Eradication of melanomas by targeted elimination of a minor subset of tumor cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 6; pp. 2474 - 2479
• Main Authors: Schmidt, Patrick, Kopecky, Caroline, Hombach, Andreas, Zigrino, Paola, Mauch, Cornelia, Abken, Hinrich
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.02.2011; National Acad Sciences
• Subjects: Adoptive Transfer; Animals; Antibodies; Antigens, CD20 - immunology; Biological Sciences; Biopsies; Cancer; Cancer therapies; Cell Line, Transformed; Cells; Humans; Lesions; Melanoma; Melanoma - immunology; Melanoma - therapy; Melanoma-Specific Antigens - immunology; Mice; Mice, Mutant Strains; Molecular weight; Natural killer cells; Neoplasm Proteins - immunology; Stem cells; T cell receptors; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1009069108

Proceeding on the assumption that all cancer cells have equal malignant capacities, current regimens in cancer therapy attempt to eradicate all malignant cells of a tumor lesion. Using in vivo targeting of tumor cell subsets, we demonstrate that selective elimination of a definite, minor tumor cell subpopulation is particularly effective in eradicating established melanoma lesions irrespective of the bulk of cancer cells. Tumor cell subsets were specifically eliminated in a tumor lesion by adoptive transfer of engineered cytotoxic T cells redirected in an antigen-restricted manner via a chimeric antigen receptor. Targeted elimination of less than 2% of the tumor cells that coexpress high molecular weight melanoma-associated antigen (HMW-MAA) (melanoma-associated chondroitin sulfate proteoglycan, MCSP) and CD20 lastingly eradicated melanoma lesions, whereas targeting of any random 10% tumor cell subset was not effective. Our data challenge the biological therapy and current drug development paradigms in the treatment of cancer.