Safety and Efficacy of KSVCBD Injection in B-cell Non-Hodgkin's Lymphoma Expressing CD19 and/or BCMA

A Clinical Study on the Safety and Efficacy of KSVCBD Injection in the Treatment of B-cell Non-Hodgkin's Lymphoma With Positive Expression of CD19 and/or BCMA

KSVCBD injection is an in vivo Chimeric Antigen Receptor T-Cell (CAR-T cell) therapy product. This multicenter, single-arm, open-label, early exploratory clinical study is designed to evaluate the preliminary safety and efficacy of KSVCBD injection in patients with relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL) CD19 and/or BCMA.

A structurally modified, third-generation, self-inactivating lentiviral vector was used in KSVCBD injection. This modified vector exhibits reduced immunogenicity and enables efficient T-cell targeting, thereby facilitating the in vivo generation of CD19/BCMA CAR T cells from endogenous T cells. Simultaneously targeting BCMA to eliminate plasma cells producing anti-lentivirus and anti-CD19 scFv antibodies enables repeated infusion. The safety and efficacy of CD19/BCMA dual-target autologous CAR-T therapy for the treatment of r/r B-cell NHL have already been validated in clinical studies. In this study, dose-escalation research will be conducted to explore the safety and preliminary efficacy of CD19/BCMA dual-target in vivo CAR-T therapy in patients with r/r B-cell NHL who are positive for CD19 and/or BCMA expression.

Key Inclusion Criteria:

1. Age 18-75 years (inclusive), any gender.

2. Subjects must meet the following diagnostic and treatment criteria:

   2.1Histologically or cytologically confirmed B-NHL (according to the 2016 WHO classification of lymphoid neoplasms):

   • Diffuse large B-cell lymphoma, not otherwise specified.
   • Primary mediastinal large B-cell lymphoma.
   • Diffuse large B-cell lymphoma transformed from follicular lymphoma (TFL).
   • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements.
   • Follicular lymphoma (FL).
   • High-grade B-cell lymphoma, not otherwise specified.
   • Mantle cell lymphoma (pathologically confirmed, with monoclonal B cells carrying t(11.14) and/or overexpressing cyclin D1).
   • Marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue [MALT] lymphoma).

   2.2Subjects must be in a relapsed or refractory state during the screening period:

   • Definition of relapse: Disease progression (PD) after achieving remission (including PR or CR) following at least one standard treatment regimen (must include rituximab and anthracyclines).
   • Definition of refractory: Must meet any of the following criteria:

   Best response of stable disease (SD) or PD after at least 4 cycles of first-line standard treatment (e.g., 4 cycles of R-CHOP).

   Achieved remission after at least 6 cycles of first-line standard treatment but experienced PD within 6 months.

   Best response of PD after first-line standard treatment. Relapse (must be biopsy-proven) or PD within 12 months after autologous stem cell transplantation (ASCT). if salvage therapy was received, no response (SD or PD) to the last line of treatment.

   • For TFL, subjects must have received adequate prior treatment for follicular lymphoma, at least one line of treatment for TFL after transformation, and be relapsed or refractory after the last line of treatment.
   • For mantle cell lymphoma, prior treatment must include anthracycline- or bendamustine-containing chemotherapy, anti-CD20 therapy (except for CD20-negative cases), and BTK inhibitor therapy.
   • For indolent lymphomas (grade 1-3a FL and marginal zone lymphoma), subjects must have received at least two prior lines of therapy.
   • For other types, prior treatment must include anti-CD20 therapy (except for CD20-negative cases) and anthracycline-containing chemotherapy.

   2.3Subjects judged by the investigator to be intolerant to standard therapy may also be included in the study.

3. Intranodal lesion with long-axis diameter > 1.5 cm, or extranodal lesion with long-axis diameter > 1.0 cm (according to the 2014 Lugano response criteria).

4. Positive expression of CD19 and/or BCMA in tumor tissue confirmed by flow cytometry and/or histopathology (previous pathology or flow cytometry diagnosis of CD19 and/or BCMA in the patient, as confirmed by the investigator, is acceptable). For subjects who have previously received anti-CD19 and/or anti-BCMA therapy, a tumor biopsy should be performed to confirm current positive expression of CD19 and/or BCMA.

5. Toxicities from any prior therapy must be stable and have resolved to ≤ Grade 1 (excluding hematologic toxicities and clinically insignificant toxicities such as alopecia).

6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

Key Exclusion Criteria:

1. Expected survival < 3 months.
2. History of or concurrent active malignancy. Exceptions include: carcinoma in situ of the cervix that has been cured or with no recurrence for at least 3 years, non-invasive basal cell or squamous cell skin cancer, locally advanced prostate cancer that has received curative treatment, or ductal carcinoma in situ after radical surgery.
3. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) or autologous HSCT within 3 months prior to KSVCBD infusion.
4. Solitary extramedullary soft tissue plasmacytoma.
5. Diagnosis of plasma cell leukemia, Waldenström's macroglobulinemia, POEMS syndrome, or primary AL amyloidosis.
6. Presence of CNS metastasis or symptoms of CNS metastasis.
7. Receipt of anti-tumor therapy that is still within 5 half-lives prior to the planned KSVCBD infusion.
8. Presence of uncontrolled active infections.
9. Positive for human immunodeficiency virus (HIV) antibody, positive for Treponema pallidum antibody, positive for hepatitis B surface antigen (HBsAg) or positive for hepatitis B core antibody (HBcAb) with detectable peripheral blood HBV DNA, or positive for hepatitis C virus (HCV) antibody with detectable HCV RNA. except for infections that the investigator judges can be prevented or controlled with medication.
10. Known active autoimmune disease requiring systemic treatment.
11. Known severe allergy to the study drug or any of its components.
12. Pregnant or breastfeeding women.
13. Receipt of a live vaccine within 6 weeks prior to enrollment.