PITTSBURGH, March 30 -- Like a good coach who reviews game tapes and learns the opponent's weaknesses then chooses the best plays and utilizes the most talented players, University of Pittsburgh researchers have studied the immune response to tumor cells and mapped out a simple yet effective strategy to rally the immune system to recognize and destroy established tumors and prevent future tumors from developing.
In a study published as a "Cutting Edge" article in the April 1 Journal of Immunology, Pitt researchers exposed dendritic cells (DC's) to melanoma or lung carcinoma cells for a short period of time to create a cancer vaccine that effectively prevented tumor development in healthy mice and reduced tumors in 80 percent of mice with established tumors, significantly prolonging their survival.
"Not only is this approach simple, but also it appears to be relatively effective, which suggests that this model could potentially be adapted for use in the clinical setting to treat patients," commented Louis D. Falo, Jr., M.D., Ph.D., assistant professor of dermatology, vice chairman of dermatology at Pitt and member of the University of Pittsburgh Cancer Institute (UPCI). "Using tumor cells taken from patients, we may be able to create a vaccine specific for each individual. So instead of relying on a generic vaccine, we could tailor a vaccine to attack unique features of each patient's tumor."
Previous approaches to tumor vaccination have required that researchers identify and isolate antigens from cancer cells and then develop ways to introduce them to a patient to stimulate an immune response. Because identifying and obtaining tumor antigens is such a difficult task, most cancer vaccine efforts have used the few antigens which already have been identified.
"It has not yet been possible to make "customized" therapeutic vaccines for individual cancer patients," said Dr. Falo. "This new approach potentially offers a single solution to both the problem of tumor antigen identification and antigen delivery.
"By using tumor cells as a source of antigen, this approach eliminates the need to identify and purify tumor antigens," added Dr. Falo. The approach relies on the ability of DC's to "present" antigens they obtain directly from tumor cells to killer T cells, also called cytotoxic T lymphocytes, and other immune cells, that are then capable of recognizing cancer cells and destroying them.
Pitt researchers tested vaccines comprised of DC's that had been fused with tumor cells and DC's that were mixed with tumor cells for 24 hours before injection. By linking a dendritic cell with a lung carcinoma cell, Pitt researchers formed a fused DC-tumor complex that was injected into mice with established tumors. Mice receiving this fusion vaccine rejected their tumors and survived until the end of the experiment (72 days) without any evidence of tumor cells.
Similar findings were observed when researchers vaccinated another set of mice with established tumors using DC's that were simply co-cultured with tumor cells. In contrast, control mice that were injected with either DC's alone or a mixture of DC's and tumor cells that weren't previously co-cultured developed tumors at the same rate as unvaccinated animals and died within 33 days.
"We still don't know the exact mechanism of how the interaction between dendritic cells and tumor cells creates an immunogen that can stimulate immune responses against the tumor, but based on these results it appears that even a brief association between dendritic cells and tumor cells results in a vaccine that can be therapeutic," commented Dr. Falo. "We suspect that the dendritic cells can take up antigens from the tumor, or even pieces of the tumor cells and use them to train the immune system to attack the tumor."
This model suggests treating mice with pre-treated DC's provides long-term protections against tumor recurrence, as well. In fact, three months after these mice were injected with either fused DC-tumor complexes or mixtures of co-cultured DC's and tumor cells, they were able to reject additional injections of lung carcinoma cells. None of the re-challenged mice developed tumors.
"These results suggest that DC's primed by a short interaction with tumor cells can evoke long lasting immunity to the tumor," suggested Dr. Falo.
"One possible advantage of the co-culture vaccine approach over fusion based treatments or other existing tumor cell based immunotherapies is the short time period required to make the vaccine," said Dr. Falo. "Reducing the time interval between excision of a primary tumor and the beginning of treatment can be important because there is less time for tumor cells, which may have already metastasized, to continue to spread."
For additional information about the University of Pittsburgh or UPCI, please access http://www.upmc.edu..
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Journal
The Journal of Immunology