Redirecting Antiviral Immune Responses to Eliminate Melanoma with APECs 

While immunotherapy has greatly improved the survival for patients with melanoma of the sun-exposed skin, especially for those with advanced disease, at least half of the patients receiving this form of treatment still do not benefit. In addition, patients with forms of melanoma that are not caused by sun exposure, such as melanoma on the palms, soles, or under the nails, melanoma of the eyes, and melanoma of our mucosal membranes of for instance nose, mouse, or throat, respond poorly to current immunotherapies. Especially for the latter, an important reason for treatment failure is that the patient’s immune systems only weakly respond to these forms of melanoma. This happens presumably since these melanoma lack the wide-spread DNA damage that is caused by ultraviolet light and that would allow immune cells, especially so-called T cells, to “see”, infiltrate, and destroy the cancer cells. An important recent insight has been that in many forms of cancer, the majority of infiltrating T cells do not recognize the cancer but are so-called bystander T cells. Many of these bystander T cells were activated during past or ongoing common viral infections, circulate in the bloodstream, and are unspecifically recruited to the tumors, where they however do not unfold any activity since they don’t “see” the virus. It would be highly desirable to direct the activity of these bystander cells against the cancer cells, especially in poorly immunogenic forms of melanoma, which could lead to the destruction of these cancers. Our lab is working on a novel antibody-based therapy that aims to deliver small protein fragment of viruses(‘peptides’) to the surface of cancer cells in order to ‘trick’ antiviral bystander T cells into attacking the cancer cells as if they were infected by viruses.

We have already found in a mouse model of head and neck cancer that this form of immunotherapy is highly effective even in tumors that do not respond at all to conventional immunotherapies. Here we propose to develop these so-called antibody peptideepitope conjugates (APECs) for the treatment of those melanoma that fail to respond to current immunotherapies. APECs consist of antibodies that bind to the cancer cell surface and that are loaded with viral peptides. These peptides need to be released from the antibody by cancer cell-expressed enzymes called proteases. A critical aspect of designing APECs for a particular form of cancer is therefore to examine which proteases this cancer expresses. The first part of this project seeks to characterize the proteases active in melanoma, and especially in those forms of melanoma that are not caused by sun exposure and pose the greatest challenge to treatment. In the second part of the project, we will build APECs based on an improved design that will be easier to manufacture for future clinical use and test their therapeutic potential in a mouse model of melanoma, guided by knowledge of the proteases active in this melanoma model.