1. JAK/STAT-Dependent Chimeric Antigen Receptor (CAR) Expression: A Design Benefiting From a Dual AND/OR Gate Aiming to Increase Specificity, Reduce Tumor Escape and Affect Tumor Microenvironment
- Author
-
Javad Khanali, Hassan Niknejad, Mohammadreza Azangou-Khyavy, Melika Boroomand-Saboor, and Mobina Ghasemi
- Subjects
0301 basic medicine ,chimeric antigen receptors T cells ,medicine.medical_treatment ,T cell ,Immunology ,on-target/off-tumor toxicity ,Biology ,Protein Engineering ,Immunotherapy, Adoptive ,03 medical and health sciences ,bispecific T cell engagers (BiTEs) ,0302 clinical medicine ,Immune system ,Antigen ,Cancer immunotherapy ,Hypothesis and Theory ,Tumor Microenvironment ,medicine ,cancer ,Humans ,Immunology and Allergy ,Janus Kinases ,Tumor microenvironment ,Receptors, Chimeric Antigen ,RC581-607 ,Chimeric antigen receptor ,STAT Transcription Factors ,030104 developmental biology ,medicine.anatomical_structure ,Tumor Escape ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Immunologic diseases. Allergy ,adoptive immunotherapy ,cancer-associated fibroblasts ,tumor escape and relapse - Abstract
Recent advances in cancer immunotherapy have attracted great interest due to the natural capacity of the immune system to fight cancer. This field has been revolutionized by the advent of chimeric antigen receptor (CAR) T cell therapy that is utilizing an antigen recognition domain to redirect patients’ T cells to selectively attack cancer cells. CAR T cells are designed with antigen-binding moieties fused to signaling and co-stimulatory intracellular domains. Despite significant success in hematologic malignancies, CAR T cells encounter many obstacles for treating solid tumors due to tumor heterogeneity, treatment-associated toxicities, and immunosuppressive tumor microenvironment. Although the current strategies for enhancing CAR T cell efficacy and specificity are promising, they have their own limitations, making it necessary to develop new genetic engineering strategies. In this article, we have proposed a novel logic gate for recognizing tumor-associated antigens by employing intracellular JAK/STAT signaling pathway to enhance CAR T Cells potency and specificity. Moreover, this new-generation CAR T cell is empowered to secrete bispecific T cell engagers (BiTEs) against cancer-associated fibroblasts (CAFs) to diminish tumor metastasis and angiogenesis and increase T cell infiltration.
- Published
- 2021