Background: * gPhiladelphia (Ph)-like h 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....
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To assess the safety of administering escalating doses of TSLPR-CART containing a tEGFR suicide switch to determine an MTD
Timeframe: 28 days post cell infusion