CD19-specific CAR T Cells that Express a PD-1/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1-positive B-Cell Lymphoma.

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is effective against refractory or relapsed (R/R) B-cell lymphoma, but the efficacy is hindered by the existence of PD-1/PD-L1 pathway. Here, we generated a novel anti-CD19 CAR-expressing PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR). We then conducted a phase Ib study to evaluate safety and efficacy of CD19-PD-1/CD28-CAR T cells in the treatment of PD-L1+ B-cell lymphoma. We found that CD19-PD-1/CD28-CAR T cells had superior T-cell proliferation, cytokine production, and sequentially capability of killing PD-L1+ B-cell lymphoma cells in vitro and in vivo relative to the prototype, CD19-CAR T cells. Among 17 adult patients with R/R lymphoma who received the CAR T therapy, 10 patients had objective response (58.8%), including seven patients with complete remission (41.2%). At a median follow-up 15 months, median overall survival for all patients was not reached. Remarkably, no severe neurologic toxicity or cytokine release syndrome was observed. This first-in-human study demonstrates the tolerability, safety, and encouraging efficacy of CD19-PD-1/CD28-CART in PD-L1+ large B-cell lymphoma.

Liu H ，Lei W ，Zhang C ，Yang C ，Wei J ，Guo Q ，Guo X ，Chen Z ，Lu Y ，Young KH ，Lu Z ，Qian W ... -  《-》

CD19 CAR-T expressing PD-1/CD28 chimeric switch receptor as a salvage therapy for DLBCL patients treated with different CD19-directed CAR T-cell therapies.

Liang Y ，Liu H ，Lu Z ，Lei W ，Zhang C ，Li P ，Liang A ，Young KH ，Qian W ... -  《-》

PD-1-CD28-enhanced receptor and CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors.

Chen X ，Zhao X ，Mou X ，Zhao J ，Zhang Z ，Zhang X ，Huang J ，Liu Y ，Wang F ，Zhang M ，Wang L ，Gu W ，Zhang Y ... -  《-》

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》

ShRNA-mediated silencing of PD-1 augments the efficacy of chimeric antigen receptor T cells on subcutaneous prostate and leukemia xenograft.

Chimeric antigen receptor T cells (CAR-T) immunotherapy has shown promising clinical results in the treatment of leukemia and lymphoma, but the effectiveness is limited for solid tumors. The PD-1/PD-L1 pathway is a key immunosuppressive mechanism for cancer cells to avoid eradication by CAR-T cells. In this study, the shRNA (short hair RNA) gene-silencing technique was used to construct the third-generation of CAR-T cells with PD-1 silencing which targeted CD19 antigen (CD19/△PD-1 CAR-T) and prostate stem cell antigen (PSCA/△PD-1 CAR-T), thereby blocking the PD-1/PD-L1 pathway in treatment of lymphoma and prostate subcutaneous xenograft and enhancing the anti-tumor effect of CAR-T cells. The cell experiments showed that PD-1 silencing in CAR-T cells effectively blocked the PD-1 / PD-L1 pathway. When the ratio of effector to target cell is 8:1, △PD-1 CAR-T cells exhibited higher killing ability and cytokine releasing ability than normal CAR-T cells did. The subcutaneous tumor models were constructed using human chronic myelogenous leukemia cells expressing CD19 (K562-CD19) and human prostate cancer cells expressing PSCA (PC3-PSCA), and treated with CD19/△PD-1 CAR-T and PSCA/△PD-1 CAR-T cells, respectively. The tumor volumes significantly reduced within one week, indicating the good tumor growth inhibitory effect of △PD-1 CAR-T cells. Mice injected with △PD-1 CAR-T cells showed a significantly prolonged survival time compared to those with normal CAR-T cells. This study proved that shRNA-mediated PD-1 silencing technology is an effective strategy for blocking the PD-1/PD-L1 immunosuppression pathway and enhancing the therapeutic effect of CAR-T cells on subcutaneous xenograft. SUMMARY: The effect of CAR-T in treating solid tumors has not been as successful as that in hematological malignancies. The key immunosuppressive mechanism is the expression of PD-1/PD-L1. We used gene silencing technique mediated by shRNA (short hair RNA) to block the PD-1/PD-L1 pathway in lymphoma and prostate tumors, thus enhancing the anti-tumor effect of CAR-T cells on subcutaneous xenograft.

Zhou JE ，Yu J ，Wang Y ，Wang H ，Wang J ，Wang Y ，Yu L ，Yan Z ... -  《-》