Gene Therapy in Cancer Treatment: Why Go Nano?

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Abstract

The proposal of gene therapy to tackle cancer development has been instrumental for the development of novel approaches and strategies to fight this disease, but the efficacy of the proposed strategies has still fallen short of delivering the full potential of gene therapy in the clinic. Despite the plethora of gene modulation approaches, e.g., gene silencing, antisense therapy, RNA interference, gene and genome editing, finding a way to efficiently deliver these effectors to the desired cell and tissue has been a challenge. Nanomedicine has put forward several innovative platforms to overcome this obstacle. Most of these platforms rely on the application of nanoscale structures, with particular focus on nanoparticles. Herein, we review the current trends on the use of nanoparticles designed for cancer gene therapy, including inorganic, organic, or biological (e.g., exosomes) variants, in clinical development and their progress towards clinical applications.

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Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy

Tongyan Liu, Chencheng Han, Siwei Wang … (2019)

Among all the stromal cells that present in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor mesenchyme, which not only provide physical support for tumor cells but also play a key role in promoting and retarding tumorigenesis in a context-dependent manner. CAFs have also been involved in the modulation of many components of the immune system, and recent studies have revealed their roles in immune evasion and poor responses to cancer immunotherapy. In this review, we describe our current understanding of the tumorigenic significance, origin, and heterogeneity of CAFs, as well as the roles of different CAFs subtypes in distinct immune cell types. More importantly, we highlight potential therapeutic strategies that target CAFs to unleash the immune system against the tumor.

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Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?

Yuko Nakamura, Ai Mochida, Peter L. Choyke … (2016)

Nanotechnology offers several attractive design features that have prompted its exploration for cancer diagnosis and treatment. Nanosized drugs have a large loading capacity, the ability to protect the payload from degradation, a large surface on which to conjugate targeting ligands, and controlled or sustained release. Nanosized drugs also leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as the enhanced permeability and retention (EPR) effect. However, while the EPR effect is widely held to improve delivery of nanodrugs to tumors, it in fact offers less than a 2-fold increase in nanodrug delivery compared with critical normal organs, resulting in drug concentrations that are not sufficient for curing most cancers. In this Review, we first overview various barriers for nanosized drug delivery with an emphasis on the capillary wall's resistance, the main obstacle to delivering drugs. Then, we discuss current regulatory issues facing nanomedicine. Finally, we discuss how to make the delivery of nanosized drugs to tumors more effective by building on the EPR effect.

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Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.

Liang-Chuan S Wang, Albert Lo, John Scholler … (2014)

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8(+) T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted.

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Author and article information

Journal

Journal ID (nlm-ta): Pharmaceutics

Journal ID (iso-abbrev): Pharmaceutics

Journal ID (publisher-id): pharmaceutics

Title: Pharmaceutics

Publisher: MDPI

ISSN (Electronic): 1999-4923

Publication date (Electronic): 05 March 2020

Publication date Collection: March 2020

Volume: 12

Issue: 3

Electronic Location Identifier: 233

Affiliations

[1 ]UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Campus de Caparica, 2829-516 Caparica, Portugal; catromar@ 123456fct.unl.pt (C.R.-R.); lorenrivas@ 123456ugr.es (L.R.-G.)

[2 ]Biomedical Research Centre, Institute of Nutrition and Food Technology, Department of Physiology, Faculty of Pharmacy, University of Granada, Avda. del Conocimiento s/n. 18071 Armilla, Granada, Spain

Author notes

[* ]Correspondence: pmvb@ 123456fct.unl.pt (P.V.B.); ma.fernandes@ 123456fct.unl.pt (A.R.F.); Tel.: +351-212-948-530 (P.V.B. & A.R.F.)

Author information

Catarina Roma-Rodrigues https://orcid.org/0000-0002-8676-6562

Lorenzo Rivas-García https://orcid.org/0000-0002-0413-8432

Pedro V. Baptista https://orcid.org/0000-0001-5255-7095

Alexandra R. Fernandes https://orcid.org/0000-0003-2054-4438

Article

Publisher ID: pharmaceutics-12-00233

DOI: 10.3390/pharmaceutics12030233

PMC ID: 7150812

PubMed ID: 32151052

SO-VID: 9a64a852-bbc7-4354-bf93-101a35bca431

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Gene Therapy in Cancer Treatment: Why Go Nano?

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Abstract

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Most cited references 228

Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy

Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?

Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.

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