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Immunotherapy in high-risk pediatric sarcomas shows promising response

PHILADELPHIA Based on a pilot study in children with sarcoma, researchers at the National Institutes of Health (NIH) believe that immunotherapy could prove beneficial in treating high-risk forms of this cancer.

The researchers tested a novel dendritic vaccine as well as a standard flu vaccine to potentially strengthen the immune system post chemotherapy. Their findings, published in the August 1 issue of Clinical Cancer Research, a journal of the American Association for Cancer Research, show that although the dendritic vaccine they tested did not perform as well as hoped, children participating in the study responded well to the standard flu vaccine suggesting that a strategy to bolster immune function in these patients holds promise for fighting their cancer.

Researchers also found that survival in these patients was at the higher end of what is generally seen with recurrent and/or metastatic Ewing's sarcoma (ESFT) or alveolar rhabdomyosarcoma (AR) the two sarcomas tested in this single arm study. The 22 enrolled patients who did not receive immunotherapy had a 31 percent five-year overall survival, compared to 43 percent five-year survival in 30 patients who ultimately received the novel immunotherapy.

Although the study is small, these early findings are promising, says the study's senior investigator, Crystal Mackall, M.D., of the National Cancer Institute's (NCI) Pediatric Oncology Branch. "We need new therapies. While outcomes overall for these tumors have improved during the past 40 years, there has not been substantial improvement for patients with metastatic or recurrent disease. This study shows that immunotherapy is safe and well tolerated, and could ultimately be beneficial for this high risk population. Mackall calls the study a rational approach to improving treatment of ESFT and AR. "We now know that the immune system of patients recovering from chemotherapy is malleable, so we just need to find the best immunologic approach to exploit this window of opportunity," she said.

Both ESFT and AR develop due to chromosomal translocations, which fuse a gene from one chromosome to a different chromosome. The dendritic vaccine included peptides derived from each patient's individual cancer in a way that was designed to alert a patient's immune system to the unique genetic alteration on the cancer cells.

In this clinical trial of 52 patients, researchers attempted to use immunotherapy as "consolidation" therapy that is, after standard therapy provided a remission. Patients underwent aphaeresis to harvest blood lymphocytes that were then frozen. From this, dendritic cells were later extracted. These are cells that present an antigen to T cells and other immune system fighters in order to elicit a response.

All patients then had chemotherapy, radiation or surgery, as appropriate, and in some cases a stem cell transplant to induce remission. The 30 patients who initiated immunotherapy received a common flu vaccine, as well as their own lymphocytes and their own dendritic cells, which had been infused with tumor antigens. Some of these patients also received interleukin-2, which stimulates activity of T cell lymphocytes.

"The good news was the surprisingly nice T cell response patients had to the flu vaccination, even relatively soon after completing chemotherapy," Mackall said. "That shows that the general idea of using immunotherapy following chemotherapy to prevent recurrence is not a flawed one. Chemotherapy depleted the immune system, but we could restore it."

The bad news, she added, is that the dendritic vaccine "was not very immunogenic. We have a long way to go to optimizing this vaccine." Current studies are underway to test a new version of the vaccine, which utilizes more mature dendritic cells and tumor lysate in lieu of the translocation peptides. Ultimately, effective immunotherapy requires that one is capable of reproducing a strong and sustained immune response to tumor antigens," she said.

Mackall also notes that the vaccine in this trial was tested in patients whose cancer had recurred or metastasized. If the favorable safety profile continues and the efficacy of the vaccine is improved with the subsequent versions, one could ultimately consider the use of immunotherapy to consolidate remission in lower risk populations.


Contact: Jeremy Moore
American Association for Cancer Research

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