Combating cancer through immunotherapy includes approaches from administration of chemotherapy-conjugated antibodies to using bacterial infection to bolster the immune system. Even without external encouragement, the immune system can produce antibodies against cancer cells.
In the Dec. 7, 2004, issue of the Proceedings of the National Academy of Sciences, in a paper available via early online publication, researchers from the Scripps Research Institute and the Scripps Cancer Center in La Jolla, Calif., report on isolating and characterizing antibodies from cancer patients that are specific to metastatic breast cancer cells, and on using such antibodies to retard metastasis in mice.
The researchers searched for those antibodies in B lymphocytes of cancer patients.
"Even after the B cells have stopped making antibodies, there are still low levels of B memory cells around," said Brunhilde Felding-Habermann, associate professor in the department of molecular and experimental medicine at the Scripps Research Institute, and lead author of the study. "It's those memory cells from which you can access what we call the fossil record' of immune surveillance."
Felding-Habermann and her colleagues focused on finding antibodies to the integrin avß3 receptor, because of its role in metastasis. For metastatic colonies to be set up, at least two things must happen: A cancer cell first must hitch a ride in the bloodstream, a process known as dissemination, and later, it must leave the bloodstream and "arrest" in a new target organ. In previous research, Felding-Habermann and her group had shown that the avb3 receptor exists in two states on breast cancer cells, and the activated state specifically supports the ability of breast cancer cells to set up metastatic colonies through interacting with platelet cells.
After isolating RNA from the lymphocytes, the scientists selected antibody fragments that were specific to the activated, arrest-supporting integrin avb3 receptor. Those antibody fragments mimicked the regular ligands of the receptor. Next, they set up something akin to a vein in a test tube, testing the ability of the fragments to affect the binding of metastatic breast cancer cells to a collagen matrix. The fragments interfered with the attachment of cells to the matrix, both in a stationary experiment and under conditions designed to simulate venous blood flow. The antibody fragments also induced apoptosis in circulating metastatic cells.
In a final step, Felding-Habermann and colleagues tested the ability of the fragments to prevent metastasis formation in mice, and to affect already-established metastases. When mice received antibodies at the same time as metastatic cell injections, the antibodies almost completely inhibited the formation of metastases in the lungs. Even when the mice were treated with the fragments after metastases already had been established, the treatment reduced both the number and the size of metastases compared to control-treated animals.
The ultimate hope is that the antibody fragments might be of clinical benefit when administered to patients who do not produce them endogenously. In work that is ongoing, the group is looking into whether the fragments can affect the primary tumor and the initial dissemination stage of metastasis, as well. They also are using molecular engineering to generate whole antibodies and different molecular formats of the antibody fragments to explore their usefulness for diagnosis and therapy of metastatic breast cancer.
In one sense, the results in their totality illustrate one of the fundamental dilemmas of cancer research: While the antimetastasic effects in mice were impressive, the antibodies were not enough to stave off the progression of cancer in the donors. Felding-Habermann is nevertheless optimistic about their potential clinical use. The donor samples used in the current study were anonymous, so it is not possible to correlate them with clinical outcomes, but she wants to do research on another group of patients - those diagnosed with cancer, who chose not to pursue aggressive treatment for one reason or another, and survived for longer than expected periods.
Endogenous antibodies could be one reason for those better-than-expected outcomes, though Felding-Habermann cautioned that "it's a difficult study, because a negative result is very, very difficult to prove. Maybe the experiments weren't sensitive enough, or maybe the patients produced antibodies, but not the ones you were looking for."
And though it is speculative, such antibodies could potentially also explain another puzzling observation of cancer research. At autopsy, a sizable number of tumors are discovered in people that not only died of unrelated causes, but never had clinical symptoms of cancer at all.