Phase I Trial Integrating HLA-Haploidentical Anti-CD19 CAR-T Cells With Post-Transplantation Cyclophosphamide-Based HLA-Haploidentical Hematopoietic Cell Transplantation

Background:

• High-risk hematologic malignancies generally are incurable without an allogeneic hematopoietic cell transplant (HCT), but even with HCT they are at high-risk of relapse and poor overall survival.
• Chimeric-antigen-receptor (CAR) T-cell therapy can offer a high remission rate for relapsed or refractory B-cell malignancies but is not curative in the majority of patients.
• Currently, these two therapies (HCT and CAR-T cells) are used individually or sequentially, with HCT being used as consolidation or salvage post-CAR-T cells or CART cells being used to treat post-HCT relapse.
• Allogeneic CAR-T cells may be given to treat post-transplant relapse, but have not been used early post-transplant due to potential increased risk of graft-versus-host disease (GVHD).
• Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic GVHD and the immunosuppressive burden after HCT, including allowing LAhaploidentical HCT to be performed safely and routinely worldwide.
• In pre-clinical major histocompatibility complex (MHC)-haploidentical HCT models, CAR-T cells can be given on day 0 or day +5 (before or early after PTCy) and exert potent anti-tumor effects without impairing PTCy s efficacy in preventing GVHD. Administration of CAR-T cells on day +9 or +14 was ineffective in eradicating leukemia.
• In our preclinical models, administration of CAR-T cells on day 0 (prior to PTCy) surprisingly led to better anti-tumor efficacy than when given on day +5, associated with better early expansion, less CD4+ CAR-T cells with a regulatory phenotype, more activated CD4+ CAR-T cells, and more cytotoxic CD8+ CAR-T cells.
• The premise for the clinical application is that the CAR-T cells given in conjunction with or early post-transplant would induce an initial deep remission, while the polyclonal allogeneic T cells contained in the HCT would eliminate escape clones and promote longterm cure.
• The direct integration of CAR-T cells with PTCy-based HCT has the potential to provide synergistic reduction of relapse, reduce the duration of treatment, and allow CAR-T cells to persist post-transplant.

Objectives:

• To identify the safety of donor-derived HLA-haploidentical anti-CD19 CAR-T cells that can be given in combination with PTCy-based HLA-haploidentical allogeneic HCT in participants who have high-risk CD19-expressing hematologic malignancies (Phase I -dose escalation).
• To estimate 1 year relapse and survival outcomes at the maximum tolerated dose (MTD) (Phase I - dose expansion)

Eligibility:

• Adults age 18-75 years
• High-risk CD19-expressing hematologic malignancies
• Available HLA-haploidentical donor
• Adequate organ function
• KPS >= 60%

Design:

• Open-label, single-center, non-randomized, phase I study
• All recipient participants will receive reduced intensity conditioning, HLA-haploidentical bone marrow HCT, GVHD prophylaxis including post-transplantation cyclophosphamide, and allogeneic donor-derived anti-CD19 CAR-T cells.
• The study will proceed to a small, four-level phase I dose escalation study based on the standard 3+3 approach. CAR-T cells will be administered on day 0, except in the case of dose de-escalation wherein alternative dose levels would be employed and CAR-T cells would then be administered on day +7.
• Dose-escalation will be based on absence of grade III-IV acute GVHD (aGVHD), severe cytokine release syndrome (CRS), severe neurotoxicity or other toxicities as specified, or non-relapse mortality by day +28
• We will expand to include 6 additional participants at the maximum tolerated dose level determined by the phase I dose escalation to better estimate relapse and GVHD outcomes. Recipient participants will be followed for 5 years.

