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》

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. Juno Therapeutics, a Bristol-Myers Squibb Company.

Abramson JS ，Palomba ML ，Gordon LI ，Lunning MA ，Wang M ，Arnason J ，Mehta A ，Purev E ，Maloney DG ，Andreadis C ，Sehgal A ，Solomon SR ，Ghosh N ，Albertson TM ，Garcia J ，Kostic A ，Mallaney M ，Ogasawara K ，Newhall K ，Kim Y ，Li D ，Siddiqi T ... -  《-》

Systematic Review and Meta-analysis of CD19-Specific CAR-T Cell Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia in the Pediatric and Young Adult Population: Safety and Efficacy Outcomes.

Acute lymphoblastic leukemia (ALL) typically responds better when treated with multiagent chemotherapy in the pediatric and young adolescent populations. Treatment of relapsed/refractory (RR) ALL remains a challenge. Even after stem-cell transplantation and intensive chemotherapy, the prognosis of RR-ALL remains grave. The advent of chimeric antigen receptors has demonstrated promising results in RR-ALL. Chimeric antigen receptor-modified T cells (CAR-T) and engineered T cells are used to target cancer cells. In 2017, the US Food and Drug Administration approved CD19-specific CAR-T (tisagenlecleucel) therapy for RR-B-cell ALL in patients under 25 years old. In this systematic review, we discuss the efficacy and safety of CD19-specific CAR-T therapy in RR-B-cell ALL in the pediatric and young adult population. We searched the PubMed, Embase, Web of Science, Cochrane Library, and clinical trials databases. A total of 448 patients received a CD19-specific CAR-T product, and 446 patients had evaluable data. The age range was 0 to 30 years. The incidence rate of complete remission was 82%. The cumulative incidence of relapse after CD19-specific CAR-T therapy is 36%. Similarly, the incidence rate of grade 3 or higher adverse events of neutropenia, thrombocytopenia, neurotoxicity, infections, and cytokine release syndrome were 38%, 23%, 18%, 29%, and 19%, respectively. Our subgroup analysis shows the incidence rate of minimal residual negative complete remission was 69% with the CD28z costimulatory domain, 81% with the 4-1BB domain, and 77% with fourth-generation CD19-specific CAR-T therapy.

Aamir S ，Anwar MY ，Khalid F ，Khan SI ，Ali MA ，Khattak ZE ... -  《-》

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 ... -  《-》