Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin's Lymphoma

Yan, Zi; Li, Li; Wang, Wen; Ouyang, Bang; Cheng, Shu; Wang, Li; Wu, Wen; Xu, Peng; Müftüoğlu, Muharrem; Hao, Ming; Su, Yang; Zhang, Mu Chen; Zheng, Zhong; Li, James; Zhao, Wei

doi:10.1158/1078-0432.ccr-19-0101

Cited by 82 publications

(72 citation statements)

References 32 publications

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“…To date, CD19-targeted CAR T-cell therapy has been largely successful in hematological malignancies, showing up to 90% complete response in relapsed or treatment-refractory acute lymphoblastic leukemia (ALL) patients (Maude et al, 2014). However, despite extensive research, the efficacy of CAR-T cell therapy on controlling solid tumors is limited effects due to the influence of TME Li et al, 2018d;Yan et al, 2019). Studies suggest that solid tumors may induce hyporesponsiveness of CAR-T cells (Irving et al, 2017;Martinez and Moon, 2019).…”

Section: Cancer Immunotherapy and T Cell Dysfunction In The Tmementioning

confidence: 99%

T Cell Dysfunction and Exhaustion in Cancer

Zhang

et al. 2020

Front. Cell Dev. Biol.

259

209

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Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. T cell dysfunction induces the out of control of tumors. Recently, T cell dysfunction has been investigated in many experimental and clinical settings. The molecular definition of T cell dysfunction and the underlying causes of the T cell dysfunction has been advanced regardless of the fact that the pathways involved are not well elucidated, which proposing promising therapeutic opportunities in clinic. In this review, we will discuss the recent advances in the molecular mechanisms that affect TME and induce T cell dysfunction, and the development of promising immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction. Better understanding these underlying mechanisms may lead to new strategies to improve the clinical outcome of patients with cancer.

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Section: Cancer Immunotherapy and T Cell Dysfunction In The Tmementioning

confidence: 99%

T Cell Dysfunction and Exhaustion in Cancer

Zhang

et al. 2020

Front. Cell Dev. Biol.

259

209

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“…Compared with those of patients with CR, the baseline tumor samples of patients with PR are characterized with low levels of the gene expression of chemokines (i.e., CCR6, CCR10, CXCR3, and CXCR4) and adhesion molecules (i.e., CD226, ITGAE, TNFRSF18). Increased tumor-associated macrophage infiltration and decreased tumor-infiltrating T cells in lymphoma are correlated with negative remission after the CAR-T therapy [122].…”

Section: Enhancing the Efficacy And The Persistence Of Car-t Cells Anmentioning

confidence: 98%

A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma

et al. 2020

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The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

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“…Increased tumorassociated macrophage infiltration was negatively associated with remission status. 429 In addition to studies targeting CD19 CAR-T cells, studies on CD20, CD22, and CD30 CAR-T cell therapy have also been carried out. In a phase 2 study (NCT01735604) of anti-CD20 CAR-T therapy, the ORR was 81.8% (CR 54.5%).…”

Section: Car-t Therapy In Lymphomamentioning

confidence: 99%

Advances in targeted therapy for malignant lymphoma

Wang

Qin

Huo

et al. 2020

Sig Transduct Target Ther

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The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.Signal Transduction and Targeted Therapy (2020) 5:15; https://doi.

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Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin's Lymphoma

Cited by 82 publications

References 32 publications

T Cell Dysfunction and Exhaustion in Cancer

T Cell Dysfunction and Exhaustion in Cancer

A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma

Advances in targeted therapy for malignant lymphoma

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