Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment

Chimeric antigen receptor (CAR)-T cell therapy has achieved successful outcomes against hematological malignancies and provided a new impetus for treating solid tumors. However, the efficacy of CAR-T cells for solid tumors remains unsatisfactory. The tumor microenvironment has an important role in interfering with and inhibiting the effector function of immune cells, among which upregulated inhibitory checkpoint receptors, soluble suppressive cytokines, altered chemokine expression profiles, aberrant vasculature, complicated stromal composition, hypoxia and abnormal tumor metabolism are major immunosuppressive mechanisms. In this review, we summarize the inhibitory factors that affect the function of CAR-T cells in tumor microenvironment and discuss approaches to improve CAR-T cell efficacy for solid tumor treatment by targeting those barriers.     

CD276 suppresses CAR-T cell function by promoting tumor cell glycolysis in esophageal squamous cell carcinoma

BackgroundAs an immune checkpoint that suppresses antitumor immunity, CD276 is a potential therapeutic target for cancer immunotherapy. However, the role of CD276 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly examined. A greater understanding of the regulatory mechanism of CD276 may improve the clinical response and efficacy of cancer immunotherapy.MethodsThe expression of CD276 was measured by qRT-PCR, IHC and flow cytometry analysis. T cell infiltration in ESCC was measured by qRT-PCR and immunofluorescence analysis. The regulation function of CD276 in glucose metabolism was examined by metabolism assays, western blotting and small molecule inhibitors. Transfection was used for gene editing. The oncogenic function of CD276 was examined in vivo by CAR-T cell therapy model.ResultsBased on our findings, CD276 regulated the expression of the PKM2 gene in ESCC. Overexpression of CD276 induced the phosphorylation of PKM2 by the STAT3 signalling pathway to promote glucose metabolism in tumors. The accumulation of lactic acid in the tumor microenvironment has been reported to regulate the immune cells, particularly CD8+ T cells. We further analyzed the effect of CD276 on the function of T cells. Chimeric antigen receptor T cells (CAR-T) targeting human epidermal growth factor receptor 2 (HER2) were used as effector cells to detect the effect of CD276 on immunotherapy. The therapeutic effects of CAR-T cells were markedly limited by CD276 overexpression.ConclusionsOur results are the first to show that tumor-derived CD276 supports disease progression. Overexpression of CD276 promoted glucose metabolism in tumor and inhibited the function of CD8+ T cells. Therefore, strategies targeting CD276 might improve the response to cancer immunotherapy of ESCC patients.     

Toxicities associated with immunotherapies for hematologic malignancies

Immunotherapy has generated tremendous hope for patients with cancer that is refractory to standard approaches. Hematologic malignancies have taken the lead in harnessing the most recent advances in cell-based immunotherapies, such as CAR T cells, and some patients have achieved durable remissions. However, these T-cell-engaging therapies are associated with a new set of toxicities which need to be managed by caretakers, oncologists, nurses, and healthcare staff. In this review we provide an overview of the toxicity of some of these revolutionary agents including bispecific T cell engagers, checkpoint inhibitors, chimeric antigen receptor T-cells.     

Study on the Prognostic Value of Aberrant Antigen in Patients With Acute B Lymphocytic Leukemia

BackgroundApproximately 30% to 60% of patients with acute B-lymphocytic leukemia (B-ALL) show as refractory or relapsed, which is one of the major causes of death in patients with B-ALL, but the methods of the treatment for relapsed/refractory B-ALL (R/R B-ALL) are limited. The chimeric antigen receptors redirected T cells (CAR-T cells) have showed a strong anti-leukemia role for B-ALL. About 90% of patients with R/R B-ALL treated with CD19-CAR-T cells achieved complete remission. However, 60% to 70% of patients relapsed after CAR-T cells treatment, which may be related to target antigen reduction or escape. New products are urgently needed to prevent and treat antigenic escapes causing recurrence.Patients and MethodsIn this article, we retrospectively analyzed the immunophenotype of patients with B-ALL initially diagnosed in our center from January 2010 to December 2015 to determine whether aberrant antigen expression was associated with the prognosis of patients in order to find new targets for immunotherapy.ResultsThe results show that disease-free and overall survival in patients without aberrant antigen expression were better than patients with aberrant antigen expression. The most common abnormal antigens were CD123, CD13, and CD56. Correlation analysis showed a negative correlation between aberrant CD123 expression and both disease-free and overall survival.ConclusionTherefore, in the construction of CAR-T cells in patients with R/R B-ALL, conventional CD19 can be combined with aberrant antigens such as CD123 to form CARs with bi-specific antigens or multi-specific antigens may achieve the purpose of improving efficacy. However, more clinical trials are needed.     

CAR-T细胞治疗多发性骨髓瘤优化策略

多发性骨髓瘤(multiple myeloma,MM)是第二大最常见的血液系统恶性肿瘤,尽管现代疗法使患者症状得到了显著改善,整体生存率明显提高,但多数患者仍然复发并死亡.嵌合抗原受体T(chimeric an-tigen receptor T,CAR-T)细胞疗法在多种肿瘤治疗特别是血液系统肿瘤治疗中显示出明显疗效,...     

CAR-T细胞治疗淋巴造血系统恶性肿瘤临床试验设计相关问题的考虑

[摘要] 嵌合抗原受体T 淋巴细胞（CAR-T）在淋巴造血系统恶性肿瘤,如B淋巴细胞白血病、B细胞淋巴瘤和多发性骨髓瘤等的治疗中展现出非常有吸引力的治疗前景。目前有多个课题申请人向中国国家药品监督管理局药品审评中心提交新药临床试验申请,其中很多CAR-T细胞临床试验课题在受试者筛选、疗效预后指标、风险控制等方面存在共性问题,可能影响受试者的安全性和疗效判断。药品审评中心通过总结国内外临床试验设计方面的经验并与国内临床专家交流探讨,对上述共性问题形成了若干考虑,供申办方或研究者开展药品注册临床试验时参考。     

Anti-tumor efficacy of human anti-c-met CAR-T cells against papillary renal cell carcinoma in an orthotopic model

Chimeric antigen receptor (CAR)-T cell therapy has shown salient efficacy in cancer immunotherapy, particularly in the treatment of B cell malignancies. However, the efficacy of CAR-T for solid tumors remains inadequate. In this study, we displayed that c-met is an appropriate therapeutic target for papillary renal cell carcinoma (PRCC) using clinical samples, developed an anti-human c-met CAR-T cells, and investigated the anti-tumor efficacy of the CAR-T cells using an orthotopic mouse model as pre-clinical research. Administration of the anti-c-met CAR-T cells induced marked infiltration of the CAR-T cells into the tumor tissue and unambiguous suppression of tumor growth. Furthermore, in combination with axitinib, the anti-tumor efficacy of the CAR-T cells was synergistically augmented. Taken together, our current study demonstrated the potential for clinical application of anti-c-met CAR-T cells in the treatment of patients with PRCC.     

BRD4 inhibition boosts the therapeutic effects of epidermal growth factor receptor-targeted chimeric antigen receptor T cells in glioblastoma

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