Vaccines

Are Cancer Vaccine Trials Being Disregarded Too Quickly?

Allison Gandey

July 5, 2007

Results of trials testing cancer vaccines have been largely disappointing, yet experts report that patients receiving immunization tend to survive longer and respond better to subsequent therapy.

"Clinical data are providing evidence that patients are living longer following vaccination, despite the fact that trials do not show the vaccines can induce the immune system into shrinking tumors," lead author Jeffrey Schlom, PhD, chief of the laboratory of tumor immunology and biology at the National Cancer Institute, in Bethesda, Maryland, told reporters.

"The data suggest that the scientific community and regulatory committees ought to rethink the design of clinical vaccine trials and our current approach to measuring the effectiveness of a cancer vaccine."

The group's review article appears in the July 1 issue of Clinical Cancer Research. The investigators explain that it may be more useful to think of the effectiveness of a vaccine in terms of the response of the patient rather than the effect on the tumor.

While the Response Criteria in Solid Tumors (RECIST) experimental standards work well in evaluating therapies that are toxic to tumors such as radiation or chemotherapy, they are less effective in measuring more subtle systemic effects of immune response, the authors suggest.

In a news release highlighting the findings, Dr. Schlom said the evidence suggests that vaccines are in effect priming the immune system. "Vaccines are not passive," he noted. "They induce a dynamic process of immune response that, in many cases, may keep the tumor in check and enhance the effectiveness of subsequent therapies."

No therapeutic cancer vaccine has been approved to date by the US Food and Drug Administration. The current review covered 5 prostate cancer vaccine trials and showed that patients who are immunized appear to respond better to subsequent chemotherapy or hormone treatment.

But the end points of the trials did not include long-term survival and focused instead on the effect of treatment on the tumor itself. According to the researchers, since they didn not achieve their primary end points, these vaccines may be abandoned despite their real therapeutic value in prolonging survival.

Will Vaccines Prolong Survival?

Unlike preventive vaccines such as the flu shot or those developed to protect against human papillomavirus, cancer vaccines treat existing disease. Included in the review were 2 cell-based vaccines sipuleucel-T (Provenge, Dendreon Corp) and Cell Genesys Inc's GVAX. Three of the trials evaluated engineered poxvirus vectors.

The researchers point out that they looked at only a small number of vaccines showing evidence of clinical benefit. Allogeneic whole-tumor cells, peptide- or protein-pulsed antigen-presenting cells (including dendritic cells), recombinant DNA and viral vectors, and recombinant Saccharomyces (yeast) are all currently in active clinical-trial development.

There is a wide array of newly defined potential tumor-associated targets primed for cancer vaccine development, including neoplastic or tumor progression processes, they add. As the field of cancer-vaccine therapy matures, long-term safety profiles of several of these agents will most likely be realized.

At that juncture, vaccines may well also be used in neoadjuvant settings and in certain preneoplastic conditions, they suggest.

While the review focused on prostate cancer vaccines, the researchers say these trials are examples of ongoing progress in similar vaccine therapies for lymphoma, melanoma, and pancreatic, lung, and other types of cancer. Why are vaccines enhancing outcome to subsequent therapies?

The investigators suggest this may be due to several factors. The subsequent therapy may:

Reduce suppressor cell populations, allowing for enhancement of prior established T-cell responses.

Lyse some tumor cells that are then, as a consequence of cross priming, activating relatively dormant T cells to elicit an antitumor response.

Enhance host T-cell activity.

Alter the phenotype of tumor cells.

"Skepticism is an important component of the scientific process, and it should be an integral component in the development of any potential new therapy," write Dr. Schlom and his team. "Many are very much aware, for instance, of those skeptics and 'naysayers' who, for a decade, dismissed monoclonal antibody-mediated cancer therapy."

There are now 7 monoclonals approved for cancer management. "This too may well be the case for cancer vaccines. Although skepticism is important, there are also those who realize the need for paradigm shifts in both exploiting vaccine combination therapy and analysis of patient benefit in terms of survival (with minimal toxicity) as the appropriate clinical trial end point."

Clin Cancer Res. 2007;13:3376-3782.

Our Source: Medscape

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