CD19 CAR-T treatment shows limited efficacy in r/r DLBCL with double expression and TP53 alterations.

Autologous CD19 chimeric antigen receptor T-cell therapy (CAR-T) significantly modifies the natural course of chemorefractory diffuse large B-cell lymphoma (DLBCL). However, 25% to 50% of patients with relapsed/refractory DLBCL still do not achieve remission. Therefore, investigating new molecular prognostic indicators that affect the effectiveness of CAR-T for DLBCL and developing novel combination therapies are crucial. Data from 73 DLBCL patients who received CD19 CAR-T (Axi-cel or Relma-cel) were retrospectively collected from Shanghai Tongji Hospital of Tongji University, The Second Affiliated Hospital Zhejiang University School of Medicine, and The Affiliated People's Hospital of Ningbo University. Prior to CD19 CAR-T-cell transfusions, the patients received fludarabine and cyclophosphamide chemotherapy regimen. Our study revealed that relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) patients with both Double-expression (MYC > 40% and BCL2 > 50%) and TP53 alterations tend to have a poorer clinical prognosis after CAR-T therapy, even when CAR-T therapy is used in combination with other therapies. However, CAR-T therapy was found to be effective in patients with only TP53 alterations or DE status, suggesting that their prognosis is in line with that of patients without TP53 alterations or DE status. Our study suggests that r/r DLBCL patients with both DE status and TP53 alterations treated with CAR-T therapy are more likely to have a poorer clinical prognosis. However, CAR-T therapy has the potential to improve the prognosis of patients with only TP53 alterations or DE status to be similar to that of patients without these abnormalities.

Xue B ，Liu Y ，Zhou J ，Zhou L ，Ye S ，Lu Y ，Zhang W ，Xiu B ，Liang A ，Li P ，Lu Y ，Qian W ，Luo X ... -  《-》

Phase II trial of co-administration of CD19- and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma.

Anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy for refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). However, this therapy failed in nearly 25% patients mainly due to antigen loss. The authors performed a phase Ⅱ trial by coadministration of anti-CD19 and anti-CD20 CAR-T cells treatment for R/R DLBCL and evaluated its efficacy and toxicity. Totally 21 patients with DLBCL were enrolled in this study. The patients were conditioned with fludarabine and cyclophosphamide before the infusion of anti-CD19 and anti-CD20 CAR-T cells. Treatment response, toxicity, and persistence were monitored continuously. Of the 21 patients received the treatment, the objective response rate (ORR) is 81.0% (95% confidence interval [CI], 58.1%-94.6%) with four cases of bulk (4/5) and one case of testis involvement; 52.4% (95% CI, 29.8%-74.3%) had a complete response (CR). Peak levels of anti-CD19 and anti-CD20 CAR cells were associated with response (P = .007 and .002). Grade 3-4 cytokine release syndrome (CRS) and neurologic events occurred in 28.5% and 9.5% patients, respectively. Median overall survival (OS) and progression-free survival (PFS) were 8.1 and 5.0 months, respectively. The maximum standard uptake value (SUVmax) of CD4/CD8 ratio before and after infusion were associated with responses, and the total lesion glycolysis (TLG) before infusion correlates with cytokines level. Coadministration of anti-CD19 and CD20 CAR-T cells therapy for DLBCL is feasible with manageable toxicity. Cytokine markers are related to toxicity and SUVmax could predict efficacy. This trial was registered at www.clinicaltrials.gov as NCT03207178.

Sang W ，Shi M ，Yang J ，Cao J ，Xu L ，Yan D ，Yao M ，Liu H ，Li W ，Zhang B ，Sun K ，Song X ，Sun C ，Jiao J ，Qin Y ，Sang T ，Ma Y ，Wu M ，Gao X ，Cheng H ，Yan Z ，Li D ，Sun H ，Zhu F ，Wang Y ，Zeng L ，Li Z ，Zheng J ，Xu K ... -  《Cancer Medicine》

Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.

Kochenderfer JN ，Dudley ME ，Kassim SH ，Somerville RP ，Carpenter RO ，Stetler-Stevenson M ，Yang JC ，Phan GQ ，Hughes MS ，Sherry RM ，Raffeld M ，Feldman S ，Lu L ，Li YF ，Ngo LT ，Goy A ，Feldman T ，Spaner DE ，Wang ML ，Chen CC ，Kranick SM ，Nath A ，Nathan DA ，Morton KE ，Toomey MA ，Rosenberg SA ... -  《-》

Persistent Cytopenia After CD19 CAR T Therapy in Relapsed/Refractory DLBCL Patients Could Be a Predictor of Efficacy and Side Effects.

Li J ，Mu J ，Wang J ，Li X ，Li Q ，Jiang Y ，Cui R ，Deng Q ... -  《-》

Phase I Trial of Fourth-Generation Anti-CD19 Chimeric Antigen Receptor T Cells Against Relapsed or Refractory B Cell Non-Hodgkin Lymphomas.

The administration of second- or third-generation anti-CD19 chimeric antigen receptor (CAR) T cells has remarkably improved the survival of patients with relapsed or refractory B cell malignancies. However, there are limited clinical results from fourth-generation CAR-T cell therapy, and the factors affecting response rate and survival have not been fully determined. Lymphoma patients with progression or relapse after intensive treatments, including hematopoietic stem cell transplantation, and life expectancy >2 months were enrolled in the study. Peripheral lymphocytes were collected through apheresis, and magnetically selected T cells were lentivirally transduced with a 4th-generation CAR featuring an anti-CD19 CAR and the iCasp9 suicide switch (4SCAR19). The patients received 4SCAR19 T cell infusion after approximately seven days of expansion and a conditioning regimen comprising cyclophosphamide/fludarabine. The efficacy, safety, and risk factors were evaluated. A total of 21 patients with relapsed/refractory B cell non-Hodgkin lymphoma were enrolled and received 4SCAR19 T cell infusions at a median dose of 8.9×105 CAR-T cells/kg. The overall response rate was 67% [95% confidence interval (CI), 43 to 85], with 43% of patients achieving a complete response and 24% having a partial response. The overall and complete response rates were 58 and 33% in the diffuse large B-cell lymphoma (DLBCL) group and 78 and 56% in the non-DLBCL group, respectively. The median overall survival was 23.8 months (95% CI, not reached), with a median follow-up of 13.7 months. Factors affecting overall survival were International Prognostic Index (IPI), disease type, and remission status after CAR-T cell treatment. The most common adverse events of grade 3 or 4 during treatment were neutropenia (76%), leukopenia (71%), and thrombocytopenia (29%). The incidence of cytokine release syndrome (CRS) was 14%, and all cases were grade 1. One patient developed grade 3 neurotoxicity. No deaths were attributed to infusion of 4SCAR19 T cells, CRS, or neurotoxicity. In this study, patients with relapsed or refractory B cell non-Hodgkin's lymphoma who received 4SCAR19 T cell therapy had durable responses and few of adverse events. The IPI model is suitable for evaluating the prognosis of patients receiving CAR-T cell therapy. Chinese Clinical Trial Registry (http://www.chictr.org.cn): ChiCTR-OOC-16007779.

Zhou X ，Tu S ，Wang C ，Huang R ，Deng L ，Song C ，Yue C ，He Y ，Yang J ，Liang Z ，Wu A ，Li M ，Zhou W ，Du J ，Guo Z ，Li Y ，Jiao C ，Liu Y ，Chang LJ ，Li Y ... -  《Frontiers in Immunology》