Stymieing skin cancer

Immunotherapy treatments for cancer have been boosting recovery rates of patients in recent years, but a new study from the Weizmann Institute shows how it’s possible for immune cells to home in on melanoma cancer cells—and destroy them—more effectively than ever.

Today’s immunotherapies involve administering antibodies that unlock T cells’ natural ability to recognize and kill cancer cells, or reengineering these T cells outside the body and returning them in a ‘weaponized’ form. “But none of this will kill the cancer if the immune cells do not recognize the ‘red flags’ that mark cancer cells as foreign,” says Prof. Yardena Samuels of the Institute’s Department of Molecular Cell Biology. 

Groups around the world are searching for such red flags—mutated peptides known as neo-antigens that appear on the cancer cells’ outer membranes. Identifying the particular peptides that present themselves to the T cell can then help develop personalized cancer vaccines based on neo-antigen profiles.

One of the problems in uncovering neo-antigens in cancers like melanoma, however, is that they are presented by a protein complex called HLA–a complex that can come in thousands of versions, even without the addition of cancerous mutations. Indeed, the algorithms often used to search the cancer-cell genome for possible neo-antigens predicted hundreds of candidates. This makes it extremely challenging for pharmaceutical companies to use neo-antigen targeting as the basis of a “one-fits-all” immunotherapy drug.

Now, Prof. Samuels, in a study published in the journal Cancer Discovery together with her PhD student Shelly Kalaora, and in collaboration with Prof. Arie Admon of Faculty of Biology at the Technion, has devised a new way to identify neo-antigens of melanoma cells, together with the specific T cells “primed” to respond to them. Using this method, the team discovered that tumors present many fewer neo-antigens than expected.

The group’s neo-antigen and corresponding T-cell-identification strategies were so robust that their neo-antigen-specific T cells killed ninety percent of the target melanoma cells both on plates and in mice.

In a related finding, Prof. Samuels also demonstrated that cancer cells from different metastases within the same patient have neo-antigen “profiles” that are remarkably uniform. This discovery may eventually contribute to clinical strategies in which doctors would create personalized drug regimens that would stimulate T cells to destroy not just an individual patient’s primary tumor, but secondary malignancies as well.

“Although this research is experimental right now, the findings are highly relevant to clinical research,” Prof. Samuels says. “As almost all the neo-antigens detected in patients thus far are individual and unique to the particular cancerous tissue, they constitute an ideal class of anti-cancer targets. This would be the ultimate ‘personalized’ cancer therapy—a new immunotherapy drug created for every patient.”

Profs. Samuels and Kalaora worked with a team that included Dr. Eytan Ruppin of the National Cancer Institute, USA; Dr. Jennifer Wargo of the University of Texas MD Anderson Cancer Center, Houston; and Prof. Nir Friedman of the Weizmann Institute of Science’s Department of Immunology.

Prof. Yardena Samuels is the head of the EKARD Institute for Cancer Diagnostics and head of the Weizmann-Brazil Tumor Bank. Her research is supported by the Laboratory in the  name of M.E.H Fund established by Margot and Ernst Hamburger; the European Research Council; the Wagner-Braunsberg Family Melanoma Research Fund; the Comisaroff Family Trust; the Rising Tide Foundation; and Paul and Toni Green. Prof. Samuels is the incumbent of the Knell Family Professorial Chair.