Targeted therapies specifically attach to and hinder cancer-causing proteins, but cancer cells can quickly evolve to thwart their action. A second drug class, immunotherapies, harnesses the immune system to attack cancer cells, but these agents often cannot “see” the disease-causing changes happening inside cancer cells, which look normal from the outside.
Now, a new study led by researchers from the Perlmutter Cancer Center at NYU Langone Health describes a strategy to overcome these limitations based on several insights. First, the research team recognized that certain targeted drugs called “covalent inhibitors” form stable attachments with the disease-related proteins they target inside cancer cells. They also knew that proteins once inside cells are naturally broken down and presented as small pieces (peptides) on cell surfaces by major histocompatibility complex (MHC) molecules. Once bound to MHC, peptides are recognized as foreign by the immune “surveillance” system if they are sufficiently different from the body’s naturally occurring proteins.
Although tumor cells usually develop ways to escape immune surveillance, the study authors reasoned that a cancer-related peptide target tightly bound to its covalent inhibitor could act as an MHC-displayed “flag” that could be recognized by immune proteins called antibodies. The team then engineered such antibodies and joined them to another antibody known to “recruit” T lymphocytes, the “killer cells” of the immune system, to form “bi-specific” antibodies that destroyed tumor cells.
“Even when genetic and other changes frustrate targeted therapies, they often still attach to their target proteins in cancer cells, and this attachment can be used to label those cells for immunotherapy attack,” says co-corresponding study author Shohei Koide, PhD, professor in the Department of Biochemistry and Molecular Pharmacology and a member of Perlmutter Cancer Center at NYU Langone. “Further, our system, conceptually, has the potential to increase the efficacy of any cancer drug when attached to the drug’s disease-related target where the combination can be displayed by MHCs.”
Published online October 17 in Cancer Discovery, a journal of the American Association for Cancer Research, the new study tested the researchers’ approach on two FDA-approved, targeted drugs, sotorasib and osimertinib. Recently approved based on a study co-led by NYU Langone researchers, sotorasib works by attaching to an altered form of the protein KRAS called p.G12C, in which a glycine building block has been mistakenly replaced by a cysteine in its structure. This change causes the KRAS protein switch to become “stuck in the on mode” and signal for abnormal growth. Sotarasib effectively blocks this activated signal to start, but cancer cells rapidly become resistant.
In experiments with KRAS mutant cancer cells grown in a dish (cell cultures), the team’s HapImmuneTM antibodies recognized, recruited T cells, and led to the killing of treatment-resistant lung cancer cells, in which sotorasib attached to its target, KRAS p.G12C, and was displayed by MHCs. The team also developed bi-specific antibodies that bound to a peptide “flagged” with osimertinib, a drug that targets an altered form of epithelial growth factor receptor seen in other lung cancers, as well as prototypes that “saw” the drug ibrutinib when linked to its target, BTK, showing the technology’s “broad potential,” the researchers say.
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