Exploration of Circular RNA in B-cell Hematologic Malignancies

This is an investigator-initiated, open-label, single-arm, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (PD), and preliminary efficacy of an in vivo circular RNA chimeric antigen receptor T cell in adult participants with R/R B-cell malignancies.

Investigational product (IP)will be explored across four dose levels (as described in the table below) in adult participants with R/R B-cell malignancies, including diffuse large B-cell lymphoma [DLBCL], follicular lymphoma [FL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL]/small lymphocytic lymphoma [SLL], Waldenström macroglobulinemia [WM], and marginal zone lymphoma (MZL).

The study consists of three periods: screening period, treatment period, and post-treatment follow-up period.

Inclusion criteria

• Age ≥ 18 years, any gender.
• Able to provide written informed consent.
• Confirmed diagnosis of relapsed/refractory (R/R) CD19-positive B-cell malignancy, including:

• Diffuse large B-cell lymphoma (DLBCL)
• Follicular lymphoma (FL)
• Mantle cell lymphoma (MCL)
• Small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL)
• Waldenström macroglobulinemia (WM)
• Marginal zone lymphoma (MZL)
• ECOG performance status 0 or 1.and have archival tumor biopsy tissue and pathology report from the most recent relapse, or at least one palpable superficial tumor lesion at screening, and agree to biopsy/resection before the first dose of IP for disease confirmation.
• Disease refractory to or relapsed after ≥ 2 prior lines of standard therapy, including required agents per disease subtype (e.g., anti-CD20, BTK inhibitors, chemotherapy, or ASCT if applicable).
• Measurable disease per Lugano 2014 or iwCLL 2018 criteria.
• LVEF ≥ 40% by echocardiogram.
• For patients with prior CD19-targeted therapy, confirmed CD19 positivity at screening.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test and agree to use effective contraception during the study and for 6 months after last treatment.
• Male patients with female partners must agree to use condoms, and partners must use effective contraception, during the study and for 6 months after last treatment.

Exclusion criteria

• Prior anticancer therapy-related toxicities unresolved to baseline or ≤ Grade 1 (alopecia and peripheral neuropathy excepted).
• Central nervous system (CNS) involvement by lymphoma.
• Need for urgent treatment due to tumor mass effect or spinal cord compression.
• Known hypersensitivity to any component of IP, including mRNA/LNP-based products.
• History of another primary malignancy within the past 3 years, except adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ.
• Active hepatitis B (HBsAg-positive with detectable HBV DNA) or hepatitis C (HCV RNA-positive) infection.
• Active or prior HIV infection.
• Uncontrolled active systemic infection requiring IV therapy within 1 week before dosing.
• Active or history of acute/chronic GVHD.
• Inadequate hematologic function (ANC <1.0×10⁹/L, Hb <70 g/L, PLT <50×10⁹/L, lymphocytes ≤0.5×10⁹/L) or coagulation abnormalities (INR/APTT ≥1.5×ULN).
• Hepatic impairment (ALT/AST >2×ULN, or >3×ULN with hepatic involvement; bilirubin >2×ULN, unless Gilbert syndrome).
• Renal impairment (CrCl <50 mL/min by Cockcroft-Gault).
• Uncontrolled ischemic heart disease, NYHA Class III-IV heart failure, or baseline QTcF ≥450 ms (male) / ≥470 ms (female).
• Severe psychiatric disorder history.
• Pregnancy or breastfeeding.
• Received prohibited treatments within 4 weeks before dosing, including high-dose corticosteroids (>20 mg prednisone equivalent daily), chemotherapy, immunosuppressive therapy, prior CAR-T or other gene/cell therapy, or T-cell engagers.
• Participation in another clinical study with investigational therapy within 3 months before dosing, or prior participation in cell/gene therapy trials.
• Planned radiotherapy within 6 weeks after screening (unless only non-irradiated PET-positive lesions remain eligible).
• Planned allogeneic HSCT within 90 days after screening.
• Significant comorbidities or unstable medical conditions deemed by the investigator to compromise safety or study compliance.