Monitoring Biological Effects

When we began designing the phase I study in 1995, we attempted to select an MBAD that would serve as the basis for establishing dosages for future phase II trials. Our reasoning was based on the assumption that the molecular effect (HER2 down-regulation) triggered by the therapeutic gene (E1A) would be the dominant mechanism of antitumor activity. Our thought was that E1A may downregulate HER2 at dose A, but to induce rapid apoptosis, it may have to be given at a higher or lower dose. Alternatively, low E1A gene expression may induce strong antitumor activity by triggering a bystander effect, which could depend on the dose of the therapeutic gene or on a particular genetic abnormality in the cancer cells.

However, in the end, we abandoned the attempt to use MBAD to define the dosages for the phase II trial. Despite the confirmation that E1A had a biological effect at a dose lower than the MTD, the traditional MTD was used instead, for the following reasons. First, the possible therapeutic mechanisms suggested by the preclinical experiments do not always match the antitumor mechanism in clinical settings. Research by us and others suggested that E1A could reverse the malignant phenotype through more than one mechanism,(e.g., by triggering the host immune system), inducing apoptosis, inducing tumor lysis, and suppressing metastatic capability (41). Even if antitumor activity could be detected in the treated patients, other activities associated with the E1A/DC-Chol complexes could have contributed to the antitumor effect in addition to the down-regulation of HER2. In attempts to clarify these issues, we studied several indices in several types of samples (i.e., tumor, intracavitary fluid, and serum) in the phase I trial. For example, we studied apoptosis and Ki-67 expression (an index of cellular proliferation) because E1A is known to induce apoptosis and suppress proliferation of certain cell types; we also measured cytokines (TNF-a and interferon [IFN]-y) in the cavitary fluid because E1A is suspected of sensitizing cells to TNF-a.

Another problem was that assays to measure apoptosis, Ki-67, and cytokines had not been validated with clinical samples, and so any retrospective analyses of samples collected prospectively from phase I participants were limited by the possibility that the samples may not have been collected under the appropriate conditions or at appropriate times. Hence, the appearance of apparent associations among variables generated did not confirm the molecular mechanism of E1A; rather, they generated new hypotheses that needed to be tested in future trials.

By this reasoning, an accurate and useful MBAD for use in phase II trials would be difficult—if not impossible—to choose. In gene therapy trials for cancer, the threshold for triggering the molecular effect of a therapeutic gene is generally not known. This does not mean that one should not make an effort to determine these factors. Rather, a tremendous effort is needed to identify biological markers and at the same time come up with assays that can allow those markers to be monitored in a scientifically valid and reproducible manner.

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