TCRαβ/CD19 Depletion of Stem Cell Grafts for Transplant

A Feasibility Study Using the CliniMACS Device for T-Cell Receptor (TCR) αβ+/CD19+ Depleted Hematopoietic Stem Cells for Patients Undergoing Transplant

The CliniMACS® device is FDA-approved only for one indication (CD34+ selection). Additional use of this device outside of this indication requires the use of feasibility studies. Children, adolescents and young adults with malignant and non-malignant conditions undergoing hematopoietic stem cell transplants will have stem cells selected using alpha-beta+/CD19+ cell depletion. This is a single arm feasibility study using this processing of peripheral stem cells with alternative donor sources (haploidentical, mismatched, matched unrelated) to determine efficacy as seen by engraftment and graft-versus-host disease (GVHD).

Hematopoietic stem cell transplantation (HSCT) is recognized as an effective cure for a wide range of diagnoses including hematologic malignancies, bone marrow failure syndromes, red blood cell disorders (sickle cell, beta thalassemia), white blood cell disorders (CGD), and immune deficiency disorders. Current therapy with allogeneic HCT from HLA-matched sibling donors has shown to be a potentially curative option for children with high-risk and/or relapsed hematologic malignancies (ALL/AML) as well as primary immune deficiency disorders (PID), however only 25-30% of patients have an HLA-identical matched sibling. Alternative stem cell sources include matched unrelated donors (MUD) and unrelated cord blood (UCB), however, the likelihood of finding an unrelated match can range between 29-79% depending on the patient's ethnic background. Since 2015, the CHLA Transplant and Cellular Therapy Program has performed approximately 90 ex vivo processed haploidentical transplants. Greater than 80% of our patients belong to racial/ethnic groups with limited unrelated donor availability, relying heavily on haploidentical donors. This lack of matched stem cells represents a significant access disparity for underrepresented minorities with life-threatening hematologic or immunologic conditions to undergo a potentially curative HSCT. The FDA approved the use of the CliniMACS CD34+ Reagent System as a Humanitarian Use Device for the prevention of GVHD in patients with acute myeloid leukemia (AML) in first complete remission undergoing allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor. The CliniMACS CD34+ Reagent System decreases the risk of developing GVHD by efficiently removing donor T-cells from the graft prior to infusion by enriching CD34+ blood stem cells, which help to repopulate the patient's immune system. FDA approval was based on data from a phase II, single-arm, multi-center study conducted by the Blood and Marrow Transplant Clinical Trials Network that showed after an intensive myeloablative conditioning, receiving a stem cell transplant from a matched related donor processed through the CliniMACS CD34+ Reagent System as a GVHD prophylaxis led to a low incidence of chronic GVHD, about 19% at 2 years post-transplant. However, removal of all cells except CD34+ selected complicates immune recovery (delay in CD4+ cells) leading to higher rates of opportunistic viral infections and transplant-related mortality. The use of CD34+ selected processing has facilitated approximately 42 HSCTs in combination of TCRαβ+/CD19 depletion at CHLA. The new approach to ex vivo processing utilizes negative depletion of cells thought to be responsible for the development of aGVHD, αβ TCR positive T-cells and includes simultaneous depletion of CD19+ B-cells. Since 2015, CHLA has conducted TCRαβ/CD19+ depleted HSCTs successfully on several protocols, including the ONC1401 KIR Study (IDE#16412).

Graft Vs Host Disease, Graft-versus-host-disease, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Non-hematologic Malignancy, Hematologic Malignancy

The test product is an αβ+/CD19+ T-cell depleted stem cell product using the CliniMACS system. The test product is given intravenously over a period of time as dictated by the final volume of the infused product (5mL/kg/hour). The target dose of CD34+ cells is 20-40 x 10^6/kg, but a minimum of 5 x 10^6/kg is required. The target dose of TCRαβ+ T-cells and CD19+/CD20+ T-cells is ≤ 1 x 10^5/kg.

CliniMACS TCR αβ+/CD19+ cell depletion for related or unrelated haploidentical/mismatched/matched hematopoietic stem cell transplant patients and/or high risk GVHD patients.

Assess the cumulative incidence of severe GVHD following HSCT with TCRαβ+/CD19+ T-cell depleted grafts, as determined by the presence of Grade III-IV aGVHD and/or cGVHD by Day+100 post-HSCT.

Assess the efficacy of TCRαβ+/CD19+ T-cell depleted HSCTs as measured by the engraftment of donor cells by Day+30 post-HSCT.

Assess the efficacy of TCRαβ+/CD19+ T-cell depleted HSCTs as measured by the incidence of transplant-related mortality at 1-year post-HSCT.

Incidence of T-cell reconstitution at Day+180 (CD4+ T-cell count > 200 and proliferation to PHA > 50% control).

Assess the immune reconstitution following TCRαβ+/CD19+ T-cell depleted HSCTs as measured by the presence of expanded T-cell numbers and function at Day+180 post-HSCT(CD4+ T-cell count > 200 and proliferation to PHA > 50% control).

Incidence of microbial contamination of the infused cells product leading to possible infection in the recipient (i.e., antibiotics needed for > 48 hours).

Assess the risk of microbial contamination in TCRαβ+/CD19+ T-cell depleted products from the CliniMACS® device.

Inclusion Criteria: Written informed consent (and written assent, if applicable) obtained prior to enrollment. Age < 21. Lansky Play-Performance Scale or Karnofsky Index score ≥ 60%. Adequate organ function (within 4 weeks of initiation of preparative regimen) as evaluated per institutional guidelines. Adequate major organ system function as demonstrated by: Renal: Creatinine clearance or GFR of ≥ 60mL/min/1.73m2. Hepatic: total bilirubin < 2 mg/dL (unless due to Gilbert syndrome) and ALT/AST ≤ 2.5 times the upper limit of normal. Cardiac: LVEF at rest ≥ 50% or SF ≥ 27% (by MUGA or ECHO). Pulmonary: DLCO, FEV1, and FVC ≥ 50% of predicted corrected for hemoglobin. For patients < 7 years of age or those unable to perform PFTs: O2 Sat ˃ 92% on room air by pulse oximetry and on no supplemental O2 at rest. Available donor (matched/mismatched unrelated, mismatched related, related haploidentical) who is healthy and willing to donate peripheral blood stem cells. Patients that have been diagnosed with graft rejection/failure or relapse may be eligible to receive a second transplant pending patient status. Exclusion Criteria: Patients with HIV or uncontrolled fungal, bacterial, or viral infections. Patients with active CNS leukemia or any other active site of extramedullary disease at the time of enrollment. Recipient with HLA antibody against donor. Patients that are pregnant, breastfeeding or unwilling to practice birth control during participation of the study. Any condition that, in the opinion of the Sponsor-Investigator, would compromise the safety of the participant, prevent study participation, or interfere with the evaluation of study endpoints.

The data will be made available internally to other sub-investigators that have expressed interest. Data that will be shared must go through the Sponsor-Investigator and will be redacted (if not already done) prior to receiving the data so that no identifying information is present.

Data will be made available upon request by submitting criteria of interest. The Sponsor-Investigator will provide a copy of the data. The copy will be indefinitely available to the interested party.

Data will be made available upon request by submitting criteria of interest. A copy of the redacted data will be given. No other party will have access to the database at any time outside of the Sponsor-Investigator and data management/CRC team.

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