-INCLUSION CRITERIA - Recipient

• Participants with high or very high-risk hematologic malignancies, as defined by the revised Disease Risk Index (DRI), or malignancy that remains persistently MRD+ (by flow cytometry, cytogenetics, FISH, PCR, or NGS) on most recently assessed disease specimen (within 2 months of initiating conditioning).
• Hematologic malignancy must be CD19+ (uniform expression on immunohistochemistry or >= 80% on flow cytometry) as confirmed by CD19 IHC assay (BT51E) or flow cytometry (BD QuantiBRITE(TM) Beads PE Fluorescence Quantitation Kit). (Participants do not have to have refused or lack access to commercial anti-CD19 CAR-T-cell therapies since this study focuses on the integration of CAR-T cells and HCT and not specifically the CAR-T cells themselves; furthermore the construct used to manufacture this product is the same as used in a current commercial product, but developed from a new batch and with a similar but not identical manufacturing process.)
• Age 18-75
• Karnofsky >= 60%.
• Participants must have adequate organ and marrow function as defined below:

• Cardiac ejection fraction >= 45% by 2D echocardiography;
• Forced expiratory volume-1 (FEV-1) and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of >= 50% predicted;
• Estimated serum creatinine clearance of >= 60 ml/minute/1.73m^2 calculated using eGFR in the clinical lab (participants with estimated serum creatinine clearance less than 60 may have measured creatinine clearance performed and if >= 60 will be considered eligible);
• Total bilirubin <= 2X the upper limit of normal (participants with documented or suspected Gilbert s are exempt from this requirement);
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 5X the upper limit of normal.
• At least one available HLA-haploidentical donor
• Women of child-bearing potential (WOCBP) must agree to use a highly effective method of contraception (hormonal, intrauterine device (IUD), surgical sterilization, abstinence) at the study entry and for 1 year after transplant (restriction period).

Men must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and for 1 year after transplant. We also will recommend men with female partners of childbearing potential to ask female partners to be on highly effective birth control (hormonal, intrauterine device (IUD), surgical sterilization). Men must not freeze or donate sperm within the same period.

• Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 1 year after transplant.
• Participants seropositive for human immunodeficiency virus (HIV) not due to intravenous immunoglobulin, must have been on effective combination anti-retroviral therapy for 6 months and without detectable viral load prior to the beginning of conditioning.
• For participants seropositive for hepatitis B virus (HBV) core antibody not due to intravenous immunoglobulin, a HBV viral load should be undetectable.
• Participants seropositive for hepatitis C virus (HCV) not due to intravenous immunoglobulin must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Ability of participant to understand and the willingness to sign a written informed consent document.
• Ability and willingness of participant to co-enroll on 20-C-0051: Gene Therapy Follow Up Protocol for Subjects Previously Enrolled in NCI for Immuno-Oncology Studies

14 Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH (<60 minutes drive), for a minimum of 100 days after transplant or longer if there are complications. Participants must commit to having an adult caregiver with them during the first 100 days after transplant in case of discharging from the hospital before 100 days.

Inclusion criteria

- Donor

• Related donor (age >=12) deemed suitable, eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, bone marrow, and stool for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation.

Exclusion criteria

- Recipient

• Participants who are receiving any other investigational agents within 3 weeks prior to the beginning of conditioning.
• Active CNS involvement of primary hematologic malignancy
• Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is metastatic, relapsed/refractory to treatment, or locally advanced and not amenable to intended curative treatment per standard of care.
• Prior checkpoint inhibitor therapy within 6 weeks prior to the beginning of conditioning.
• Prior history of seizure.
• Uncontrolled infection.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents used in study.
• Positive beta-HCG serum or urine pregnancy test performed in females of childbearing potential at screening. (A low positive test in a post-menopausal woman may not be exclusionary if deemed not indicative of pregnancy per gynecology.)
• Uncontrolled intercurrent illness evaluated by medical history, physical exam, EKG, and laboratory testing (e.g., severe endocrinopathy, disseminated intravascular coagulation, profound electrolyte disturbance) that would make it unsafe to proceed with transplantation.

Exclusion criteria

- donor

• Pregnancy