Expression of inducible factors reprograms CAR-T cells for enhanced function and safety

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Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade

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Research progress and clinical prospect of immunocytotherapy for the treatment of hepatocellular carcinoma

As a common malignant tumor, hepatocellular carcinoma (HCC) has high fatality rate due to its strong metastasis and high degree of malignancy. Current treatment strategies adopted in clinical practice were still conventional surgery, assisted with interventional therapy, radiotherapy and chemotherapy. However these treatments have limited effects with high recurrence rate. Current research progress of immunocytotherapy has shown that tumor cells can be directly identified and killed by stimulating the immune function and enhancing the anti-tumor immunity in tumor microenvironment. Targeted immunotherapeutics have therefore become the hope of conquering cancer in the future. It can kill tumor cells without damaging the body's immune system and function, restore and strengthen the body's natural anti-tumor immune system. It can reduce the toxic side effects of radiotherapy and chemotherapy, reduce the recurrence rate and prolong the survival period of patients with HCC. Currently, the immune cells widely studied are mainly as follows: Dendritic cells (DC), Cytokine-induced killer (CIK), DC-CIK, Chimeric antigen receptor T cells (CAR-T), Tumor infiltrating lymphocyte (TIL) and Natural killer cell (NK). Immunocytotherapy is a long-term treatment method, some studies have combined traditional therapy with immunocytotherapy and achieved significant effects, providing experimental basis for the application of immunocytotherapy. However, there are still some difficulties in the clinical application of immune cells. In this article, we discuss the application of immunocytotherapy in the clinical treatment of HCC, their effectiveness either alone or in combination with conventional therapies, and how future immunocytotherapeutics can be further improved from investigations in tumour immunology.     

肿瘤免疫治疗中过继性细胞疗法的研究进展

肿瘤免疫疗法旨在利用免疫系统建立针对性的抗肿瘤免疫反应,激活肿瘤免疫细胞是免疫疗法的关键点。过继性细胞疗法是通过体外改造、扩增免疫细胞提高免疫功能,再回输患者体内以发挥抗肿瘤效应。除了已广泛应用于临床的嵌合抗原受体T细胞疗法,近年来T细胞受体-T细胞疗法、肿瘤浸润淋巴细胞疗法、嵌合抗原受体-自然杀伤细胞疗法、嵌合抗原受体-巨噬细胞疗法等新型过继性细胞疗法也开始进入临床。综述近年来过继性细胞疗法的研究进展,以期为基于该疗法进行肿瘤的免疫治疗提供参考。     

BCMA CAR-T细胞治疗的耐药机制及优化策略研究

嵌合抗原受体T细胞（chimeric antigen receptor T cells,CAR-T）疗法在血液系统肿瘤治疗中已展示出卓越成效。BCMA抗原在骨髓瘤细胞表面普遍表达,是合适高效的CAR-T治疗靶抗原。尤其是对于复发/难治性多发性骨髓瘤患者,BCMA CAR-T细胞治疗缓解率高,多数患者在输注1年后仍可在体内检测到CAR-T细胞。但是耐药与疾病复发仍是目前临床管理中面对的关键问题。本文将从多发性骨髓瘤细胞免疫逃逸、CAR-T产品因素、既往治疗方案及肿瘤免疫微环境的抑制等几个方面来探讨BCMA CAR-T细胞疗法的应答响应因素及耐药诱导机制,并提出可能的优化策略,以期为未来探索提供参考意义。     

Radiation enhances the efficacy of EGFR-targeted CAR-T cells against triple-negative breast cancer by activating NF-κB/Icam1 signaling

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Manufacture of Chimeric Antigen Receptor T Cells from Mobilized Cyropreserved Peripheral Blood Stem Cell Units Depends on Monocyte Depletion

Cytotoxic chemotherapy and radiation can render lymphocyte repertoires qualitatively and quantitatively defective. Thus, heavily treated patients are often poor candidates for the manufacture of autologous chimeric antigen receptor (CAR)-T cell products. In the United States and Europe, children with high-risk neuroblastoma undergo apheresis early in the course of treatment to collect peripheral blood stem cells (PBSCs) for cryopreservation in preparation for high-dose chemotherapy followed by autologous stem cell rescue. Here, we investigate whether these cryopreserved chemotherapy and granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs can serve as starting material for CAR-T cell manufacturing. We evaluated T cell precursor subsets in cryopreserved PBSC units from 8 patients with neuroblastoma using fluorescent activated cell sorting-based analysis. Every cryopreserved unit collected early in treatment contained both CD4 and CD8 precursors with significant numbers of naïve and central memory precursors. Significant numbers of Ki67⁺/PD1⁺ T cells were detected, presumably the result of chemotherapy-induced lymphopenia and subsequent homeostatic proliferation. Cryopreserved PBSC units containing 56 to 112?×?10⁶ T cells were amenable to immunomagnetic selection, CD3?×?28 bead activation, lentiviral transduction, and cytokine-driven expansion, provided that CD14 monocytes were depleted before the initiation of cultures. Second- and third-generation CD171 CAR⁺ CD4 and CD8 effector cells derived from cryopreserved units displayed antineuroblastoma lytic potency and cytokine secretion comparable to those derived from a healthy donor and mediated in vivo antitumor regression in NSG mice. We conclude that cryopreserved PBSCs procured via standard methods during early treatment can serve as an alternative starting source for CAR-T cell manufacturing, extending the options for heavily treated patients.     

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children

Abstract

CD19 chimeric antigen receptor T (CD19CAR-T) cell therapy has shown striking response in treating relapsed and refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, side-effects including cytokine release syndrome (CRS) and neurotoxicity can be fatal to patients. In this report, five patients with r/r B-ALL were treated with CD19CAR-T cells. Cytokine release syndrome experienced by four patients who achieved complete remission (CR) with minimal residual disease (MRD) negative. One patient who did not response to the treatment had no CRS. Acute toxicities including fever, hypotension and other neurological toxicities occurred in responding patients within 2?weeks post infusion and managed properly with tocilizumab and/or steroids according to the “real-time” monitoring of a simple 6 Th1/Th2 cytokine pattern. In conclusion, our study demonstrates that CD19CAR-T cell therapy can be safely administered for patients with relapsed and refractory leukemia under the “real-time” monitoring of a simple 6-cytokine pattern.