CD19/CD22 CAR-T as First-line Consolidation in 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.