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World J Stem Cells. Jan 26, 2022; 14(1): 54-75
Published online Jan 26, 2022. doi: 10.4252/wjsc.v14.i1.54
Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications
Carla Vicinanza, Elisabetta Lombardi, Francesco Da Ros, Miriam Marangon, Cristina Durante, Mario Mazzucato, Francesco Agostini
Carla Vicinanza, Elisabetta Lombardi, Francesco Da Ros, Miriam Marangon, Cristina Durante, Mario Mazzucato, Francesco Agostini, Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
Author contributions: Vicinanza C wrote the manuscript; Lombardi E, Da Ros F, Marangon M, Durante C and Mazzucato M edited the manuscript; Agostini F conceived, designed and wrote the article, and provided final approval; all authors have read and approved the final manuscript.
Supported by the grant from the Italian Ministry of Health “Ricerca Corrente” funding (J34I19003280007), the organization “Alleanza Contro il Cancro (ACC)” (J34I20000600001), the association “Finchè ci siete voi ci sono anch'io” (J31I17000440007)”.
Conflict-of-interest statement: The authors declare no conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Francesco Agostini, PhD, Senior Researcher, Senior Scientist, Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Via F. Gallini, 2, Aviano 33081, Italy.
Received: March 26, 2021
Peer-review started: March 26, 2021
First decision: July 18, 2021
Revised: August 6, 2021
Accepted: December 22, 2021
Article in press: December 22, 2021
Published online: January 26, 2022

Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.

Keywords: Cancer, Mesenchymal stem stromal cells, Good manufacturing practice, Homing, Targeted therapy, Ex vivo cell modification

Core Tip: Natural tropism towards a tumor mass and the cytotoxic potential of mesenchymal stem stromal cells (MSC) need to be ex vivo ameliorated in order to improve clinical effectiveness of cell therapies against cancer. We review genetic engineering, membrane modification and other approaches to upgrade migration and tumor killing activity of MSC. As cell manipulation must be compliant with good manufacturing practice (GMP) guidelines, ex vivo cell modification protocols were selected as potentially compatible with GMP regulations, after appropriate protocol design and validation. Modified cell products must be tested for their clinical relevance in cancer patients within highly standardized clinical trials.