Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth

Chen, Xin; Amar, Norhan; Zhu, Yuankui; Wang, Chunguang; Xia, Chen; Yang, Xiaoqing; Wu, Dongde; Feng, Mingqian

doi:10.1136/jitc-2020-000785

Cited by 51 publications

(26 citation statements)

References 26 publications

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“…On the other hand, Chen and colleagues introduced delta-like 3 (DLL3) as an attractive target for the treatment of small cell lung cancer (SCLC). They showed that DLL3 targeted with antibody and CAR-T cell alone or along with PD-1 inhibition kill DLL3 tumor cells including H82, H196, and H446 cell lines [96].…”

Section: Lung Cancermentioning

confidence: 99%

CAR T cells in solid tumors: challenges and opportunities

et al. 2021

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Background CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Main body Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as “living drugs” presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Conclusion Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

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Section: Lung Cancermentioning

confidence: 99%

CAR T cells in solid tumors: challenges and opportunities

et al. 2021

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“…Engineered cell-based therapies for lung cancer have so far been designed to target epidermal growth factor receptor (EGFR) and variant III (EGFRviii), glypican 3 (GPC3), human epidermal growth factor receptor 2 (HER2), Protein tyrosine kinase 7 (PTK7), erythropoietin-producing hepatocellular carcinoma A2 (EphA2), mesothelin (MSLN), prostate stem cell antigen (PSCA), mucin 1 (MUC1), carcinoembryonic antigen (CEA), natural killer group 2D (NKG2D), tyrosine kinase-like orphan receptor 1 (ROR1), and programmed cell death ligand 1 (PD-L1),lung-specific X (LunX), and delta-like 3 (DLL3) (101)(102)(103)(104).…”

Section: Cellular Therapy In Lung Cancermentioning

confidence: 99%

Immunotherapy in Lung Cancer: Current Landscape and Future Directions

et al. 2022

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Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy.

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“…C600952-0501; Sangon Biotech Co., Ltd; Shanghai, China). The purity of the preparations was analyzed by SDS-PAGE (31).…”

Section: Preparation Of Recombinant B7-h4 Proteinsmentioning

confidence: 99%

Strengthening of antitumor effects in breast cancer from a novel B7-H4- and CD3-targeting bispecific antibody by an oncolytic virus

Tang¹,

Ma²,

Chen³

et al. 2022

Ann Transl Med

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Background: For programmed cell death protein 1/programmed death-ligand 1 (PD-L1)-positive triplenegative breast cancer (TNBC), the addition of immune checkpoint inhibitors (ICIs) to chemotherapy has been shown to increase the objective response rate (ORR) by only 13.4-16.3%. Thus, examining converting tumor immunogenicity and targeting novel pathways may be needed to improve response to immunotherapy. B7-H4 is an emerging target for breast cancer immunotherapy. However, the antitumor effect of B7-H4 is unstable during cell generation and further research is necessary to strengthen the antitumor efficacy of B7-H4.Methods: To explore the potential of B7-H4-targeted immunotherapy of breast cancer, current study generated four monoclonal antibodies (mAbs) against B7-H4 through immunization of mice followed by phage display technology. T cell-engaged bispecific antibodies and immunotoxins were created based on these mAbs. To evaluate the anti-tumor activity of B7-H4-targeting bispecific antibody and immunotoxin, the anti-tumor efficacy test in vitro and in mice models in vivo were performed. Moreover, to boost the efficacy, oncolytic virus herpes simplex virus type 2 (HSV-2) was combined with the bispecific antibody and tested in mice models.Results: Rigorous in vitro cytotoxicity assay showed that both B7-H4 bispecific antibodies and immunotoxins were toxic to B7-H4 positive cells, with the former being more potent. However, in vivo studies showed that immunotoxin was slightly more effective in suppressing tumor growth. Further, bispecific antibody combined with oncolytic virus HSV-2 revealed a synergistic effect in suppressing tumor growth without causing obvious adverse effects.Conclusions: Collectively, our findings uncover a novel strategy of combining oncolytic virus HSV-2 with bispecific antibody reinforce antitumor immune response, which warranted further translational investigation.

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Combined DLL3-targeted bispecific antibody with PD-1 inhibition is efficient to suppress small cell lung cancer growth

Cited by 51 publications

References 26 publications

CAR T cells in solid tumors: challenges and opportunities

CAR T cells in solid tumors: challenges and opportunities

Immunotherapy in Lung Cancer: Current Landscape and Future Directions

Strengthening of antitumor effects in breast cancer from a novel B7-H4- and CD3-targeting bispecific antibody by an oncolytic virus

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