CAR T-cell Therapy A new Era in Cancer Immunotherapy.pdf -...

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Current Pharmaceutical Biotechnology 1 873 - 43 1 6 /18 $58.00+.00 © 2018 Bentham Science Publishers Send Orders for Reprints to [email protected] Current Pharmaceutical Biotechnology, 2018 , 19 , 5-18 5 REVIEW ARTICLE Androulla N. Miliotou and Lefkothea C. Papadopoulou * Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Macedonia, Greece A R T I C L E H I S T O R Y Received: December 08, 2017 Revised: March 06, 2018 Accepted: April 13, 2018 DOI: 10.2174/1389201019666180418095526 Abstract: Background : Cancer is one of the leading causes of death worldwide. Over the years, a number of conventional cytotoxic approaches for neoplastic diseases has been developed. However, due to their limited effectiveness in accordance with the heterogeneity of cancer cells, there is a con- stant search for therapeutic approaches with improved outcome, such as immunotherapy that utilizes and enhances the normal capacity of the patient’s immune system. Methods : Chimeric Antigen Receptor (CAR) T-cell therapy involves genetic modification of patient’s autologous T-cells to express a CAR specific for a tumor antigen, following by ex vivo cell expansion and re-infusion back to the patient. CARs are fusion proteins of a selected single-chain fragment vari- able from a specific monoclonal antibody and one or more T-cell receptor intracellular signaling do- mains. This T-cell genetic modification may occur either via viral-based gene transfer methods or non- viral methods, such as DNA-based transposons, CRISPR/Cas9 technology or direct transfer of in vitro transcribed-mRNA by electroporation. Results : Clinical trials have shown very promising results in end-stage patients with a full recovery of up to 92% in Acute Lymphocytic Leukemia. Despite such results in hematological cancers, the effec- tive translation of CAR T-cell therapy to solid tumors and the corresponding clinical experience is lim- ited due to therapeutic barriers, like CAR T-cell expansion, persistence, trafficking, and fate within tumors. Conclusion : In this review, the basic design of CARs, the main genetic modification strategies, the safety matters as well as the initial clinical experience with CAR T-cells are described. Keywords: Cancer, immunotherapy, T-cell therapy, chimeric antigen receptor (CAR), genetic engineering, safety. 1. INTRODUCTION - CANCER IMMUNOTHERAPY Conventional cytotoxic approaches for neoplastic dis- eases have only modest efficacy in treating cancer of ad- vanced stage. Treatment responses vary considerably among patients and a high relapse rate with poor prognosis contin- ues to be a major challenge. It is thus interesting that immu- notherapy has emerged as a challenging approach, altering the face of cancer treatment during the last decades. Immu- notherapy utilizes and enhances the normal capacity of the immune system and is considered one of the most promising approaches for the treatment of various serious diseases (in- cluding cancer, autoimmune diseases, allergic - hypersensi- tivity reactions) [1].
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