U69-CART-Cells For R/R T-ALL

Inclusion criteria

• Subjects must meet all of the following criteria to be eligible for the study:

• Informed Consent: Voluntary provision of written informed consent and anticipated ability to complete all required study procedures and follow-up assessments.
• Age: ≥15 and ≤75 years of age at the time of signing the informed consent form.For minors (age ≤ 18 years), informed consent must be provided by a legal guardian; minors with capacity to sign should co-sign the consent form alongside their guardian.
• Diagnosis and Disease Status: Histologically or cytologically confirmed diagnosis of relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) according to the 2022 WHO Classification of Haematolymphoid Tumours, for which standard curative treatments are no longer effective.

3.1 For T-ALL: Presence of ≥5% blasts in bone marrow or peripheral blood at screening. Relapse: Defined as recurrence of blasts (≥5%) in peripheral blood or bone marrow or emergence of extramedullary disease after prior achievement of complete remission (CR/CRi). This includes early relapse (within 12 months of first remission), late relapse (≥12 months) failing to achieve remission after one multi-agent re-induction chemotherapy cycle, or relapse after autologous or allogeneic hematopoietic stem cell transplantation (HSCT).

Refractory: Defined as failure to achieve CR after at least two cycles of induction chemotherapy, or failure to achieve CR after one cycle of salvage therapy following relapse.

3.2 For T-LBL: Presence of at least one measurable lesion at screening, defined as a nodal lesion with a long axis >15 mm or an extranodal lesion with a long axis >10 mm, as assessed by CT or MRI per the 2014 Lugano criteria.

Relapsed/Refractory: Defined as relapse or disease progression after at least two prior lines of therapy; primary refractory disease (failure to achieve at least a partial response, PR, after first-line therapy); or relapse/progression after autologous or allogeneic HSCT (must be confirmed by tissue biopsy).

• Biomarker: Confirmed CCR9 positivity on tumor cells via flow cytometry of bone marrow samples and/or via immunohistochemistry of extramedullary lesion biopsies at screening.
• Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Life Expectancy: Estimated life expectancy of greater than 3 months.
• Bone Marrow Reserve: Adequate bone marrow reserve at screening, defined as:

Absolute Neutrophil Count (ANC) ≥ 1.0 × 10⁹/L Absolute Lymphocyte Count (ALC) ≥ 0.3 × 10⁹/L Platelet Count (PLT) ≥ 20 × 10⁹/L (transfusion support is permitted).

• Organ Function: Adequate organ function defined as:

Hepatic: Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 × Upper Limit of Normal (ULN); Total Bilirubin ≤ 2 × ULN.

Renal: Serum Creatinine ≤ 1.5 × ULN, OR Creatinine Clearance ≥ 50 mL/min (calculated by the Cockcroft-Gault formula).

Cardiac: Left Ventricular Ejection Fraction (LVEF) ≥ 45%. Pulmonary: Oxygen saturation ≥ 92% on room air.

• Contraception: Female subjects of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective contraception for at least one year post-infusion. Male subjects with female partners of childbearing potential must agree to use barrier contraception and refrain from sperm donation for at least one year post-infusion.
• Leukapheresis: Must have adequate venous access for leukapheresis or venous blood draw and no other contraindications to leukapheresis.

Exclusion criteria

• Subjects will be excluded from the study if they meet any of the following criteria:

• Diagnosis of any other malignancy within 3 years prior to screening, except for those who have completed curative therapy and achieved over 3 years of disease-free survival with a low risk of recurrence as determined by the investigator (e.g., carcinoma in situ of the lung, basal cell carcinoma of the skin).
• History or presence of central nervous system (CNS) disorders unrelated to the disease under study at screening or previously, such as seizure, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the CNS.
• Prior receipt of cell therapies targeting CCR9, including but not limited to CAR-T or CAR-γδT cells.
• Significant or active parenchymal CNS or cranial nerve lesions where, in the investigator's judgment, the risks outweigh the benefits.
• Systemic corticosteroid use discontinued ≤72 hours prior to apheresis, except for physiological replacement doses (e.g., prednisone <10 mg/day or equivalent).
• Donor lymphocyte infusion (DLI) within 6 weeks prior to apheresis.
• Treatment with any anti-T-cell antibody therapy within 4 weeks prior to apheresis.
• Presence of any of the following: positive hepatitis B e antibody (HBe-Ab) and/or hepatitis B core antibody (HBc-Ab) with HBV-DNA above the lower limit of quantification; positive hepatitis C antibody (HCV-Ab) with HCV-RNA above the lower limit of quantification; positive treponema pallidum antibody (TP-Ab); positive human immunodeficiency virus (HIV) antibody test; or EBV-DNA or CMV-DNA levels above the lower limit of quantification by quantitative PCR.
• Active or uncontrolled infection requiring systemic therapy at the time of screening (excluding mild genitourinary or upper respiratory tract infections), as assessed by the investigator.
• Coronary angioplasty or stent placement within 12 months prior to informed consent; congestive heart failure of New York Heart Association (NYHA) Class III-IV; myocardial infarction, unstable angina, or other clinically significant cardiac conditions within 6 months deemed ineligible by the investigator; QTc interval >480 ms (calculated using Fridericia's formula) at screening; or uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) or pulmonary hypertension despite standard treatment.
• Unstable systemic diseases per investigator judgment, including but not limited to severe hepatic, renal, or metabolic diseases requiring pharmacological intervention.
• Active or uncontrolled autoimmune disease, or primary/secondary immunodeficiency.
• History of severe immediate hypersensitivity to any drug used in the study.
• Administration of any live vaccine within 6 weeks prior to screening.
• Pregnant or lactating individuals.
• History of autoimmune disease requiring systemic immunosuppressive or disease-modifying medication within the past 2 years (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus).
• Allogeneic hematopoietic stem cell transplantation within 12 weeks prior to apheresis; presence of acute or moderate-to-severe chronic GVHD within 4 weeks prior to screening; or any systemic GVHD treatment within 4 weeks prior to cell infusion, including those requiring concomitant corticosteroid use.
• Participation in any other interventional clinical trial within 4 weeks prior to screening.
• Inability to comply with study procedures, or any other condition considered by the investigator to render the subject unsuitable for the study.