Tumors typically contain lots of hypoxic cells, and hypoxic cells overexpress carbonic anhydrase-9. “Virtually every tumor has large fractions of the tumor mass that overexpress carbonic anhydrase-9, and we have a ligand that binds very specifically to that,” Dr. Low said.
To address the problem of tumor heterogeneity, with different mutations within different areas of the tumor or over time because of genetic instability in the cells, Dr. Low said, “We have a cocktail of about five of these small molecules… they are inexpensive to produce… and they clear very rapidly… and with the cocktail we can hit nearly all cancer cells, even in heterogeneous cancers.”
One limitation, as with standard CAR T cell therapy, is that the technique will still depend on using an individual patient’s T cells to modify through use of a lentiviral vector, so there would not be a universal, off-the-shelf T cell to use for everyone.
The technique and materials have been tested only in animals so far, using tumor-specific ligands for the folate receptor, a prostate-specific membrane antigen, and an antigen overexpressed on neuroendocrine tumors. Dr. Low has intentions to move the technology into human trials. He said the bridging molecules exist in highly purified form, and CAR T cell technology has already been developed by others. “Today we see great success in animal models and have no reason to believe that it won’t translate at least to a good extent to the clinic,” he said. Still, he expects some obstacles along the way and is willing to partner with others working on similar problems as well as large pharmaceutical companies.
The research has been supported by Endocyte, a company that Dr. Low founded and for which he is Chief Scientific Officer and a member of the board of directors. He has filed two patents on the technology, which are held by Purdue University and licensed to Endocyte.