Long-term activity of tandem CD19/CD20 CAR therapy in refractory/relapsed B-cell lymphoma: a single-arm, phase 1-2 trial.

Increasing the remission rate and reducing the recurrence rate can improve the clinical efficacy of chimeric antigen receptor (CAR) T cell therapy in recurrent/refractory non-Hodgkin lymphoma (r/rNHL). In this open-label, single-arm phase I/II trial, 87 patients with r/rNHL, including 58 patients with aggressive diffuse large B-cell lymphoma and 24 with high tumour burden, received an infusion at doses of 0.5 × 106-8 × 106 TanCAR7 T cells per kilogram of body weight after conditioning chemotherapy. The best overall response rate was 78% (95% confidence interval [CI], 68-86); response rates were consistent across prognostic subgroups. The median follow-up was 27.7 months. The median progression-free survival was 27.6 months (95% CI, 11 to not reached). Cytokine release syndrome (CRS) occurred in 61 patients (70%) with 60% of cases being grade 1 or 2 and 10% being grade 3 or greater. Grade 3 CAR T cell-related encephalopathy syndrome (CRES) occurred in 2 patients (2%). Two patients died from treatment-associated severe pulmonary infection, and one died from CRS-related pulmonary injury between 1 and 3 months post infusion. Long-term remissions were observed following the use of TanCAR7 T cells in r/rNHL with a safety profile that included CRS but few cases of CRES.

Zhang Y ，Wang Y ，Liu Y ，Tong C ，Wang C ，Guo Y ，Ti D ，Yang Q ，Qiao S ，Wu Z ，Han W ... -  《-》

Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma.

Chimeric antigen receptor (CAR) T cells targeting CD19 have achieved breakthroughs in the treatment of hematological malignancies, such as relapsed/refractory non-Hodgkin lymphoma (r/rNHL); however, high rates of treatment failure and recurrence after CAR T-cell therapy are considerable obstacles to overcome. In this study, we designed a series of tandem CARs (TanCARs) and found that TanCAR7 T cells showed dual antigen targeting of CD19 and CD20, as well as formed superior and stable immunological synapse (IS) structures, which may be related to their robust antitumor activity. In an open-label single-arm phase 1/2a trial (NCT03097770), we enrolled 33 patients with r/rNHL; 28 patients received an infusion after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of TanCAR7 T cells. Efficacy, progression-free survival, and overall survival were evaluated as secondary objectives. Cytokine release syndrome occurred in 14 patients (50%): 36% had grade 1 or 2 and 14% had grade 3. No cases of CAR T-cell-related encephalopathy syndrome (CRES) of grade 3 or higher were confirmed in any patient. One patient died from a treatment-associated severe pulmonary infection. The overall response rate was 79% (95% confidence interval [CI], 60-92%), and the complete response rate was 71%. The progression-free survival rate at 12 months was 64% (95% CI, 43-79%). In this study, TanCAR7 T cells elicited a potent and durable antitumor response, but not grade 3 or higher CRES, in patients with r/rNHL.

Tong C ，Zhang Y ，Liu Y ，Ji X ，Zhang W ，Guo Y ，Han X ，Ti D ，Dai H ，Wang C ，Yang Q ，Liu W ，Wang Y ，Wu Z ，Han W ... -  《-》

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》

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》

Sequential CD19 and BCMA-specific CAR T-cell treatment elicits sustained remission of relapsed and/or refractory myeloma.

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T-cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19-CART and B-cell maturation antigen (BCMA)-CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow-up time was 20 months. The most common grade 3/4 treatment-emergent toxicities were hematological toxicities. Cytokine-release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose-limited toxicity (DLT) was observed for BCMA-CAR-positive T cells ≤5 × 107 /kg), while two patients with dose-levels of 5-6.5 × 107 /kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression-free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy.

Yan L ，Qu S ，Shang J ，Shi X ，Kang L ，Xu N ，Zhu M ，Zhou J ，Jin S ，Yao W ，Yao Y ，Chen G ，Chang H ，Zhu X ，Yu L ，Wu D ，Fu C ... -  《Cancer Medicine》