This is a single arm, open-label, uni-center, phase I-II study to evaluate the safety and effectiveness of CAR-T/TCR-T cell immunotherapy in treating with different malignancies patients.

Start Date01 Mar 2018

Sponsor / Collaborator

The First Affiliated Hospital of Zhengzhou University

NCT03371381 / TerminatedPhase 1/2

An Open-Label Randomized Phase 1b/2 Study of the Efficacy and Safety of JNJ-64041757, a Live Attenuated Listeria Monocytogenes Immunotherapy, in Combination With Nivolumab Versus Nivolumab Monotherapy in Subjects With Advanced Adenocarcinoma of the Lung

The purpose of this study is to evaluate whether the efficacy of JNJ-757 combined with nivolumab is better than the efficacy of nivolumab monotherapy for participants with mesothelin-positive relapsed/refractory Stage IIIB or Stage IV adenocarcinoma of the lung. The open-label study comprises of two parts i.e. Phase 1b (safety run-in) and Phase 2. Phase1b consists of 1 arm whereas Phase 2 is randomized into 2 groups i.e. Group A and Group B.

Start Date02 Jan 2018

Sponsor / Collaborator

Janssen Research & Development LLC

100 Clinical Results associated with MSLN x EGFRvIII

100 Translational Medicine associated with MSLN x EGFRvIII

0 Patents (Medical) associated with MSLN x EGFRvIII

Literatures (Medical) associated with MSLN x EGFRvIII

01 Feb 2020·Science China Life SciencesQ1 · BIOLOGY

Chimeric antigen receptor T cells in solid tumors: a war against the tumor microenvironment

Q1 · BIOLOGY

Review

Author: Huang, Hongyan ; Nie, Yan ; Chen, Jiewen ; Zhao, Zijun ; Xiao, Xiaoyun ; Wu, Wei ; Saw, Phei Er

Chimeric antigen receptor (CAR) T cell is a novel approach, which utilizes anti-tumor immunity for cancer treatment. As compared to the traditional cell-mediated immunity, CAR-T possesses the improved specificity of tumor antigens and independent cytotoxicity from major histocompatibility complex molecules through a monoclonal antibody in addition to the T-cell receptor. CAR-T cell has proven its effectiveness, primarily in hematological malignancies, specifically where the CD 19 CAR-T cells were used to treat B-cell acute lymphoblastic leukemia and B-cell lymphomas. Nevertheless, there is little progress in the treatment of solid tumors despite the fact that many CAR agents have been created to target tumor antigens such as CEA, EGFR/EGFRvIII, GD2, HER2, MSLN, MUC1, and other antigens. The main obstruction against the progress of research in solid tumors is the tumor microenvironment, in which several elements, such as poor locating ability, immunosuppressive cells, cytokines, chemokines, immunosuppressive checkpoints, inhibitory metabolic factors, tumor antigen loss, and antigen heterogeneity, could affect the potency of CAR-T cells. To overcome these hurdles, researchers have reconstructed the CAR-T cells in various ways. The purpose of this review is to summarize the current research in this field, analyze the mechanisms of the major barriers mentioned above, outline the main solutions, and discuss the outlook of this novel immunotherapeutic modality.

01 Oct 2019·Clinical Cancer ResearchQ1 · MEDICINE

Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy

Q1 · MEDICINE

Article

Author: Karches, Clara H. ; Ding, Jian ; Klaus, Richard ; Kurzay, Mathias ; Sustmann, Claudio ; Rataj, Felicitas ; Schmidbauer, Moritz L. ; Heise, Constanze ; Cadilha, Bruno L. ; Klein, Christian ; Murr, Ramona ; Lesch, Stefanie ; Jastroch, Martin ; Endres, Stefan ; Lamp, Daniel ; Niederfellner, Gerhard ; Benmebarek, Mohamed-Reda ; Geiger, Martina ; vom Berg, Johannes ; Kobold, Sebastian ; Duewell, Peter

AbstractPurpose:Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing.Experimental Design:BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell–induced lysis were characterized in three murine and human tumor models in vitro and in vivo.Results:Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo.Conclusions:We describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.

01 Sep 2019·EBioMedicineQ1 · MEDICINE

MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers

Q1 · MEDICINE

ArticleOA

Author: De Santo, Carmela ; Shannon-Lowe, Claire ; Middleton, Gary ; Mussai, Francis ; Booth, Sarah ; Ng, Margaret ; Noyvert, Boris ; Panetti, Silvia ; Fultang, Livingstone ; Rizkalla, Nagy ; Collins, Paul ; Graef, Suzanne ; Lenton, Richard

BACKGROUNDTargeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation.METHODSRNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CAR-T cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin.FINDINGSRNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin.INTERPRETATIONThe study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CAR-T cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel anti-myeloid strategy. FUND: This work was supported by Cancer Research UK, CCLG, Treating Children with Cancer, and the alumni and donors to the University of Birmingham.

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