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....
Background: * Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subgroup of B-ALL associated with high rates of chemotherapy resistance and relapse. Ph-like ALL is defined by an activated cytokine receptor and kinase signaling profile similar to that of Philadelphia chromosome-positive (Ph+) ALL yet lacking BCR-ABL1 rearrangement. * Approximately half of childhood and adult Ph-like ALL cases have rearrangement in cytokine receptor like factor-2 (CRLF2), which encodes one subunit of the thymic stromal lymphopoietin receptor (TSLPR) and heterodimerizes with the interleukin-7 receptor alpha (IL7Ra) subunit. Its ligand, TSLP, is a cytokine that plays a critical role in regulation of the immune response and in the differentiation of hematopoietic cells. TSLP binding to the TSLPR in B-ALL induces constitutive Janus kinases and signal transducers and activators of transcription (JAK/STAT) pathway signaling. * Most CRLF2-rearranged (CRLF2-R) Ph-like ALL cases can be readily identified by increased TSLPR surface expression by flow cytometric immunophenotyping, and specific CRLF2 rearrangements can then be confirmed by genetic testing. Given the prevalence of CRLF2 rearrangements and the poor clinical outcomes of patients with Ph-like ALL, TSLPR is a promising target for new immunotherapies. * Chimeric antigen receptor-expressing T cells (CAR) have proven highly successful in patients with cancer with dramatic responses in \>70% of patients with relapsed/refractory B-ALL treated with CD19-redirected CAR T cells, resulting in Food and Drug Administration (FDA) approval of a CD19 CAR T-cell immunotherapy in children and young adults. A trial of CAR T cells targeting CD22 is currently ongoing at the NCI and has demonstrated comparable efficacy and toxicity results as the CD19 CAR. * Emerging data have indicated that not all patients respond, and up to 50% of those who achieve remission will subsequently relapse. The most common cause of relapse is the target antigen loss, which is likely multi-factorial in etiology and for which this mechanism of escape is under active investigation. Novel targets are needed. * This will be the first in human testing of anti-CRLF2-R/TSLPR CAR T cell (TSLPRCART) adoptive cell therapy. Objective: -To assess the safety of administering escalating doses of autologous anti-CRLF2-R/TSLPR-CAR engineered T cells (TSLPR-CART) containing a truncated epidermal growth factor (tEGFR) suicide switch to determine a maximum tolerated dose (MTD) in participants with recurrent or refractory CRLF2/TSLPR-overexpressing B-cell acute lymphoblastic leukemia (ALL) following a cyclophosphamide/fludarabine lymphodepletion regimen. Eligibility: * Age \>= 18 years * Participants must have confirmed diagnosis of a B-cell ALL with TSLPR+ expression on flow cytometry who have relapsed or refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options. Design: * This is a first-in-human Phase I trial aimed to determine the safety of TSLPR-CART in participants with recurrent or refractory B-cell ALL. * Participants will undergo apheresis and TSLPR-CART will be manufactured from the enriched T-cell product * Participants will receive LD preparative regimen of fludarabine and cyclophosphamide followed by an infusion of TSLPR-CART. * The MTD of autologous TSLPR-CAR T cells using a 3 + 3 dose escalation design will be determined. Additional participants in an expansion cohort will be treated at an MTD dose to evaluate the rate of response to TSLPR-CAR T cells. Participants will be evaluated for toxicity, anti-tumor response, CAR expansion and persistence, and other biologic correlatives.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
57
TSLPR CAR transduced T cells on D0 after lymphodepleting preparative regimen
Cyclophosphamide 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 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).
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
RECRUITINGTo 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
Time frame: 28 days post cell infusion
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
Time frame: 2 years post cell infusion
1-year and 2-year OS (overall survival)
OS will be determined as the time from the start of the preparative regimen until death.
Time frame: 2 years post cell infusion
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