Safety and Efficacy of ZZSW-01 in Relapsed/Refractory B-cell Malignancies

This investigator-initiated clinical study aims to evaluate ZZSW-01 injection, the extracellular vesicle vector that carries CD19 CAR mRNA, in patients with relapsed/refractory B-cell hematologic malignancies. Under this design, eligible subjects will receive multiple injections. The study adopts a dose-escalation design to assess safety, tolerability, and preliminary efficacy.

Inclusion criteria

Participants must meet all of the following inclusion criteria:

• Age ≥18 years, no restriction on sex.
• ECOG (Eastern Cooperative Oncology Group) performance status score of 0-2.
• Expected survival ≥3 months.
• Histologically or cytologically confirmed CD19-positive relapsed or refractory B-cell malignancies according to the WHO classification of lymphoid neoplasms, including:

Relapsed/refractory B-NHL: patients who have failed at least two prior lines of therapy, are intolerant to the toxicity of second-line regimens, or are not eligible for autologous stem cell transplantation, including but not limited to diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL/high-grade B-cell lymphoma with MYC and BCL2 rearrangements, high-grade B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, mantle cell lymphoma, grade 3b follicular lymphoma, and transformed large B-cell lymphoma from indolent B-NHL.

Relapsed/refractory precursor B-ALL: patients who relapse after achieving CR following second-line therapy, or who fail to achieve CR/CRi after completion of second-line therapy.

• For relapsed/refractory B-NHL: at least one measurable lesion as assessed by the investigator (e.g., lymph node with long axis >15 mm, or extranodal lesion with long axis >10 mm).

For relapsed/refractory precursor B-ALL: baseline bone marrow blasts ≥5%.

• Adequate organ function as defined below (no administration of blood components or hematopoietic growth factors within 14 days prior to first dosing):

Hematology:

Relapsed/refractory B-NHL: ANC ≥1.5×10^9/L, platelets ≥75×10^9/L, hemoglobin ≥70 g/L, absolute CD8+ T-cell count ≥0.3×10^9/L; if bone marrow involvement is present: ANC ≥1.0×10^9/L, platelets ≥50×10^9/L, hemoglobin ≥70 g/L.

Relapsed/refractory precursor B-ALL: ANC ≥1.0×10^9/L (G-CSF support permitted), platelets ≥50×10^9/L (no platelet transfusion within 7 days), hemoglobin ≥80 g/L (no RBC transfusion within 7 days); if bone marrow involvement or not in remission: ANC ≥0.5×10^9/L (G-CSF support permitted), platelets ≥30×10^9/L (no platelet transfusion within 7 days), hemoglobin ≥70 g/L (no RBC transfusion within 7 days). Additionally, absolute CD8+ T-cell count ≥0.2×10^9/L and CD19+ B-cell percentage ≤5%.

Liver function: TBIL ≤1.5×ULN; ALT and AST ≤2.5×ULN (≤5×ULN if liver metastases are present).

Renal function: Serum creatinine ≤1.5×ULN (if >1.5×ULN, creatinine clearance must be ≥50 mL/min).

Coagulation: INR ≤1.5×ULN and APTT ≤1.5×ULN; patients on anticoagulation may be included if INR ≤2.5×ULN.

Oxygenation: Oxygen saturation >92% on room air.

• Non-hematologic toxicities from prior therapies (except disease-related) have resolved to ≤grade 1 before enrollment (excluding alopecia and ≤grade 2 neurotoxicity from chemotherapy).
• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to ZZSW-01 infusion. All fertile male and female participants must agree to use effective contraception during the study and for at least 6 months after the last dose. (Definition of women of childbearing potential and contraceptive methods are detailed in Appendix 1.)
• Ability and willingness to provide written informed consent and to comply with study procedures, follow-up assessments, and treatment.

