Although p53 is the most frequently mutated gene across cancers, it has not been successfully targeted with drugs. RAS, a commonly mutated oncogene, has also proved notoriously difficult to target with traditional targeted therapies. Ludwig Center researchers and colleagues at Johns Hopkins developed an approach to direct an immune attack against cancer cells bearing specific mutations to the two genes.
They did so by adapting an antibody technology to enhance the detection of those mutations and, at the same time, link that recognition to the recruitment of T cells that destroy cancer cells. This was required because both mutations are ordinarily “presented” to the immune system as antigens—protein fragments that stimulate an immune attack—at very low levels by cancer cells. They are therefore typically missed by T cells that should kill the cells that express them.
The Ludwig Johns Hopkins researchers first developed antibodies to recognize the targeted antigens and used them to design bispecific antibodies that recognize two distinct molecules: the antigens bound to the protein machinery that presents them, known as HLA, and a receptor on T cells that is critical to their function. By linking the two, the bispecific antibodies prompted the linked T cells to kill the cancer cells presenting the targeted antigens.
The researchers demonstrated that the immune attack elicited by the bispecific antibodies is restricted to cancer cells bearing mutant antigens, does not affect healthy cells and prompts the destruction of tumor cells in mouse models of cancers driven by the mutations. The researchers also separately devised bispecific antibodies to target T-cell lymphomas, for which they targeted a different molecule expressed on cancer cells and showed that its use led to the massive destruction of cancerous T cells in a mouse model of the disease.
The strategy is dependent on a cancer containing at least one targeted antigen and the patient having the particular molecular machinery—or HLA type—that presents that antigen to the immune system.
Many cancers, such as pancreatic cancer and ovarian cancer, do not harbor enough functional anti-cancer immune cells to be amenable to existing immunotherapies. However, these so-called “cold tumors” often have mutant RAS and/or p53 genes, and the new approach could render them susceptible to immunotherapy.
Another benefit of this type of immunotherapy would be that it has the potential to work broadly on patients who have the HLA subtype and any type of cancer that expresses the mutant p53 or RAS gene. It should also be relatively simple to produce because it does not entail any engineering of patient immune cells. The researchers are now further studying the strategy to assess its potential toxicities and trying to adapt their approach to other gene alterations commonly found in cancer.
This summary is derived from a Johns Hopkins