Combined suicide and granulocyte–macrophage colony-stimulating factor gene therapy induces complete tumor regression and generates antitumor immunity

ABSTRACT The use of prodrug-activated (“suicide”) gene therapy has been shown to be effective in inducing tumor regression when only a small proportion of tumor cells contains the suicide

gene. These experiments were designed to test whether additional therapeutic benefit may be obtained by stimulating the immune response. Murine MC26 colon carcinoma cells, either

untransduced or transduced with genes for herpes simplex virus-1 thymidine kinase (HSV1-TK) or human GM-CSF, were injected subcutaneously into syngeneic BALB/c mice in various combinations.

Inoculation of equal numbers of untransduced and HSV1-TK–containing cells followed by ganciclovir (GCV) treatment resulted in almost complete tumor regression, but by 7 weeks, tumors had

recurred in all mice. A similar initial regression was obtained using equal numbers of cells containing HSV1-TK and GM-CSF genes, but >80% of these mice remained tumor-free after 3

months. Groups of tumor-free mice that had received GM-CSF–containing cells were left for different periods of time and rechallenged with unmodified MC26 cells on the opposite flank. Of the

mice rechallenged 14, 28, and 108 days later, 100%, 88%, and 57%, respectively, showed complete resistance to unmodified tumor cells. In mice that showed tumor regrowth, tumor volume was

much less than in control mice. Adoptive transfer of spleen cells from resistant mice to naı¨ve syngeneic mice resulted in partial resistance to challenge with unmodified tumor cells.

Specific cytotoxicity against MC26 cells was only demonstrable in mice receiving GM-CSF– and HSV1-TK–containing tumor cells. These experiments show that the presence of cells secreting

GM-CSF in HSV1-TK–containing, regressing tumor is able to induce complete or partial resistance to tumor rechallenge. This indicates the potential usefulness of GM-CSF in enhancing other

antitumor therapies. _Cancer Gene Therapy_ (2000) 7, 1519–1528. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ANTITUMOR EFFECTS OF IL-12 AND GM-CSF CO-EXPRESSED IN AN ENGINEERED ONCOLYTIC

HSV-1 Article 04 November 2020 STEM CELL FACTOR PRODUCED BY TUMOR CELLS EXPANDS MYELOID-DERIVED SUPPRESSOR CELLS IN MICE Article Open access 09 July 2020 INTRAVENOUS INJECTION OF THE

ONCOLYTIC VIRUS M1 AWAKENS ANTITUMOR T CELLS AND OVERCOMES RESISTANCE TO CHECKPOINT BLOCKADE Article Open access 12 December 2020 AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Immunology, University of Liverpool Medical School, Liverpool, UK Rebecca K Jones & Stephen E Christmas * Department of Surgery, University of Liverpool Medical School, Liverpool, UK Ian

M Pope & Anne R Kinsella * Department of Medicine, University of Liverpool Medical School, Liverpool, UK Alastair JM Watson Authors * Rebecca K Jones View author publications You can

also search for this author inPubMed Google Scholar * Ian M Pope View author publications You can also search for this author inPubMed Google Scholar * Anne R Kinsella View author

publications You can also search for this author inPubMed Google Scholar * Alastair JM Watson View author publications You can also search for this author inPubMed Google Scholar * Stephen E

Christmas View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Stephen E Christmas. RIGHTS AND PERMISSIONS Reprints

and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jones, R., Pope, I., Kinsella, A. _et al._ Combined suicide and granulocyte–macrophage colony-stimulating factor gene therapy induces

complete tumor regression and generates antitumor immunity. _Cancer Gene Ther_ 7, 1519–1528 (2000). https://doi.org/10.1038/sj.cgt.7700259 Download citation * Received: 01 June 2000 *

Accepted: 03 September 2000 * Published: 01 January 2001 * Issue Date: 01 December 2000 * DOI: https://doi.org/10.1038/sj.cgt.7700259 SHARE THIS ARTICLE Anyone you share the following link

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content-sharing initiative KEYWORDS * Bystander effect * prodrug-activated gene therapy * tumor immunity * granulocyte–macrophage colony-stimulating factor