Exclusion criteria

Participants meeting any of the following conditions will be excluded from this study:

• Patients with CNS involvement of B-cell malignancies confirmed by lumbar puncture and/or MRI with CNS-related symptoms.
• Patients with isolated extramedullary relapse of B-ALL.
• Patients with severe hereditary diseases or congenital hematopoietic dysfunction.
• Patients with Burkitt's lymphoma/leukemia or blast phase chronic myeloid leukemia (p210 BCR-ABL+).
• Current or past history of central nervous system disorders, including: seizures, ischemic/hemorrhagic cerebrovascular disease, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychiatric illness, or any autoimmune disease involving the CNS.
• Receipt of chemotherapy within 2 weeks prior to ZZSW-01 infusion (except intrathecal chemotherapy for prevention of CNS leukemia, which must be stopped ≥1 week prior to infusion).
• Prior systemic immune checkpoint inhibitor therapy (e.g., anti-PD-1/PD-L1 mAbs) within fewer than 3 half-lives before ZZSW-01 infusion; or other systemic antitumor therapy within fewer than 2 weeks or 5 half-lives (whichever is shorter) before infusion.
• Use of systemic therapeutic corticosteroids within 72 hours prior to ZZSW-01 infusion (physiologic replacement doses are allowed, e.g., prednisone <10 mg/day or equivalent).
• Receipt of targeted therapies or antibody drugs (including BiTEs, antibody-drug conjugates) within 2 weeks, or cytotoxic therapy within 1 week prior to ZZSW-01 infusion.
• Autologous stem cell transplantation (ASCT) within 6 weeks prior to ZZSW-01 infusion.
• Any prior allogeneic hematopoietic stem cell transplantation (allo-HSCT).
• Known history of the following diseases:

• . Systemic vasculitis (e.g., Wegener's granulomatosis, polyarteritis nodosa)
• Systemic lupus erythematosus (SLE)
• . Active or uncontrolled autoimmune diseases (e.g., Crohn's disease, rheumatoid arthritis, autoimmune hemolytic anemia)
• . Primary or secondary immunodeficiency (e.g., HIV infection or severe infectious diseases)
• Evidence of any of the following infections:

• . Chronic or active hepatitis B (HBV) infection (except HBcAb-positive with HBV DNA <500 IU/mL)
• . Hepatitis C virus (HCV) infection
• . Human immunodeficiency virus (HIV) infection
• . Syphilis infection
• Major surgery within 4 weeks prior to screening, if deemed unsuitable for enrollment by the investigator.
• Concurrent active malignancy. (Patients with prior malignancies cured ≥2 years may be eligible).
• Any of the following cardiac conditions:

• . Left ventricular ejection fraction (LVEF) ≤45% (by echocardiography)
• . NYHA class III or IV congestive heart failure
• . Severe arrhythmia requiring treatment, including QTc ≥450 ms in males or ≥470 ms in females (QTcB=QT/RR1/2)
• . Uncontrolled hypertension (systolic ≥140 mmHg and/or diastolic ≥90 mmHg), pulmonary hypertension, or unstable angina
• . Myocardial infarction, bypass surgery, or stent placement within 12 months prior to dosing
• . Clinically significant valvular heart disease
• . Any other cardiac disease deemed unsuitable by the investigator
• Lymphoma involving the atrium or ventricle.
• Clinical emergencies caused by obstruction or compression from lymphoma masses at screening (e.g., bowel obstruction, vascular compression).
• History of deep vein thrombosis or pulmonary embolism within 6 months prior to screening.
• Hypersensitivity (allergy to ≥2 drugs or foods), or known hypersensitivity to components of the investigational product (compound electrolyte injection, 5% human serum albumin).
• Receipt of live vaccines within 6 weeks prior to screening.
• Uncontrolled active infection at screening (e.g., sepsis, bacteremia, fungemia, viremia).
• Participation in another interventional clinical trial with investigational drugs within 3 months prior to ZZSW-01 infusion, or intent to participate in another clinical trial or receive non-protocol antitumor therapy during the study.
• Any other condition that, in the judgment of the investigator, renders the patient unsuitable for participation.