Objective. The objective is to explore the effectiveness and safety of CAR T-cell therapy in advanced relapsed/refractory central nervous system B-cell lymphoma and compare the impact of autologous stem cell transplantation (ASCT) plus CAR T-cell therapy versus sequential CART therapy on the survival of patients. Methods. The retrospective analysis was based on the data of 17 patients with advanced relapsed/refractory central nervous system B-cell lymphoma. Bridging chemotherapy was applied before CAR T-cell infusion to further reduce the tumor burden. For patients with autologous hematopoietic stem cell successful collection, CD19/20/22CAR T-cell immunotherapy following ASCT was performed with the thiotepa-containing conditioning regimen, while sequential CD19/CD20/CD22CAR T-cell therapy was applied. For lymphodepletion, patients received bendamustine or fludarabine monotherapy or fludarabine combined with cyclophosphamide pre-CART-cell infusion. Results. Out of the 17 patients, 8 completed ASCT plus CART cell therapy, while 9 patients completed CART cell alone therapy. In efficacy assessment at 3 months after infusion, the objective response rate (ORR) was 12/17 (71%) and the complete response rate (CRR) was 11/17 (65%). The CRR of the ASCT group and non-ASCT was 100% and 44.4%, respectively ( P < 0.01 ). The median progression-free survival was 16.3 (2.6–24.5) months, and the median overall survival was 19.3 (6–24.5) months. Patients who underwent ASCT plus CART cell therapy had significantly longer PFS ( P < 0.01 ) and OS ( P < 0.01 ). Grade 3 or higher immune effector cell-associated neurologic toxicity syndrome (≥grade 3 ICANS) and cytokine release syndrome (≥grade 3 CRS) events occurred in 29% and 41% of the patients, respectively. No treatment-related death occurred. Conclusion. The CAR T-cell therapy could augment its efficacy in the treatment of advanced relapsed/refractory CNS B-cell lymphoma, while ASCT in combination with CART can induce durable responses and OS with a manageable side effect.

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In our research, we screened 1,495 documents, compiled the whole-exome sequencing data of several studies, formed a data set including 92 observations of RRDLBCL (Relapsed and refractory diffuse large B-cell lymphoma), and performed association analysis on the high-frequency mutations among them. The most common mutations in the data set include TTN, KMT2D, TP53, IGLL5, CREBBP, BCL2, MYD88, and SOCS1 etc. Among these, CREBBP, KMT2D, and BCL2 have a strong association with each other, and SOCS1 has a strong association with genes such as STAT6, ACTB, CIITA, ITPKB, and GNA13. TP53 lacks significant associations with most genes. Through SOM clustering, expression-level analysis and protein interaction analysis of common gene mutations, we believe that RRDLBCL can be divided into five main types. We tested the function of the model and described the clinical characteristics of each subtype through a targeted sequencing RRDLBCL cohort of 96 patients. The classification is stated as follows: 1) JAK-STAT-related type: including STAT6, SOCS1, CIITA, etc. The genetic lineage is similar to PMBL and cHL. Retrospective analysis suggests that this subtype responds poorly to induction therapy (R-CHOP, p &lt; 0.05). 2) BCL-CREBBP type: Epigenetic mutations such as KMT2D and CREBBP are more common in this type, and are often accompanied by BCL2 and EZH2 mutations. 3) MCD type: including MYD88 and CD79B, PIM1 is more common in this subtype. 4) TP53 mutation: TP53 mutant patients, which suggests the worst prognosis (p &lt; 0.05) and worst response to CART treatment. 5) Undefined type (Sparse item type): Major Genetic Change Lacking Type, which has a better prognosis and better response to CART treatment. We also reviewed the literature from recent years concerning the previously mentioned common gene mutations.

The prognosis for patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. CD19 chimeric antigen receptor (CAR) T cell therapy has dramatically improved objective response rate, however, up to 70% eventually develop progression after treatment with CD19CAR T-cell therapy, usually within 1 year. Antigen escape and short duration of CART cell persistence in vivo are important determinants of recurrence. CD20 is an important target for the treatment of lymphoma, and CD20 monoclonal antibody has dramatically changed the treatment landscape for B cell lymphoma, to which sequential different targeting of CD19 and CD20 has been proposed as a potential solution.

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