Overview

Overall Introduction This single-arm, open-label clinical trial aims to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of CXCR4-enabled CCR9 chimeric antigen receptor T-cell injection (CXCR4 CCR9 CAR-T) in patients with relapsed or refractory T-lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL). Additionally, the study seeks to preliminarily assess the efficacy of CXCR4 CCR9 CAR-T cells and explore the appropriate dosage and administration schedule for subsequent Phase II clinical trials. A dose escalation study following the 3+3 design was implemented across three dose cohorts, with each cohort planned to enroll 3 to 6 patients, totaling 9 to 18 participants. Following cell infusion, subjects underwent safety and efficacy follow-up, which continued until 2 years post-infusion, subject withdrawal, or study termination-whichever occurred first. For subjects with available follow-up information after study completion or early termination, long-term follow-up-including long-term safety monitoring-was conducted for up to 15 years.

Eligibility

Inclusion Criteria:

• Subjects must meet all of the following criteria to be eligible for the study:
  1. Informed Consent: Voluntary provision of written informed consent and anticipated ability to complete all required study procedures and follow-up assessments.
  2. 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.
  3. 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).

  4. Biomarker: Confirmed CCR9 positivity on tumor cells via flow cytometry of bone marrow samples and/or via immunohistochemistry of extramedullary lesion biopsies at screening.
  5. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  6. Life Expectancy: Estimated life expectancy of greater than 3 months.
  7. 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).

  8. 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.

  9. 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.
  10. 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:
  1. 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).
  2. 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.
  3. Prior receipt of cell therapies targeting CCR9, including but not limited to CAR-T or CAR-γδT cells.
  4. Significant or active parenchymal CNS or cranial nerve lesions where, in the investigator's judgment, the risks outweigh the benefits.
  5. Systemic corticosteroid use discontinued ≤72 hours prior to apheresis, except for physiological replacement doses (e.g., prednisone \<10 mg/day or equivalent).
  6. Donor lymphocyte infusion (DLI) within 6 weeks prior to apheresis.
  7. Treatment with any anti-T-cell antibody therapy within 4 weeks prior to apheresis.
  8. 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.
  9. 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.
  10. 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.
  11. Unstable systemic diseases per investigator judgment, including but not limited to severe hepatic, renal, or metabolic diseases requiring pharmacological intervention.
  12. Active or uncontrolled autoimmune disease, or primary/secondary immunodeficiency.
  13. History of severe immediate hypersensitivity to any drug used in the study.
  14. Administration of any live vaccine within 6 weeks prior to screening.
  15. Pregnant or lactating individuals.
  16. 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).
  17. 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.
  18. Participation in any other interventional clinical trial within 4 weeks prior to screening.
  19. Inability to comply with study procedures, or any other condition considered by the investigator to render the subject unsuitable for the study.