CD19-STAR T（异体 T 细胞）治疗非霍奇金淋巴瘤：I/II 期临床试验

Inclusion Criteria:

1. Age 18-75 (inclusive).
2. Patients with histologically confirmed CD19-positive B-cell NHL, including the following types defined by the World Health Organization (WHO) 2016:

   * Diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), including activated B-cell type (ABC) / germinal center B-cell Type (GCB);
   * Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
   * Transformed follicular lymphoma (TFL);
   * High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBCL);
   * Follicular lymphoma (FL);
   * Mantle cell lymphoma (MCL) \[pathologically confirmed, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1\];
   * Marginal zone lymphoma (MZL), including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma.
3. Relapse after treatment with ≥2 lines systemic therapy for all the above disease types, or refractory disease for aggressive types (DLBCL-NOS, PMBCL, TFL and HGBCL). Relapse disease is defined as disease progression after last regimen. Refractory disease is defined as no CR to first-line therapy:

   * Evaluation of PD (never reached response or SD) after standard first-line treatment, or
   * SD as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R-CHOP), or
   * PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or
   * Refractory post-autologous stem cell transplant (ASCT): i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy proven recurrence in relapsed individuals); ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy.
4. Individuals must have received adequate prior therapy:

   For MCL, prior therapy must have included:
   * Anthracycline or bendamustine-containing chemotherapy and
   * Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
   * Bruton tyrosine kinase inhibitor (BTKi)

   For other types, prior therapy must have included:
   * Anti-CD20 monoclonal antibody (unless investigator determines that tumor is CD20-negative) and
   * Anthracycline containing chemotherapy regimen.

   For individual with TFL must have relapse or refractory disease after transformation to DLBCL.
5. The estimated survival time is over 3 months.
6. The Eastern Cooperative Oncology Group (ECOG) score is 0-2.
7. According to Lugano response criteria 2014, there should be at least one evaluable tumor focus. Evaluable tumor focus was defined as that with the longest diameter of intranodal focus \> 1.5cm, the longest diameter of extranodal focus \> 1.0cm assessed by computed tomography (CT) or magnetic resonance imaging (MRI).
8. Subjects must be willing to undergo either excised or large-needle lymph node or tissue biopsy, or provide formalin-fixed paraffin-embedded (FFPE) tumor tissue block or freshly cut unstained slides.
9. Functions of important organs meet the following requirements:

   * Echocardiography showed left ventricular ejection fraction ≥50%;
   * Serum creatinine ≤1.5 × upper limit of normal range (ULN) or endogenous creatinine clearance ≥45mL/min (cockcroft-gault formula);
   * Total bilirubin ≤1.5× ULN;
   * Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) ≥91% in indoor air environment.
10. Blood routine: hemoglobin (Hgb) ≥ 80g/L, neutrophil count (ANC) ≥ 1 × 10 \^ 9/L, platelet count (PLT) ≥ 75 × 10 \^ 9/L. Excluding when there is bone marrow infiltration. It is not allowed to obtain normal values through growth factor intervention.
11. Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
12. Toxicity from previous antitumor therapy ≤ grade 1 (according to CTCAE version 5.0) or to an acceptable level of inclusion/exclusion criteria (other toxicities such as alopecia and vitiligo considered by the investigator to pose no safety risk to the subject).
13. No obvious hereditary diseases.
14. Able to understand the requirements and matters of the trial, and willing to participate in clinical research as required.
15. Informed consent must be signed.

