Promising results reported for lung cancer gene therapy

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SCIENCE AND MEDICINE

NEWS Promising results reported for lung cancer gene therapy

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nsertion of functional p53 tumoursuppressor genes directly into lung cancers can result in “significant tumour destruction” or growth stabilisation, says Jack Roth (M D Anderson Cancer Center, Houston, USA), lead investigator of the first trial for p53 gene therapy in human lung cancer. But Roth also stresses that results so far are “preliminary”. Only local, endobronchial cancers regressed. Consequently, none of the patients was permanently cured. The phase I study (Nature Med 1996; 2: 985–91) enrolled nine men (median age 68) with primary nonsmall-cell lung cancer (NSCLC) in whom conventional therapies had failed. Roth and colleagues injected retroviral vectors expressing wild-type p53 genes into cancers with documented p53 mutations. Injections were done locally into the cancers using either a fibreoptic bronchoscope or percutaneous needle with radiological guidance. Measurable cancer regression occurred in three patients, and cancer growth stabilised in three others. For two patients the results could not be evaluated, and in one the disease progressed during treatment. Survival was 3–22 weeks

A pot-pourri of tumour-suppressor genes p53 may be one of the most frequently mutated tumour-suppressor genes but reports of new tumour-suppressor genes and their mutations in different cancers are a regular occurrence. This month’s offerings include: v EXT2, a gene associated with the rare bone disorder, hereditary multiple exostoses (reported in Nature Genetics). The primary feature of this disease is the proliferation of benign tumours, so EXT2 may be a tumour-suppressor gene; v mutations in the human homologue of Drosophila patched occur in one third of sporadic basal-cell carcinomas (Nature Genetics). The patched homologue was identified as a putative tumour-suppressor gene earlier this year when the gene responsible for nevoid basalcell carcinoma syndrome was identified; and v 22 of 26 head and neck squamous-cell carcinoma cell lines have mutations in the FHIT gene (Proc Natl Acad Sci USA). FHIT is also frequently mutated in lung cancer and many other epithelial cancer cell-lines.

Jane Bradbury after treatment. Roth is cautiously positive about the results to date. “This was a phase I study with a primary objective of assessing whether the procedure is safe, and a secondary objective of seeing whether the gene would be taken up and could mediate cell death.” No clinically significant vector-related toxicities were observed and post-treatment biopsy samples confirmed gene transfer. Apoptosis was also more frequent in post-treatment samples than in pretreatment samples. Roth and colleagues are conducting another trial which is currently accruing NSCLC patients with unresectable local, regional, or isolated metastatic stage IV disease. In this

Measured enthusiasm urged by NCI scientist While acknowledging that the p53 gene transfer study in lung cancer patients represents a “significant first step”, Curtis Harris, chief of the laboratory of human carcinogenesis at the US National Cancer Institute (Bethesda, USA), is urging clinicians and the public to view the results with “measured enthusiasm”. After an efficacy trial, he says, “we can make some assessment about whether or not gene therapy will be effective on its own or, more likely, as a supplement to chemotherapy and radiotherapy, or both”. Using viral vectors “is still a very inefficient way of delivering a therapeutic agent”, Harris says. In the lung cancer study, the researchers “maximised the accessibility of the vector to tumour cells by injecting it into the tumour for local control. Since the patients had widespread disease, the number of cells targeted certainly wasn’t complete. What I would like to see”, he adds,“is a method for systemic administration [of the gene] to treat Vol 348 • September 7, 1996including micrometastases”. metastatic cancer,

study, a defective adenovirus vector will be used to deliver the wild-type p53 gene locally. This vector may be more efficient in mediating gene transduction and could achieve higher levels of expression than the retroviral vector. “And in one arm”, says Roth, “we’re using a combination of cisplatin and the vector because a recent study showed synergy” between the two in inducing apoptosis in tumours. “For now, we’re only permitted to do lung cancer trials”, emphasises Roth, “but NCI [US National Cancer Institute] is working with us” to develop gene-therapy protocols for selected cancers of the breast, brain, bladder, ovary, liver, and head and neck. In an accompanying commentary, John Minna and Adi Gazdar (University of Texas Southwestern Medical Center, Dallas, USA) note that “of the approximately one million new cancer cases [of all types] diagnosed in the USA annually, about 50% carry a mutation in one copy of the p53 tumour-suppressor gene and exhibit loss of the other wide-type allele”. Among the 170 000 new cases of lung cancer each year, they write, p53 mutations are found in about 55% of NSCLC cases and in 90% of cases of small-cell lung cancer. As Minna and Gadzar observe, “local p53 therapy represents an early step in a long journey”. But the incidence of p53 mutations in common cancers surely makes it a journey worth continuing. Marilynn Larkin

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