A Single-center Clinical Study to Evaluate the Safety, Tolerability, and Efficacy of LCAR-L10D Cell Formulations Targeting CD19 and CD22 in Patients With CD19- and/or CD22-Positive Relapsed/Refractory B-cell Lymphoma

1. Volunteer to participate in the clinical study; fully understand and be informed of the information on this study, and sign the written Informed Consent Form (ICF); willing to follow and able to complete all trial procedures.

2. According to the criteria for B-cell lymphoma defined in the National Comprehensive Cancer Network (NCCN) Guidelines for Lymphoma (5th edition 2018), and with CD19- and/or CD22-positive lymphoma cells detected by flow cytometry or immunohistochemistry;

3. Must have at least 1 evaluable or measurable lesion meeting Lugano 2014 criteria \[Evaluable lesions: Fluorodeoxyglucose/positron emission tomography (FDG/PET) showed increased local uptake in lymph nodes or extranodal sites (higher than the liver), and PET and/or computed tomography (CT) findings are consistent with lymphoma manifestations. Measurable lesions: defined as nodule lesions with a long diameter greater than 15 or extranodal lesions with a long diameter greater than 10 mm (if the only measurable lesion has been previously treated with radiation therapy, the evidence of radiographic progression after radiation therapy is required), with increased FDG uptake). Absence of measurable lesion and diffuse increase of hepatic FDG uptake should be excluded.

4. Relapsed/refractory BCL (meet one of the following conditions):

1. Subjects in this category had received at least two cycles of two or more lines of standard of care and had been evaluated for best clinical response per Lugano 2014 at the time of enrollment: (one of the following conditions are met)

* The subject had a best clinical response of PD after the most recent standard chemotherapy;

* The subject had a best clinical response of SD after the most recent standard chemotherapy, but PD occurred when SD persisted for less than 6 months;

2. Recurrence or progression within ≤ 12 months after autologous hematopoietic stem cell transplantation;

3. In one of the following situations, the benefit of the subject may outweigh the risk as judged jointly by the investigator and the partner:

* The subject had received at least two lines of standard of care, and the best response after the most recent standard chemotherapy was SD, which persisted for less than 6 months, and the evaluable or measurable disease was larger than before but did not achieve PD;

* The subject had received at least two lines of standard of care, and the best response after the most recent standard chemotherapy was partial response (PR) or higher, but persisted for less than 6 months before progression;

* The subject had received at least two lines of standard of care and was intolerant to the most recent chemotherapy.

5. All subjects must have received standardized treatment regimens with anti-CD20 monoclonal antibodies (except for those with CD20-negative tumors as determined by the investigator) and anthracyclines. For standardized treatment regimens, please refer to the criteria in the NCCN Guidelines for B-cell Lymphoma (version 5, 2018);

6. Male or female, aged 18-75 years at the time of signing the ICF;

7. Primary laboratory test values met the following criteria to demonstrate adequate organ and bone marrow function without severe hematopoietic abnormalities and heart, lung, liver, renal dysfunction and immunodeficiency:

Serum albumin ≥30g/L Haemoglobin ≥ 8.0 g/dL (no red blood cell \[RBC\] infusion within 7 days prior to laboratory tests; recombinant human erythropoietin is allowed) \* Absolute neutrophil count ≥ 0.75 × 109/L (growth factor support is allowed but must not have received supportive care within 7 days prior to laboratory tests) Platelet ≥ 40 × 109/L (must not have received blood transfusion support within 7 days prior to laboratory tests) Creatinine clearance ≥ 40 mL/min/1.73 m2, calculated according to Modified Dietary Formula for Renal Disease (Attachment 11) or 24-hour urine collection results.

ALT and AST ≤ 3.0 x upper limit of normal (ULN) Total bilirubin ≤ 2.0 × ULN; except for subjects with congenital bilirubinemia, such as Gilbert's syndrome (in this case, direct bilirubin ≤ 1.5 x ULN is required) Coagulation PT and APTT \<2ULN SpO2 ≥95%

8. ECOG performance status of 0-1;

9. Estimated survival time of patients \> 90 days;

10. A highly sensitive serum pregnancy test (beta human chorionic gonadotropin \[beta-HCG\]) must be negative at screening and prior to first treatment with cyclophosphamide and fludarabine in women of childbearing potential.

11. Women of childbearing potential must comply with the following requirements:

* Subjects must agree to use a highly effective method of contraception (annual failure rate \< 1% for continuous and correct use) and agree to use a highly effective method of contraception from signing the informed consent form (ICF) until at least 1 year after receiving infusion of LCAR-L10D cell formulation. Highly effective methods of contraception include:

* User-independent methods: 1) implantable progesterone contraceptives that inhibit ovulation; 2) intra-uterine devices (IUDs); intrauterine hormone-releasing systems; 3) vasectomies in sexual partners;

* User-dependent methods: 1) compound (estrogen- and progestogen-containing) hormonal contraceptives that inhibit ovulation: oral, vaginal and transdermal; 2) progesterone contraceptives (oral or injectable) that inhibit ovulation.

In addition to highly effective methods of contraception, male subjects should:

Agree to use barrier contraception (e.g. condoms plus spermicidal foam/gel/film/emulsion/suppository) upon sexual intercourse with a woman of childbearing potential from signing the ICF to at least 1 year after receiving infusion of the LCAR-L10D cell formulation.

Use condoms when having sex with a pregnant woman Women and men must agree not to donate ova (oocytes, oocytes) or sperm during the study and within 1 year after infusion of LCAR-L10D cell formulation.

Note: Hormonal contraceptives may interact with study treatment, resulting in decreased contraceptive efficacy.

What this study is about