Clinical Trial of CD5-targeted CAR-NK Therapy for Relapse/Refractory T-Cell Hematologic Malignancies

This study is a single-arm, open-label, dose-finding and expansion clinical trial aimed at evaluating the safety and efficacy of anti-CD5 CAR-NK therapy for the treatment of patients with relapsed/refractory T-Cell hematologic malignancies. The goal is to determine the recommended dose of CAR-NK cell therapy for these conditions. The study includes three dose groups: 1×10⁷ CAR-positive cells/kg, 3×10⁷ CAR-positive cells/kg, and 5×10⁷ CAR-positive cells/kg. Each patient will initially receive a single infusion of CAR-NK cells on Day 0. If a suboptimal response is observed after the first infusion (assessed by Day 28) and the safety profile remains acceptable, a second infusion may be administered as a remedial dose after Day 28. The investigaors have the flexibility to adjust the second infusion dose based on the subject's condition.

Inclusion criteria

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1.Gender and Age: No gender restriction; age 18-75 years (inclusive). 2.Diagnosis: Confirmed diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoma, including:

• T-ALL Patients: Bone marrow morphology during screening shows ≥5% blasts/immature lymphocytes and/or flow cytometry confirms minimal residual disease (MRD)+, and meets any of the following:

• Refractory to ≥2 cycles of standard induction chemotherapy (failure to achieve CR).
• Relapsed within 12 months after achieving CR with first-line induction therapy.
• Failure to achieve CR or relapse after ≥2 lines of chemotherapy.
• Relapse after hematopoietic stem cell transplantation (HSCT).
• T-cell Lymphoma Patients: Confirmed diagnosis of T-lymphoblastic lymphoma (T-LBL) or T-cell non-Hodgkin lymphoma (including but not limited to: peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), extranodal NK/T-cell lymphoma (ENKL), T-cell prolymphocytic leukemia (T-PLL), adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides/Sézary syndrome (MF/SS) stage IIB or higher), and meets both:

• At least one bidimensionally measurable lesion per Lugano 2014 criteria: nodal lesions >1.5 cm in long axis; extranodal lesions >1.0 cm in long axis.
• Refractory to ≥2 lines of chemotherapy, primary resistance, or relapse post-HSCT.

3.CD5 Positivity: Confirmed by flow cytometry (≥80% tumor cells express CD5 with mean fluorescence intensity [MFI] equivalent to normal T cells; Dim defined as MFI ≥1 log lower than normal T cells; partial positivity defined as 20-80% tumor cells expressing CD5) or immunohistochemistry (>30% tumor cells express CD5).

4.ECOG Performance Status: 0-2 . 5.Life Expectancy: ≥12 weeks. 6.Organ Function:

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• Cardiac: Left ventricular ejection fraction (LVEF) ≥50% by echocardiography; no significant ECG abnormalities.
• Renal: Serum creatinine ≤2.0×ULN.
• Hepatic: ALT/AST ≤3.0×ULN (≤5.0×ULN if liver involvement); total bilirubin ≤2.0×ULN.
• Pulmonary: Oxygen saturation ≥92% (room air). 7.No Contraindications: To leukapheresis, venipuncture, or cell collection. 8.No Severe Psychiatric Disorders. 9.Contraception: Agreement to use effective contraception from informed consent until 1 year post-CAR-NK infusion (for patients of childbearing potential).

10.Informed Consent: Signed by the patient or legal guardian, confirming understanding of the trial's purpose and procedures.

Exclusion criteria

• Prior CAR-NK therapy or genetically modified cell therapy.
• Active CNS involvement at screening (prior CNS involvement with resolved status post-treatment is allowed).
• Recent Anticancer Therapy:

• Chemotherapy, targeted therapy, or investigational drugs within 2 weeks or 5 half-lives prior to screening.
• Radiotherapy within 2 weeks prior to screening.
• Active/Uncontrolled Infection: Within 1 week prior to screening.
• Cerebrovascular Event or Seizure: Within 6 months prior to screening.
• Viral Infections:

• HBV DNA > ULN (if HBsAg+ or HBcAb+).
• HCV RNA > ULN (if HCV Ab+).
• HIV+, syphilis+, or active tuberculosis.
• Cardiac Disease:

• NYHA Class III/IV congestive heart failure.
• Myocardial infarction or CABG ≤6 months prior.
• Clinically significant ventricular arrhythmia or unexplained syncope (excluding vasovagal/dehydration-related).
• Severe cardiomyopathy.
• Active/Uncontrolled Autoimmune Disease.
• Prior Malignancy: Within 5 years, except for cured cervical carcinoma in situ, basal/squamous skin cancer, localized prostate cancer, or ductal carcinoma in situ.
• Live Vaccination: Within 4 weeks prior to screening.
• Pregnancy/Lactation: Pregnant, breastfeeding, or planning pregnancy within 1 year post-CAR-NK infusion.
• Other: Investigator-determined ineligibility.