The hidden target - a new cancer immunotherapy?

In the last issue of Science Translational Medicine, a team from the National University of Singapore report the intriguing finding that intracellular tumor antigen–specific monoclonal antibodies could inhibit tumor growth and metastasis and prolong survival of tumor-bearing mice. As this is a dogma-challenging discovery, a lot of questions naturally arise. Just how the antibodies directed to intracellular proteins managed to effect cell toxicity? Are these results possibly reproducible in humans? Could this be a whole new monoclonal antibody-based strategy for cancer treatment? Antibody-based therapies are targeted at specific molecular elements of cells (often receptor proteins) and thus have improved safety over standard chemotherapy regimens, which has resulted in extended survival and improved quality of life for cancer patients with conventional treatment refractoriness. Because antibodies are too large to cross intact cell membrane and access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are found within the cell (such as intracellular phosphatases/kinases and transcription factors) and have therefore not been targets for usual antibody therapies. In their proof-of-concept experiment, researchers have treated animals with antibodies directed at intracellular proteins or with endogenous antibody formation by vaccination with these protein products. As a result, they obtained in vitro and in vivo tumor growth inhibition with this strategy. Theoretical possibilities to explain these unexpected effects could be: (1) a small fraction of intracellular antigens may be released due to necrosis or cancer cell lysis; (2) some intracellular antigens may be externalized and displayed on the surface of cancer cells by unconventional secretion; (3) binding of antibodies to surface-exposed intracellular proteins may then trigger immune responses such as ADCC to destroy the cancer cells; (4) antibodies could be taken up by the cancer cells in an antigen-specific manner; (5) complement-mediated events may also be involved. Truly, this effect remains a mistery to be explained, but with plenty of promise if could be confirmed and translated to human patients.
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