CD19/CD22 CAR-T as First-line Consolidation in Follicular Lymphoma

A Study of CD19/CD22 CAR-T Cell Therapy as First-line Consolidation Treatment in Patients With Follicular Lymphoma

The purpose of this study is to determine the efficacy and safety of CD19/CD22 Chimeric Antigen Receptor (CAR) T-Cell immunotherapy as first-line consolidation therapy in patients with follicular lymphoma.

Follicular lymphoma (FL) is the most common subtype of indolent B-cell lymphoma. In the rituximab era, the overall prognosis of patients has significantly improved; however, the disease remains incurable with substantial heterogeneity. A considerable proportion of patients, particularly those with high-risk features (such as high follicular lymphoma international prognostic index score, high tumor burden, and high risk of early progression), exhibit insufficient depth of response to standard immunochemotherapy (e.g., R-CHOP, BR) or experience early relapse and drug resistance.

In recent years, first-line treatment strategies for FL have undergone profound changes. While traditional immunochemotherapy remains the cornerstone, its toxicity and limited efficacy in specific high-risk populations are increasingly recognized. On one hand, optimized chemotherapy strategies (e.g., the zanubrutinib plus BR regimen) have shown extremely high complete response rates (CRR of 81.5%) in early-phase studies, offering hope for improved efficacy. On the other hand, the exploration of chemotherapy-free regimens has achieved breakthrough progress. The RELEVANCE study confirmed the feasibility of the R² regimen (lenalidomide plus rituximab) as first-line treatment for FL, demonstrating non-inferior efficacy to traditional chemotherapy with a distinct safety profile. Furthermore, the PERSPECTIVE study showed that the combination of ibrutinib and rituximab (IR) was significantly superior to rituximab monotherapy in previously untreated FL patients unfit for chemotherapy. More encouragingly, the venetoclax, ibrutinib, and obinutuzumab (VIG) chemotherapy-free combination achieved a remarkable 12-month complete response rate of 92% in a phase II study.

However, even after achieving complete or partial remission with standard induction therapy, high-risk FL patients still face a substantial risk of disease progression and relapse. Currently, there is no established consolidation strategy following first-line induction therapy for these patients to further deepen response and reduce long-term relapse risk. The 2024 National Comprehensive Cancer Network (NCCN) guidelines for the management of high-risk FL after induction therapy are largely limited to close observation or involved-site radiotherapy, lacking more aggressive interventional strategies.

Chimeric antigen receptor T-cell (CAR-T) therapy has established an important role in relapsed/refractory B-cell lymphomas. Notably, in patients with relapsed/refractory FL who have received ≥3 prior lines of therapy, CAR-T therapy (e.g., lisocabtagene maraleucel, liso-cel) has demonstrated potential advantages over bispecific antibodies in efficacy outcomes (objective response rate, complete response rate, progression-free survival). Given the ability of CAR-T therapy to induce deep and durable molecular remissions, and the fact that its adverse event profile (e.g., cytokine release syndrome) is generally manageable with current protocols, moving CAR-T therapy forward as first-line consolidation represents a promising strategy. This approach may help eliminate minimal residual disease in high-risk FL patients, thereby reducing the risk of early progression (progression of disease within 24 months, POD24) and improving long-term survival outcomes.

Therefore, this study aims to evaluate the efficacy and safety of CD19/CD22 dual-targeted CAR-T cell immunotherapy as a consolidation strategy following standard first-line induction therapy in patients with high-risk follicular lymphoma, with the goal of providing a new treatment option for this population with an unmet medical need.

Inclusion Criteria:

• 1. With the patient's consent and signed informed consent form, willing and able to comply with the planned visits, research treatments, laboratory tests, and other experimental procedures;

• 2. CD19 and/or CD22-positive follicular lymphoma (FL) confirmed by histology according to the WHO classification:

  1. The patient's disease is still evaluated as partial response (PR) after induction treatment with standard first-line chemotherapy regimen, or
  2. The patient's disease reaches complete response (CR) after induction treatment with standard first-line chemotherapy regimen, but there are high-risk factors at the time of onset;

• 3. The possible high-risk factors for the patient's onset of the disease are as follows: Presence of at least one of the following high-risk features at diagnosis:

  1. Follicular Lymphoma International Prognostic Index (FLIPI-1) score of 3-5 or FLIPI-2 score of 3-5;
  2. Presence of any lymph node or extranodal mass >6 cm in diameter;
  3. Significant infiltration of CD68+ or CD163+ macrophages by immunohistochemistry;
  4. Gene sequencing revealing TP53 or NOTCH1 mutation;
  5. Presence of 1p36 deletion or 1q amplification;
  6. Next-generation sequencing (NGS)-defined high-risk mutation-based 7-gene Follicular Lymphoma International Prognostic Index (m7-FLIPI) subtype.

