Informed optimism

Cancer immunotherapy has been in the doghouse of ideas for years, based on the failure of clinical trials too numerous to count. As a result, attitudes toward the concept have swung from unbridled enthusiasm to deep despair.

The upcoming meeting of the American Society of Clinical Oncology on June 2-6 in Atlanta may begin to change views, as it opens a stretch of clinical milestones that should make 2006 an important year for these therapies.

Indeed, several companies will have at least initial Phase III data this year, including Genitope Corp., Dendreon Corp., Favrille Inc. and Therion Biologics Corp. At least two companies - Dendreon and IDM Pharma Inc. - are planning regulatory submissions, and if Favrille's response data are good, the company could apply for accelerated approval.

But many immunotherapies in the clinic, and many of the trials, were designed without the benefit of today's knowledge. And the results of Antigenics Inc.'s Phase III trial in kidney cancer earlier this year illustrate the frustrations of developing these products and the reasons investors have grown impatient.

The company's Oncophage vaccine missed the primary endpoint of recurrence-free survival because it turned out that it was harder than anticipated to identify patients who met the enrollment criteria of no residual disease or metastases at baseline. As a result, it's hard to draw any conclusions about the vaccine itself (see BioCentury, March 27).

Indeed, immunotherapies can't be expected to show efficacy in the same kinds of trials used for traditional cytotoxics. "These are the typical hurdles of a new paradigm and a new path," said Garo Armen, chairman and CEO of Antigenics (AGEN, New York, N.Y.). "If you are faint-hearted, this isn't for you."

Despite the disappointments, it may be time to shift gears to informed optimism, as a feedback loop between incremental advances in the understanding of the immune system and data from clinical trials has improved the design of therapies and trials alike.

"The early trials typically were single-agent, 'swing for the fence' approaches that basically hoped for a miracle to happen - which did not," noted Arthur Krieg, SVP of R&D and CSO at Coley Pharmaceutical Group (COLY, Wellesley, Mass.). "I think a key advance may be the counterintuitive point that the repeated failures have forced those remaining in the field to be more realistic, and also more clever in finding combination approaches that can yield synergistic improvements in outcome."

Jean-Loup Romet-Lemonne, chairman and CEO of IDM (IDMI, San Diego, Calif.), sounded a similar theme: "We need to be careful not to be disappointed with the death of dinosaurs. We need to learn from them."

In fact, the accretion of knowledge has led to a qualitative shift in thinking about how to design and test cancer vaccines. This includes a better understanding of the immune system and cancer biology, more insight into the combination of components required to create an effective vaccine, and better ideas about how to design trials to show efficacy and which patient populations to test.

First, it has become clear that designing and enrolling the kinds of trials suitable for showing efficacy with traditional cytotoxic drugs makes no sense.

In addition, the debate earlier in the decade over whether it was more important to elicit cellular immunity mediated by T cells or humoral immunity mediated by B cells appears to

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