome may be included once hemolysis has been excluded)
• PARTICIPANT: Ability to understand and the willingness to provide written informed consent
• PARTICIPANT: Negative serum or urine beta-human chorionic gonadotropin (HCG) test in females of childbearing potential (FCBP) within 3 weeks of enrollment * A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• PARTICIPANT: Able to give informed consent. Legal authorized representative (LAR) is permitted if subject is cognitively able to provide verbal assent
• PARTICIPANT: Karnofsky performance score ≥ 70% or Eastern Cooperative Oncology Group (ECOG) ≤ 2
• DONOR: Age ≥ 16 and ≤ 75 years at time of enrollment. Unrelated donors identified through National Marrow Donor Program (NMDP) must be 18 years of age or older and competent to provide informed consent
• DONOR: Be a related or unrelated donor available who is 7/8 match (single allele mismatched) at HLA-A, -B, -C, and -DRB1, all typed using DNA-based high-resolution methods
• DONOR: Willing to undergo apheresis collection (peripheral blood stem cell [PBSC]) for up to two consecutive days
• DONOR: Negative for human immunodeficiency virus (HIV)-1 and HIV-2, or human T-lymphotropic virus (HTLV)-1 and HTLV-2
• DONOR: Negative for anti-hepatitis C virus (HCV) antibody or HCV by nucleic acid testing (NAT)
• DONOR: Negative for the Treponema pallidum antibody syphilis screen * In the case that Treponema pallidum antibody tests are positive, donors must: ** Be evaluated and show no evidence of syphilis infection of any stage by physical exam and history ** Have completed effective antibiotic therapy to treat syphilis ** Have a documented negative non-treponemal test (such as rapid plasma reagin [RPR]) or in the case of a positive non-treponemal test must be evaluated by an infectious disease expert to evaluate for alternative causes of test positivity and confirm no evidence of active syphilitic disease
• DONOR: Donors not meeting federal eligibility criterion, may nonetheless be included if either apply, as follows: * The donor is a first-degree or second-degree blood relative of the recipient, or * Documented urgent medical need (DUMN), meaning no comparable human cell product is available and the recipient is likely to suffer death or serious morbidity without the human cell product, as attested by the investigator or sub-investigator
• DONOR: Meets all other criteria for donation as specified by standard National Marrow Donation Program (NMDP) guidelines (NMDP donors) or institutional standards (non-NMDP donors)
• DONOR: Persons of child-bearing potential must have a negative serum or urine beta human chorionic gonadotropin (HCG) test at screening and within 1 to 5 days prior to mobilization
• DONOR: Capable of undergoing leukapheresis, have adequate venous access, and are willing to undergo insertion of central catheter should leukapheresis via peripheral vein be inadequate
• DONOR: Ability to understand and the willingness to personally sign the written IRB-approved informed consent document

Exclusion Criteria

• PARTICIPANT: Prior allogeneic HCT
• PARTICIPANT: Currently receiving corticosteroids or other immunosuppressive therapy within 5 days of enrollment. Topical corticosteroids or oral systemic corticosteroid doses less than or equal to 10 mg/day are allowed
• PARTICIPANT: Planned donor lymphocyte infusion (DLI)
• PARTICIPANT: Planned pharmaceutical in vivo or ex vivo T cell depletion, e.g., post-transplant cyclophosphamide (Cy), peri-transplant anti-thymocyte globulin (ATG), or alemtuzumab. For patients that have previously been exposed to a T cell-depleting agent, a 5 half-life washout of the agent must occur prior to planned Day 0 (day of infusion of Orca-T HSPC and T^regs )
• PARTICIPANT: Recipient positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either: * Positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing), or * Presence of anti-donor HLA antibody to any of the following HLA loci: HLA-A, -B, -C, –DRB1, -DQB1, -DQA1, -DPB1, or -DPA1, with mean fluorescence intensity (MFI) > 1000 by solid phase immunoassay
• PARTICIPANT: Uncontrolled bacterial, viral, or fungal infections (currently taking antimicrobial therapy and with progression or no clinical improvement) at time of enrollment including known, active tuberculosis infection
• PARTICIPANT: Seropositive for HIV-1 or -2, HTLV-1 or -2, hepatitis B surface antigen (sAg), and/or hepatitis C antibody * History of hepatitis B or hepatitis C is permitted if viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or NAT. In this case, monitoring for hepatitis B or hepatitis C by PCR at 3, 6, and 12 months is recommended
• PARTICIPANT: Known allergy or hypersensitivity to, or intolerance of, any investigational agent or ingredient therein, or planned GVHD prophylactic medications
• PARTICIPANT: Documented allergy or hypersensitivity to iron dextran or bovine, murine, algal or Streptomyces avidinii proteins
• PARTICIPANT: Any uncontrolled autoimmune disease requiring active immunosuppressive treatment
• PARTICIPANT: Concurrent malignancy diagnosed within 12 months of enrollment, except non-melanoma skin cancers that have been curatively resected
• PARTICIPANT: Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation. The investigator will determine the most suitable form of birth control that does not interfere with the proposed investigation and that meets the health needs and preferences of the participant * FCBP definition: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• PARTICIPANT: History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment. History of stroke or pulmonary embolism within 6 months of enrollment
• PARTICIPANT: Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the recipient’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results
• DONOR: Evidence of active infection
• DONOR: Seropositive for HIV-1 or -2, HTLV-1 or -2
• DONOR: Positive for anti-hepatitis C (HCV) antibody or HCV nucleic acid test (NAT)
• DONOR: Positive serologic or PCR test results indicating acute or chronic HBV infection * Donors whose HBV infection status cannot be determined conclusively by serologic test results must be negative for HBV by PCR to be eligible for study participation
• DONOR: Potential for Zika virus infection as defined as any of the following: * Medical diagnosis of Zika virus infection in the past 6 months * Residence in, or travel to, an area with active Zika virus transmission within the past 6 months * Unprotected sex within the past 6 months with a person who is known to have either of the risk factors listed above * Donors determined to be ineligible based on the results of Zika virus screening may be determined to be eligible if: ** The donor has no signs or symptoms consistent with active Zika virus infection, and ** Either of the following is true: *** The donor is a first-degree or second- degree blood relative of the recipient *** Urgent medical need, meaning no comparable human cell product is available and the recipient is likely to suffer death or serious morbidity without the human cell product, as attested by the investigator
• DONOR: Medical, physical, or psychological reason that would place the donor at increased risk for complications from growth factor or leukapheresis
• DONOR: Pregnant or breastfeeding