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Investigational Vaccine Boosts Anti-Colorectal Cancer Immunity


NOTTINGHAM, England -- An investigational therapeutic vaccine for colorectal cancer elicited a significant anti-tumor response in 70% of patients treated.

NOTTINGHAM, England, Nov. 15 -- An investigational therapeutic vaccine for colorectal cancer elicited a significant anti-tumor response in 70% of patients treated compared with controls, researchers here reported.

The vaccine, which stimulates production of native tumor-necrosis factor-? (TNF-?), a cytokine with potent anti-tumor activity, was cloned from a patient who survived seven years with colorectal cancer that metastasized to the liver, reported Lindy Durrant, M.D., and colleagues, in the Nov. 15 issue of Clinical Cancer Research.

"This was very unusual, as most patients die within one year of getting liver metastases," said Dr Durrant, a professor of cancer immunotherapy at the University of Nottingham. "I thought if this antibody had helped this patient, if we could clone it, it might help others."

The antibody, labeled 105AD7, is a human monoclonal anti-idiotypic antibody that is structurally and chemically similar to CD55, a cell membrane protein that is expressed at low levels in normal cells. CD55 has been shown to be over-expressed in many cancer cell types, including in up to 80% of colorectal cancers, making it a potential target for specific immunotherapy, the authors noted.

They conducted a randomized tolerability and efficacy study of 105AD7 in 67 patients with resectable colorectal cancers.

The patients, 38 men and 29 women, mean age 66, were randomly assigned to receive the neoadjuvant/adjuvant vaccine pre- and postoperatively, or no vaccinations (controls).

The patients were divided into three groups:

  • Vaccination with 105AD7 100 ?g with alum (aluminum hydroxide) only intramuscularly (28 patients), or
  • 105AD7 100?g with BCG (Oncotice) intradermally at the first immunization with subsequent vaccinations with alum as an adjuvant (17 patients)
  • Unvaccinated controls (22 patients).

The immunizations were given prior to surgery, at three, six, and 12 weeks postoperatively, and then a three-month interval for up to two years.

The 28 patients who underwent postoperative chemotherapy as clinically indicated were suspended from the trial until they had completed their chemotherapy, at which point the immunization scheduled was resumed.

"When the trial was conceived there was concern for the potential immuno-suppressing effect from chemotherapy," the investigators wrote. "Recent studies now suggest these concerns are unfounded."

The patients were monitored with ELISPOT ?-interferon proliferation assay and Luminex cytokine assays.

Patients received a mean of eight immunizations (range two to 13). The vaccine was well tolerated, with no serious adverse events record, and no autoimmune reactions.

Fourteen of 32 patients were judged to have had a positive cytokine response to the vaccinations as determined by the ELISPOT assay, and induced proliferative T-cell responses were seen in 17 out of 40 monitored patients. There was no correlation between the assays however.

"The lack of correlation between the ELISPOT and proliferation assays may reflect the fact that the two methods measure different T cell responses," the authors wrote, "and highlights the importance of multiple readouts in evaluating a potential cancer vaccine."

The responses tended to peak following the initiation of the immunization protocol, and again several months later, after additional vaccinations.

In all, 69% of patients who were immunized produced both TNF-? and granulocyte macrophage-colony stimulating factor (GM-CSF) in response to both the vaccine and to native CD55, the authors noted.

"The immune responses to both the vaccine and CD55 were measurable, adding support to the use of CD55 as a target in cancer treatment," Dr. Durrant said.

Nineteen of the patients died during the follow-up period. Two died of lung cancer, two of myocardial infarction, and the remaining 15 of colorectal cancer. Seven of these patients had advanced disease at the time of their primary surgery. One patient with Duke's stage C disease had an incomplete resection of tumor. Ten patients relapsed during follow-up.

Dr. Durrant noted that the study was not designed or powered to look at the effect of the vaccine on survival.

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