PIC1 Injection Therapy for Relapsed/Refractory B-NHL

This is an open-label, single-arm study to evaluate the efficacy and safety of in vivo generated Chimeric Antigen Receptor T-cell (CAR-T) therapy in patients with relapsed/refractory B-cell Non-Hodgkin Lymphoma. Upon enrollment, subjects will receive an intravenous infusion of PIC1 injection designed for in vivo CAR-T generation. Following infusion, subjects will be hospitalized for observation and evaluated for safety and efficacy. Subjects will be followed for up to 2 years to assess long-term disease control.

Inclusion criteria

• The patient (or their legally authorized representative) has voluntarily agreed to participate in this clinical trial and has signed the Informed Consent Form (ICF), indicating full understanding of the study's objectives and procedures.
• Aged 18 to 75 years, regardless of gender.
• Histologically or cytologically confirmed B-cell Non-Hodgkin Lymphoma (NHL) according to the WHO 2017 classification, including the following subtypes:

• Diffuse Large B-Cell Lymphoma (DLBCL): Including DLBCL, not otherwise specified (DLBCL, NOS); DLBCL associated with chronic inflammation; Primary Cutaneous DLBCL, leg type; and EBV-positive DLBCL, NOS.
• High-Grade B-Cell Lymphoma (HGBL): Including HGBL, NOS; and HGBL with MYC and BCL2 and/or BCL6 rearrangements.
• Primary Mediastinal Large B-Cell Lymphoma.
• T-cell/Histiocyte-rich Large B-Cell Lymphoma.
• Transformed DLBCL: DLBCL transformed from prior lymphomas (e.g., Follicular Lymphoma, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Marginal Zone Lymphoma).
• Follicular Lymphoma Grade 3b (FL3b).
• Mantle Cell Lymphoma.
• Patients must have received adequate prior therapy including an anti-CD20 monoclonal antibody and an anthracycline, unless contraindicated or intolerant (i.e., CD20-negative status, intolerance to anti-CD20 mAb, or contraindication to anthracyclines). Patients must meet the definition of Relapsed or Refractory (R/R) disease:

• Relapsed: Disease progression or recurrence after achieving a Complete Response (CR) to standard therapy.
• Refractory: Best response of Stable Disease (SD) after at least 4 cycles of first-line therapy or at least 2 cycles of last-line therapy (≥2nd line), with SD duration ≤6 months after the last dose; or best response of Progressive Disease (PD) to the last treatment.
• No response, disease progression, or relapse after Autologous Stem Cell Transplantation (ASCT).
• Patients with transformed lymphoma who received chemotherapy prior to transformation and subsequently failed to achieve response, progressed, or relapsed after salvage therapy post-transformation.
• CD19 positivity confirmed by immunohistochemistry (IHC) or flow cytometry.
• ECOG performance status of 0 or 1.
• Estimated life expectancy of ≥12 weeks.
• At least one measurable lesion per the 2014 Lugano Criteria:

• For nodal lesions: Longest diameter >1.5 cm.
• For extranodal lesions: Longest diameter >1.0 cm.
• Adequate major organ function defined as:

• Cardiac function: Left Ventricular Ejection Fraction (LVEF) ≥40% by echocardiogram.
• Renal function: Serum creatinine ≤2.0 × ULN or Creatinine Clearance ≥50 mL/min (calculated by Cockcroft-Gault formula).
• Hepatic enzymes: ALT and AST ≤3.0 × ULN (or ≤5.0 × ULN for subjects with hepatic involvement).
• Bilirubin: Total bilirubin ≤2.0 × ULN (or ≤3.0 × ULN for subjects with Gilbert's syndrome).
• Oxygenation: Oxygen saturation (SpO2) ≥ 92% while breathing room air.
• Hematology: Neutrophil Count ≥ 1.0 × 10^9/L; Platelet count ≥ 75 × 10^9/L; Hemoglobin ≥ 80 g/L. (For subjects with bone marrow involvement: Neutrophil ≥ 0.5 × 10^9/L and Platelet count ≥ 50 × 10^9/L.)
• Women of childbearing potential must have a negative pregnancy test. All subjects must agree to use a highly effective method of contraception from the time of signing the ICF until 1 year after the infusion of the investigational product.

Exclusion criteria

• Received prior Chimeric Antigen Receptor T-cell (CAR-T) therapy or any other gene-modified cell therapy before screening.
• Received any of the following anti-tumor therapies prior to PIC1 infusion:

• medications (e.g., chemotherapy, targeted therapy) within 14 days or 5 half-lives (whichever is longer) before infusion. (excluding lymphodepleting chemotherapy and intrathecal chemotherapy for CNS lymphoma. And intrathecal chemotherapy must be discontinued at least 1 week prior to PIC1 infusion.)
• Radiation therapy within 14 days before infusion.
• Has any of the following cardiac conditions:

• New York Heart Association (NYHA) Class III or IV congestive heart failure.
• Myocardial infarction or coronary artery bypass grafting (CABG) within 6 months prior to enrollment.
• Clinically significant ventricular arrhythmias, or a history of unexplained syncope (excluding cases caused by vasovagal reactions or dehydration).
• History of severe non-ischemic cardiomyopathy.
• Has an active or uncontrolled infection requiring systemic treatment within 1 week prior to screening.
• Has Grade 2-4 acute GVHD or moderate-to-severe chronic GVHD within 4 weeks prior to screening.
• Has experienced a cerebrovascular accident or seizure within 6 months prior to screening.
• Has experienced a deep vein thrombosis or arterial embolism event within 6 months prior to screening.
• Has a history of other malignancies except for: tumors with no evidence of active disease where treatment was completed >2 years ago; adequately treated carcinoma in situ of the cervix; basal cell or squamous cell skin cancer; radical prostatectomy; radical ductal carcinoma in situ.
• Received a live attenuated vaccine within 4 weeks prior to screening.
• Any other condition that, in the opinion of the Investigator, makes the subject unsuitable for participation in this study.