Background:
B-cell acute lymphoblastic leukemia (B-ALL) is a type of blood cancer. Some people with B-ALL have a gene mutation that makes the disease hard to treat. The mutation causes cancer cells to make too much of a protein called thymic stromal lymphopoietin receptor (TSLPR). Chimeric antigen receptor (CAR) T cell therapy is a treatment that takes immune cells (T cells) from a person s body and modifies them to attack specific proteins. Researchers want to test whether TSLPR-CART cells can be given safely to adults with forms of B-cell leukemia, and to learn whether the treatment may help fight these cancers.
Objective:
To test TSLPR-CART in people with B-ALL.
Eligibility:
People aged 18 years and older with B-ALL that did not respond or returned after treatment. They must have TSLPR on their B-ALL.
Design:
Participants will be screened. They will have imaging scans and tests of their heart function. Samples will be taken from their bone marrow. They will have a lumbar puncture: A needle will be inserted into their back to collect a sample of the fluid around the spinal cord.
Participants will undergo leukapheresis: Blood will be taken from their body through a tube. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different tube. The T cells will be used to create TSLPR-CART.
Participants will take chemotherapy over 5 days to prepare their body for the therapy; then they will receive the modified cells through a tube inserted into a vein. Staying in the hospital during part of the treatment is expected and participants will be monitored locally to evaluate for side effects. Approximately 1 month after receiving TSLPR-CART, participants will undergo evaluations to see how the TSLPR-CART impacted their leukemia. Participants will have follow-up visits for 2 years after TSLPR-CART either at NIH or at home....
Documentation of pathologic confirmation of a diagnosis of B-Cell acute lymphoblastic leukemia (ALL).
TSLPR+ expression must be detected on >=80% of the malignant cells by NSR device. Note: TSLPR+ expression does not need to be repeated by NSR device if there is a documentation of TSLPR surface expression by flow cytometry from a Clinical Laboratory Improvement Amendments (CLIA) approved laboratory.
Participants must have a disease that is relapsed or refractory after initial systemic therapy and at least one salvage treatment, and must either be ineligible for, cannot access in a timely manner, or declined alternative curative options (including commercial CAR Tcell constructs*, and/or have relapsed after allogeneic HSCT).
Participants must have measurable or evaluable disease at the screening, defined by any evidence of MRD or positron emission tomography (PET)-avid extramedullary disease
Recurrent or refractory leukemia limited to isolated testicular or isolated CNS disease
CNS 3 disease including participants with radiologically detected active CNS lymphoma, or participants who have cranial nerve palsy from active CNS leukemia. Note: Chronic complications of prior CNS disease are not exclusionary in the absence of active disease (e.g., blindness from prior ocular CNS disease or persistent cranial nerve palsy)
Hyperleukocytosis (>=50,000 blasts/mcL)
Positive serum or urine beta-human chorionic gonadotropin (beta-HCG) pregnancy test performed in WOCBP at screening.
Single group
TSLPR-CART
Biological/VaccineTSLPR CAR transduced T cells on D0 after lymphodepleting preparative regimen
Cyclophosphamide
DrugCyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the patient s body weight, at 500 mg/m\^2/dose after fludarabine infusion on days -3 and -2.
Fludarabine
DrugFludarabine is administered as an IV infusion in an appropriate solution over 30 minutes on days -5 through -2. To prevent undue toxicity the dose will be based on BSA (30 mg/m\^2/dose).
To assess the safety of administering escalating doses of TSLPR-CART containing a tEGFR suicide switch to determine an MTD
Safety analyses will consist of tabulations of grades of toxicity by type of toxicity
Efficacy of TSLPR-CART
The Best Overall Response (BOR) will be assessed at end of study, based upon the disease assessments recorded during the study visits, and reported by dose level with a separate evaluation in the 12 participants per category treated at the MTD, in terms of confirmed complete response/partial response (CR/PR), unconfirmed CR/PR, SD, or PD. The rate of relapse from CR prior to end of study will also be summarized by dose level only for the participants who achieve confirmed CR during the study. The overall objective response rate (CR + PR) will be summarized by dose level. The Duration of Response (DOR) will be summarized for those participants who achieve objective response (CR + PR). In participants who have a confirmed response, DOR will be calculated from the first date of documented response until progressive disease (PD). Unconfirmed CR or PR is defined as the first documentation of response
1-year and 2-year OS (overall survival)
OS will be determined as the time from the start of the preparative regimen until death.
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