Nanobody-Based Anti-CD5 CAR-T for Relapsed/Refractory T-ALL/NHL

This Phase I/II study aims to evaluate the safety, tolerability, and efficacy of Nanobody-Based CD5 Chimeric Antigen Receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoma (T-NHL).

In the Phase I portion, a 3+3 dose-escalation design will be utilized to assess the safety profile and determine the optimal dose of Nanobody-Based CD5 CAR-T cells. The recommended Phase II dose (RP2D) will be established based on safety data, dose-limiting toxicities (DLTs), and preliminary efficacy outcomes.

The Phase II portion will then evaluate the efficacy of Nanobody-Based CD5 CAR-T therapy at the RP2D. The primary and secondary endpoints will include:

Overall response rate (ORR) Disease-free survival (DFS) Overall survival (OS) Comprehensive safety assessments will be conducted throughout the study, with a particular focus on cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

By investigating Nanobody-Based CD5 CAR-T therapy, this study aims to address the significant unmet clinical need for effective treatment options in patients with R/R T-ALL/NHL and provide insights into its potential as a novel immunotherapeutic approach.

Inclusion criteria

• The subject or guardian understands and voluntarily signs the informed consent form (ICF).
• Male or female, aged 3-70 years at the time of signing the ICF (inclusive).
• Expected survival of at least 12 weeks.
• ECOG performance status of 0-2 at the time of ICF signing.
• Diagnosis of relapsed/refractory T-cell lymphoblastic leukemia/lymphoma (R/R T-ALL/NHL) confirmed at screening and meeting at least one of the following criteria:

• Bone marrow involvement: Morphologic examination shows ≥5% lymphoblasts, and/or
• Cerebrospinal fluid (CSF) involvement: Tumor cells detected in CSF, and/or
• Extramedullary disease: Presence of measurable lesions (lymph node/mass ≥1.5 cm in axial diameter or extranodal lesion ≥1 cm in axial diameter).
• CD5 expression: Tumor cells in bone marrow, peripheral blood, or CSF are CD5-positive by flow cytometry, and/or lymph node/mass or extranodal lesions are CD5-positive by pathology.
• Adequate major organ function, defined as:

• AST and ALT ≤5× upper limit of normal (ULN).
• Total bilirubin ≤2× ULN.
• Renal function: Serum creatinine clearance ≥60 mL/min (Cockcroft-Gault formula) or creatinine ≤1.5× ULN.
• Blood oxygen saturation >92%.
• Reproductive health requirements:

• Fertile men and women of childbearing potential must agree to use effective contraception from ICF signing until 2 years after study drug administration.
• Women of childbearing potential (pre-menopausal or within 2 years post-menopause) must have a negative blood pregnancy test at screening.

Exclusion criteria

• History of central nervous system (CNS) diseases, including but not limited to:

• Epilepsy
• Paralysis
• Aphasia
• Stroke
• Severe brain injury
• Dementia
• Parkinson's disease
• Neuropathy
• History of autoimmune diseases requiring systemic immunosuppressive therapy within 2 years prior to signing the ICF, including but not limited to:

• Crohn's disease
• Rheumatoid arthritis
• Systemic lupus erythematosus (SLE)
• Systemic sclerosis
• Inflammatory bowel disease (IBD)
• Vasculitis
• Psoriasis
• Presence of any uncontrolled active infection at the time of signing the ICF or within 4 weeks prior to apheresis that requires antibiotic, antiviral, or antifungal treatment.
• Positive virological or infectious disease markers, including:

• Hepatitis B virus (HBV): Subjects with positive HBsAg or HBcAb-positive at screening must have undetectable HBV DNA in peripheral blood to be eligible; otherwise, they should be excluded.
• Hepatitis C virus (HCV): Subjects with positive HCV antibodies and detectable HCV RNA should be excluded.
• Human immunodeficiency virus (HIV) antibody-positive subjects should be excluded.
• Cytomegalovirus (CMV) DNA test-positive subjects should be excluded.
• Epstein-Barr virus (EBV) DNA test-positive subjects should be excluded.
• Positive serological or non-specific antibodies for Treponema pallidum (syphilis).
• Clinically significant cardiovascular diseases, including any of the following:

• QTc interval ≥480 ms (Fridericia correction formula)
• New York Heart Association (NYHA) Class II or higher heart failure
• Unstable angina or acute myocardial infarction within 6 months prior to signing the ICF
• Left ventricular ejection fraction (LVEF) <50%
• Poorly controlled hypertension (as determined by the investigator)
• Clinically significant arrhythmias or those requiring antiarrhythmic treatment, including:

• Persistent ventricular tachycardia
• Ventricular fibrillation
• Torsades de pointes
• Complete left bundle branch block
• History of severe hypersensitivity or allergy to any components of the study drug.
• Receipt of any investigational drug therapy or other systemic antitumor therapy within 4 weeks before apheresis (or 5 half-lives of the drug, whichever is longer, as determined by the investigator).
• Receipt of extensive radiotherapy within 4 weeks prior to signing the ICF, except for palliative radiotherapy for non-target lesions within 2 weeks before signing the ICF or as expected during the study.
• Unresolved toxicity from prior antitumor therapy that has not returned to Grade 1 or baseline levels at the time of signing the ICF, except for hair loss and pigmentation (per NCI-CTCAE v5.0).
• Requirement for systemic corticosteroids or other immunosuppressive therapy (≥10 mg/day prednisone or equivalent) within 3 days prior to apheresis or during the study period, except for:

• Intranasal, inhaled, or topical steroids, or localized steroid injections (e.g., intra-articular injections)
• Systemic corticosteroids ≤10 mg/day prednisone (or equivalent physiological dose)
• Steroids as prophylaxis for allergic reactions (e.g., pre-medication before contrast-enhanced CT)
• Steroids used for symptomatic treatment of transfusion-related reactions
• Major surgery within 4 weeks prior to signing the ICF (excluding routine biopsy procedures) or planned major surgery during the study period.
• History of active tuberculosis infection within 1 year prior to signing the ICF, except for subjects with a history of tuberculosis more than 1 year ago, provided that the investigator determines there is no evidence of active tuberculosis.
• History of other primary malignancies within 5 years prior to signing the ICF, except for:

• Adequately treated carcinoma in situ of the cervix
• Localized basal cell carcinoma or squamous cell carcinoma of the skin
• Receipt of live-attenuated or inactivated vaccines within 4 weeks before signing the ICF or planned vaccination during the screening period.
• Any other condition or complication that, in the investigator's judgment, may affect adherence to the study protocol or make the subject unsuitable for participation.
• Pregnancy or lactation.