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Dendritic Cell Cancer Vaccines
Woondong Jeong is a hematology/oncology fellow, Brier Rolando is an internal medicine resident and Robert G. Lerner is Professor of Medicine, all at New York Medical College.
Drs. Jeong, Rolando and Lerner will discuss the unlabeled use of autologous dendritic cells and a recombinant fusion protein for the treatment of hormone-refractory prostate cancer.
An otherwise healthy 56-year-old African-American male visited his doctor because of urinary hesitancy and sensations of incomplete voiding. Upon complete examination, including CAT scans and MRI, he was found to have a tumor in his prostate but no evidence of spread to other parts of his body. Surgeons successfully removed the prostate and the patient was discharged.
Over the next two years, the patient did well with no evidence of disease. But in the third year after his surgery, as part of his routine follow-up, the patient's serum PSA (prostate specific antigen), a marker for prostate cancer, was found to be significantly elevated. Further examinations revealed that the cancer had returned. The patient was treated with hormone therapy and his PSA soon returned to normal. But within a year, however, the PSA started to rise again, an ominous sign, and new sites of cancer were detected. Because the standard hormone treatment had failed, the patient was given an experimental vaccine derived from the patient's own cells.
The experimental therapy uses a so-called "dendritic cell" vaccine (Provenge®) developed by Dr. Riner Laus, Dendrion Corp., based in Seattle, which showed much promise for prostate cancer patients in early Phase I and II trials. Though still in the final randomized Phase III trial and not yet approved by the FDA, medical researchers can offer the vaccine to patients who meet certain criteria.
What Is a Dendritic Cell?Dendritic cells (DC), derived from bone marrow, are found in the blood or in tissues. They are the single most central player in all immune responses. They trigger the systems that help the body fight off infections and any other foreign body. Specifically, their activity helps mobilize the T cells whose job it is to lead the attack against invading germs.
But DCs alone are not enough to start an efficient and effective T cell response. Other stimulatory signals are needed before the T cell response goes into high gear. And if the DCs act by themselves, without these helpers,they can even have the opposite effect on T cells — weakening their response.
In cancer treatment, the goal of researchers is to make use of the DC's ability to trigger the T cell response, in this case to treat the cancer cell as a foreign invader that needs to be repelled and neutralized. The problem is, however, that cancer cells don't set off the immune system's alarm bells — they are not really viewed as invaders. But what if, scientists speculated, they could fuse DCs with parts of cancer cells so that the new combination would trigger T cell response that would specifically seek and destroy the cancer cells?
Designing a DC VaccineWorking with a protein they engineered by combining a component of the prostate cell enzyme with other T cell stimulants, scientists then coated the patient's own dendritic cells with this combination protein, and in so doing started a "natural" immune response. The immune response mobilized the patient's T cells to attack the patient's prostate cancer cells. Overall the treatment was well tolerated. There was no treatment-related bleeding, liver or kidney problems. The only side effects were mild fever, muscle pain, fatigue and some minor urinary complaints. The lack of severe side effects is not surprising. After all, the patient's own cells, rather than a completely foreign cell or chemical, are being used to stimulate the immune response.
In one trial of of 31 patients with prostate cancer, three patients had a more than 50% decrease in PSA levels, and three patients had 25% to 49% decreases in PSA. Disease progression slowed in the treated patients — the median time to disease progression was 31.7 weeks for patients who received more than one hundred million (100 x 106) cells per infusion compared with 12.1 weeks for patients who received fewer cells. The difference between the two groups was statistically significant.(1)
In ProgressCurrently, a randomized placebo-controlled phase III trial of Provenge® dendritic cell vaccination for treatment of patients with advanced prostate carcinoma is ongoing. Other companies, such as Northwest Biotherapeutics and IDM Biotech, are also conducting trials of dendritic cell vaccine therapy. Immunotherapy not based on dendritic cells is also being developed, such as antibodies directed against tumor antigens.
December 1, 2005
(1) Comment has been made