Current challenges and emerging opportunities of CAR-T cell therapies

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Current challenges and emerging opportunities of CAR-T cell therapies

Thursday, 23.01.2020

During the past few years, the establishment of immunotherapy (e.i. stimulation of the immune system to recognize and kill malignant cells) as a reliable therapeutic option to tackle cancer, has shifted the paradigm of cancer treatment. Among the different classes of cancer immunotherapies, including checkpoint inhibitor monoclonal antibodies (2018 Nobel Prize Physiology or Medicine), adoptive T cell therapies (ACTs), harboring CAR-T cells, are emerging as a revolutionary strategy to eliminate tumors. In this context, endogenous T cells are genetically modified to express CARs (chimeric antigen receptors), which are hybrid receptors capable of recognizing a specific tumor antigen, and thus to redirect T cells specificity and cytolytic activity towards a predefined tumor target. Their antitumoral efficacy has been demonstrated in several clinical studies against hematological malignancies, and these were the clinical support for the approval of the first CAR-T cell-based products - KYMRIAH® from Novartis e YESCARTA® from Kite Pharma - by the US Food and Drug Administration (FDA) in 2017, and by the European Medicines Agency (EMA) in 2018. In Portugal, the clinical studies harboring CAR-T cells are taking their first steps in the IPO of Porto and Lisbon.

However, the clinical success in hematological cancers is stained by life-threatening side effects, which have led to some CAR-associated deaths in clinical trials. Besides, the extension of CAR-T cell-based therapies to solid malignancies have reported poor clinical effect, owing to the intrinsic physical and chemical barriers and the strong immunosuppressive milieu held by the tumor microenvironment in solid tumors.

In this context, this Review Article, developed by researchers from the Center for Neurosciences and Cell Biology from the University of Coimbra, will focus on the pathophysiological mechanisms underlying CAR-T cells related toxicities, as well as on the next-generation CAR-technologies developed to address the current issues in safety. Besides, a detailed overview will be provided on the current state of CAR-T cells application in the treatment of solid tumors and the innovative strategies developed to improve their antitumoral effect and persistence in vivo.

 

Authors and Affiliations:

Teresa R. Abreu1,2, Nuno A. Fonseca1,3, Nélio Gonçalves1, João Nuno Moreira1,2

1CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo 1), Rua Larga, 3004-504 Coimbra, Portugal

2FFUC - Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal

3TREAT U, SA, Parque Industrial de Taveiro, Lote 44, 3045-508 Coimbra, Portugal

 

Abstract:

Infusion of chimeric antigen receptor (CAR)-genetically modified T cells (CAR-T cells) have led to remarkable clinical responses and cancer remission in patients suffering from relapsed or refractory B-cell malignancies. This is a new form of adoptive T cell therapy (ACT), whereby the artificial CAR enables the redirection of T cells endogenous antitumor activity towards a predefined tumor-associated antigen, leading to the elimination of a specific tumor. The early success in blood cancers has prompted the US Food and Drug Administration (FDA) to approve the first CAR-T cell therapies for the treatment of CD19-positive leukemias and lymphomas in 2017. Despite the emergence of CAR-T cells as one of the latest breakthroughs of cancer immunotherapies, their wider application has been hampered by specific life-threatening toxicities, and a substantial lack of efficacy in the treatment of solid tumors, owing to the strong immunosuppressive tumor microenvironment and the paucity of reliable tumor-specific targets. Herein, besides providing an overview of the emerging CAR-technologies and current clinical applications, the major hurdles of CAR-T cell therapies will be discussed, namely treatment-related life-threatening toxicities and the obstacles posed by the immunosupressive tumor-microenvironment of solid tumors, as well as the next generation strategies currently designed to simultaneously improve safety and efficacy of CAR-T cell therapies in vivo.

 

Journal: Journal of Controlled Release

 

Link: https://authors.elsevier.com/c/1aMVwcI2~q0UJ