CD45RA-depleted CD19-CAR T Cell Consolidation After TCRαβ+/CD19 B Cell-depleted Haploidentical Hematopoietic Cell Transplantation for Relapsed/Refractory CD19+ ALL and Lymphoma

This is a Phase I study evaluating the addback of CD19-CAR(Mem) T cells after TCRαβ+/CD19 B cell depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.

Donors that meet eligibility criteria will be consented to undergo two separate collections: 1) G-CSF mobilized stem cell graft via apheresis for progenitor cell infusion and 2) Non-mobilized peripheral blood mononuclear cells (PBMC) via apheresis for subsequent CAR T-cell manufacturing and DLI if needed.

Patients that meet eligibility criteria to receive therapy will be consented to proceed on study. Treatment will include a conditioning chemotherapy preparative regimen followed by infusion of TCRαβ/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product, as well as collection of correlative samples.

Inclusion criteria

Recipient

• Age less than or equal to 21 years
• High risk hematologic malignancy where allogeneic transplantation is the current standard of care. This includes (but is not limited to):

• High risk CD19+ B cell ALL in CR1 or CR2
• Any CD19+ B-cell ALL in CR3 or subsequent
• If prior CNS leukemia, it must be treated and in CNS CR
• Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%
• Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2
• Forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
• Karnofsky or Lansky (age dependent) performance score ≥ 50 (See APPENDIX A)
• Bilirubin ≤ 3 times the upper limit of normal for age
• Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age

Donor

• At least single haplotype matched (≥ 4 of 8) family member
• At least 18 years of age
• HIV negative
• If sexually active, agreement to use birth control until 2 weeks after completion of the mobilization and apheresis procedure
• Regarding donation eligibility, is identified as either:

• Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR
• Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271

Exclusion criteria

Recipient

• Has a suitable HLA-identical sibling or suitable 12/12 (HLA-A, B, C, DRB1, DQB1, and DPB1) HLA-matched unrelated donor available in an appropriate time frame
• Any other active malignancy other than the one for which this HCT is indicated
• Received a prior allogeneic HCT at any time
• Pregnant, if female is of childbearing potential, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment
• If sexually active, agreement to use birth control until 6 months after T cell infusion
• Breast feeding
• Any severe current uncontrolled bacterial, fungal or viral infection

Donor

• Pregnant, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment if female
• If female, breast feeding