Taking Gene Therapy into the Clinic

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Abstract

Gene therapy represents a promising novel treatment strategy for colorectal cancer. Preclinical data has been encouraging and several clinical trials are underway. Many phase 1 trials have proven the safety of the reagents but have yet to demonstrate significant therapeutic benefit. Ongoing efforts are being made to improve the efficiency of gene delivery and accuracy of gene targeting with the aim of enhancing antitumor potency. It is envisaged that gene therapy will be used in combination with other therapies including surgery, chemotherapy, and radiotherapy to facilitate the improvements in cancer treatments in the future.

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Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans.

Caroline X. Gao, W Shu, Vernita Gordon … (1993)

Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.

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Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule.

J Tine, H Hörig, W Conkright … (2000)

The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC) constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses. Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an ALVAC-CEA-B7.1 vaccine (4.5 x 10(6), 4.5 x 10(7), and 4.5 x 10(8) plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA-B7.1 at doses up to 4.5 x 10(8) PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-gamma enzyme-linked immunoassay spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses. This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1 to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with tolerable toxicity.

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Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207.

P. Sundaresan, C Rabkin, David Walker … (1999)

Prostate adenocarcinoma is the most common nonskin malignancy in males and the second most common cause of cancer death in the United States (Landis et al., 1998). Initial treatments of surgery or radiotherapy may cause impotence and/or incontinence from neural damage (Eastham and Scardino, 1998; Porter et al., 1998). When extraprostatic or metastatic disease develops, castration or pharmaceutical androgen ablation is utilized (Catalona, 1994). Androgen-resistant recurrence indicates a poor prognosis and justifies experimental chemotherapy (Oh and Kantoff, 1998). G207 (Mineta et al., 1995; Yazaki et al., 1995) is a multimutated herpes simplex virus 1 (HSV) vector that replicates within cancer cells, causing cellular death; however, replication is limited in normal cells, including those of the nervous system. In vitro, G207 at a low multiplicity of infection (MOI of 0.01) is oncolytic for multiple human prostate cancer cells. In athymic mice, a single intraneoplastic inoculation of G207 completely eradicates >22% of established subcutaneous human prostate cancer tumors irrespective of hormonal responsiveness. Two intraneoplastic inoculations of G207 completely eradicated two of three recurrent previously irradiated tumors and two intravenous administration of G207 induced tumor regression in distant subcutaneous tumors and completely eradicated one-fourth of the tumors.

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Author and article information

Journal

Journal ID (nlm-ta): J Biomed Biotechnol

Title: Journal of Biomedicine and Biotechnology

Publisher: Hindawi Publishing Corporation

ISSN (Print): 1110-7243

ISSN (Electronic): 1110-7251

Publication date (Print): 19 March 2003

Volume: 2003

Issue: 1

Pages: 71-77

Affiliations

[1 ]CRUK Institute for Cancer Studies, The Medical School, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TF, England, UK

[2 ]Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford, OX2 6HE, England, UK

Article

DOI: 10.1155/S111072430320913X

PMC ID: 179764

PubMed ID: 12686723

SO-VID: 36301883-bf33-488d-be2f-04dab7159862

History

Date received : 4 June 2002

Date accepted : 19 July 2002

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Taking Gene Therapy into the Clinic

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Most cited references 34

Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans.

Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule.

Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207.

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