• 4. Age range from 18 to 85 years old, male or female;

• 5. Subjects with physical fitness status scores ranging from 0 to 2 in the Eastern Cooperative Oncology Group (ECOG) in the United States;

• 6. Expected survival period from the date of signing the informed consent form is greater than 3 months;

• 7. HGB ≥ 60g/L;

• 8. The absolute value of neutrophils in peripheral blood is ≥ 1000/μl, and the platelet count is ≥ 45000/μl;

• 9. Liver and kidney function, as well as heart and lung function, meet the following requirements:

  1. Total bilirubin (TBIL) ≤ 1.5 times the upper limits of normal (ULN), except for subjects with Gilbert's syndrome;
  2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN;
  3. Serum Creatinine (Cr) ≤ 1.5 times ULN or Creatinine Clearance Rate (CCr) ≥ 60mL/min, estimated based on the Cockcroft Gault formula;
  4. The left ventricular ejection fraction (LVEF) of the heart is ≥ 50%. Echocardiography (ECHO) confirms no pericardial effusion and no clinically significant arrhythmia;
  5. Baseline transcutaneous oxygen saturation under indoor ventilation>92%;
  6. No clinically significant pleural effusion;

• 10. Participants with pregnancy plans must agree to take contraceptive measures for a continuous period of 6 months from before enrollment in the study until the end of the study; If the subject is pregnant or suspected of being pregnant, the researcher should be notified immediately.

Exclusion Criteria:

• 1. Have received any form of chimeric antigen receptor cell therapy or other genetically modified T cell therapy;

• 2. Has a history of severe immediate hypersensitivity reactions to aminoglycoside antibiotics and other essential medications;

• 3. Known history of human immunodeficiency virus (HIV) infection or active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotics (active HBV infection is defined as:

  1. HBV DNA quantification ≥ 2000 IU/ml;
  2. ALT ≥ 2 times the normal upper limit value;
  3. Exclude hepatitis caused by the disease itself, medication, or other reasons; All three conditions must be met simultaneously. If a patient is diagnosed with active HBV infection at the time of initial diagnosis and becomes non active HBV infection after anti HBV treatment, they can be included in this study under the premise of sufficient anti HBV treatment;

• 4. Non hematological tumors (such as lymphoma) associated liver and kidney dysfunction: ALT>3 times the upper limit of normal, AST>3 times the upper limit of normal, TBIL>2 times the upper limit of normal, serum creatinine clearance rate<30 mL/min;

• 5. History of myocardial infarction, cardiac angioplasty or coronary stent implantation, unstable angina, active arrhythmia, or other clinically significant cardiovascular diseases within the 12 months prior to enrollment;

• 6. Other serious medical diseases may have an impact on this study (such as diabetes, gastric ulcer, other serious respiratory and circulatory diseases, severe autoimmune diseases or congenital immune defects, severe infection and inability to be effectively controlled), as well as other diseases with high risk of disease change;

• 7. Has a history of severe immediate hypersensitivity reactions to any medication necessary for use in this study; History of severe allergy to biological products (including antibiotics);

• 8. Female subjects who are currently pregnant or breastfeeding (with potential risks to the fetus or infant from pre-treatment chemotherapy regimens);

• 9. The researchers determined that the subjects were unable to complete all the required visit surveys or diagnostic procedures (including medium - and long-term follow-up visits) as per the study protocol, had poor willingness to participate in the study, were unwilling to join and fully comply with the study arrangements, and had insufficient compliance with the study by the subjects and their families. The decision-making power belongs to the researcher;

• 10. The subjects who have previously suffered from other malignant tumors cannot be included in this study unless they are disease-free and have not received any form of anti-tumor treatment for at least 3 years (except for skin tumors of non malignant melanoma and in situ cancers occurring in the cervix, bladder, breast, etc.);

• 11. History of receiving live vaccines within 6 weeks prior to initiating the pre-treatment plan;

• 12. Those who have undergone large-scale surgical treatment (excluding lymph node biopsy) within the past 14 days, or those who are expected to undergo large-scale surgical treatment during the treatment process;

• 13. There are other serious physical or mental illnesses or laboratory abnormalities that may increase the risk of participating in the study, or interfere with the study results, as well as patients deemed unsuitable by the researchers to participate in this study.