Exclusion Criteria:

1. During the screening period, there was central nervous system (CNS) invasion or a history of clinically significant CNS diseases, such as epilepsy and cerebrovascular diseases.
2. Women who are pregnant or breastfeeding, or who do not agree to use effective contraception during treatment and during the subsequent 1 year.
3. History of allogeneic hematopoietic stem cell transplantation, or organ transplantation.
4. History of other malignancies that have not been in remission.
5. Patients with primary immunodeficiency or autoimmune diseases requiring immunosuppressive therapy.
6. Received radiotherapy within 3 months before enrollment.
7. Received immunotherapy drugs within 4 weeks before enrollment, such as anti-PD-1 antibody, anti-programmed death ligand 1 (PD-L1) antibody, CD19/CD3-bispecific antibody, and so on.
8. Confirmed evidence showing positiveness of anti-CD19 scFv reaction in patient serum.
9. Prior CD19 targeted therapy.
10. Prior CAR-T therapy or other genetically modified T cell therapy.
11. Presence of DSA directed against STAR T cells.
12. Patients who participated in other clinical trials within 4 weeks prior to enrollment.
13. Uncontrolled infectious diseases or other serious illnesses, including but not limited to infections \[e.g., human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B (HBV) or C (HCV) infection\], congestive heart failure, unstable angina, arrhythmias, or that pose an unpredictable risk in the opinion of the attending physician.
14. The presence of uncontrollable serous membrane fluid, such as massive pleural effusion or ascites.
15. A history of stroke or intracranial hemorrhage within 3 months prior to enrollment.
16. Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
17. History of allergies to any of the ingredients in cell products.
18. Conditions in which a known mental or physical illness interferes with cooperation with the requirements of the study or disrupts the results or interpretation of the results and, in the opinion of the therapeutic investigator, makes the patient unfit for study participation.
19. There is the situation that the researcher's judgment will interfere with the whole study participation; Situations where there is significant risk to the subject; Or interferes with the interpretation of research data.
20. Inability to understand or unwillingness to sign informed consent.
21. Researchers believe that other reasons are not suitable for clinical trials.

主要终点：Phase 1: Incidence of Adverse Events (AEs) defined as DLT · DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the STAR T cells and meets any one of the criteria listed in the DLT criteria. Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) 2019 criteria. GvHD according to criteria defined by the Mount Sinai Acute GVHD International Consortium. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. * Grade 3 acute GVHD (aGVHD) that is not resolved to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AEs related to the STAR T that lasts for ≥14 days, except hematology toxicity. · 12 months；Phase 1: RP2D · The RP2D was determined through phase 1 study. · 12 months；Phase 2: Best objective Response Rate · The incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as the best response to treatment assessed by investigators and based on the Lugano 2014 assessment criterion. · 12 months
次要终点：Phase 2: Overall Survival (OS)；Phase 2: Progression Free Survival (PFS)；Phase 2: Time to response (TTR)；Phase 2: Duration of Response (DOR)；Pharmacokinetics: Number and copy number of CD19-STAR T cells (phase 1 and phase 2)；Pharmacokinetics: Persistence of CD19-STAR T (phase 1 and phase 2)；Pharmacodynamics: Peak level of cytokines in serum (phase 1 and phase 2)

• Allogeneic TRAC locus-inserted CD19-targeting STAR T cells · EXPERIMENTAL · A conditioning chemotherapy regimen of fludarabine and cyclophosphamide (FC regimen) will be administered followed by investigational treatment, allogeneic targeting CD19 synthetic T-cell receptor antigen receptor T cells.

The team has developed the synthetic T cell receptor (TCR) and antigen receptor (STAR) T cells which were demonstrated safety in relapsed or refractory (r/r) B-cell non-Hodgkin' s lymphoma (B-NHL) (NCT05631912). Based on this research, allogeneic STAR-T cell products utilized the CRISPR-Cas9 gene editing tool to knock out endogenous receptor α constant (TRAC), human leukocyte antigen (HLA)-A/B, CIITA, and programmed death 1 (PD-1) genes simultaneously in T cells from healthy donors, and integrated the STAR molecule into the TRAC locus using adenovirus associated virus. This strategy can reduce graft-versus-host-disease (GvHD) toxicity and host-versus-graft response, decrease the sensitivity of STAR T cells to immunosuppressive signals, and improve their anti-tumor activity. In this single center, prospective, open-label, single-arm, phase 1/2 study, the safety and efficacy of allogeneic CD19-targeting STAR T cell therapy will be evaluated in patients with r/r B-NHL.