Background:
High-risk blood cancers (leukemias and lymphomas) often come back after treatment, and many cannot be cured with chemotherapy alone. These cancers may be treated and potentially cured in 2 ways: (1) Bone marrow transplant (allogeneic hematopoietic cell transplantation, or alloHCT) gives immune and blood stem cells from a donor. These new cells can attack the cancer and also grow into healthy blood. (2) Chimeric antigen receptor (CAR) T-cell therapy takes immune cells and changes them in a lab to better recognize and target certain cancers. But these 2 treatments are not usually given at the same time.
Objective:
To test alloHCT and CAR-T cell therapy, used together, in people with high-risk blood cancers.
Eligibility:
People aged 18 to 75 years with an aggressive blood cancer that has a protein on the surface called CD19. A healthy related donor aged 12 years or older is also needed; this donor may be a parent or child or may be some siblings or even extended family members, but has to be half-matched at something called the HLA (human leukocyte antigen).
Design:
Participants will be screened. They will have imaging scans, blood tests, and tests of their heart and lung function. They will have eye and dental exams. They may have fluid drawn from around their spinal cord (spinal tap) and tissue taken from inside a bone (bone marrow biopsy).
Healthy donors will provide bone marrow, immune cells, and about 9 tablespoons of blood for both the recipient s treatment and for research. They will also provide stool, saliva, and oral swabs just for research.
Recipient participants will stay in the hospital for 4 to 6 weeks. They will be given drugs over 6 days to prepare for the cell therapies. Both the donor bone marrow cells and CAR-T-cells will be given through a tube inserted into a vein. They will receive drugs to reduce complications after the treatments.
Participants will remain within a 1-hour drive of the hospital for 2 to 3 months after they leave the hospital. They will have frequent visits during that time. They will continue to have periodic follow-up visits for 5 years.
...
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%.
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.
Sequential
mCD19-CAR-CD28-CD3-zeta.(anti-CD19 CAR) retroviral vector-transduced allogeneic peripheral blood lymphocytes (PBL)
Biological/VaccineCAR-T cell infusion given at four escalating dose levels (DL1: 3 x 10\^4 cells/kg, DL2: 1 x 10\^5 cells/kg, DL3: 3 x 10\^5 cells/kg, DL4: 1 x 10\^6 cells/kg) with a dose de-escalation dose (DL-1: 1 x 10\^4 cells/kg), if needed.
Fludarabine
DrugPre-transplant: 30 mg/m\^2 IV infusion over 30-60 minutes once daily for 5 days from day -6 through day -2
Cyclophosphamide
DrugPre-transplant: 14.5 mg/kg/day IV daily for 2 days pre-transplant on day -6 and day -5. Post-transplant: 25 mg/kg/day on day +3 and day +4.
Mycophenolate Mofetil
Drug15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35 post-transplant.
Sirolimus
DrugLoading dose of 6 mg orally given on day +5, then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +60 post-transplant.
CD19 Flow Cytometry Assay
DeviceAssay used to determine CD19+ status
CD19 Immunohistochemical Assay
DeviceAssay used to determine CD19+ status
Total Body Irradiation
Radiation400 centigray (cGy) to be delivered in 2 fractions as 200 cGy per fraction twice a day on Day -1 pre-transplant.
Identify the safety of anti-CD19 CAR T-cell therapy in combination with HLA-haploidentical HCT in participants with high risk CD19+ hematologic malignancies
Determine the fraction of evaluable recipient participants at each dose level who experience a dose-limiting toxicity (DLT).
Estimate the 1 year relapse and survival outcomes at the maximum tolerated dose
Estimates will be determined using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate for participants treated at the MTD and may be reported individually for the MTD and other dose levels. The results at indicated time points will be reported and may include 95% confidence intervals as appropriate.
Estimate the incidence and severity of CRS and ICANS
Rate and grade of CRS and ICANS will be measured by the maximum grade as assessed by the ASTCT Consensus Criteria for each condition and reported as fractions of those that attained each grade of severity.
Estimate the incidence of Grade II-IV and Grade III-IV acute GVHD at +200 days
Grade II-IV and III-IV aGVHD will be evaluated descriptively including fractions who attain each condition, along with 95% confidence intervals as appropriate.
Estimate the incidence and severity of chronic GVHD at 1 year
Analyses will be done numerically and using cumulative incidence curves with 95% confidence intervals at the stated time points as appropriate.
Estimate incidence of primary engraftment failure and kinetics of engraftment
Will be reported as a proportion of evaluation participants
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