A Model for Predicting the Risk of Cancer Consequent to Retroviral Gene Therapy

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Abstract
Theoretical estimates of the risk of cancer resulting from accidental insertion of retroviral gene therapy vectors into oncogenically vulnerable genomic sites may prove an important supplement to experimentally derived data in estimating risk/benefit ratios for future gene therapy trials. We have approached risk assessment by considering either a single vector insertion event or a single natural mutation to be potentially oncogenic, should either occur in a cell that would otherwise end with one less than the total number of mutations required for frank neoplasia. Estimates of the relative probabilities of these two phenomena yield a relative risk assessment, which in conjunction with epidemiologic data on natural cancer frequencies can be converted into an assessment of absolute risk. This approach yields an estimated range of relative risk over 10 years of about 1.00000026 to 25 for cells bearing single copies of inserted vectors; the upper limit is higher for multiple copies. These estimates, if accurate, imply that small experimental human or animal gene therapy cohorts will rarely, if ever, manifest vector-related cancers and that more precise future risk assessments will require additional data on natural and vector-induced mutation rates. Cancer secondary to mutations induced by insertion of gene therapy vectors into vulnerable genomic sites may be too uncommon to appear in small experimental cohorts but frequent enough to pose a threat to more widespread applications of gene therapy. The approach presented below permits an assessment of such small but nonnegligible risks by comparing the predicted ability of vector-induced and natural mutations to complete the process of oncogenesis in cells that would otherwise remain only partially transformed. The resulting estimate of relative risk can be converted into an absolute risk assessment by combining it with epidemiologic data on natural cancer frequencies.

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