Researchers from the Perlmutter Cancer Center at NYU Langone Health have detailed a new approach to cancer treatment that seeks to overcome tumors’ evasion of immune surveillance.
The investigators show that drugs form stable attachments with the disease-related proteins they target inside cancer cells. The researchers used prior knowledge that proteins are naturally broken down once inside the cell and the resulting peptides are bound 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.
To take advantage of this, the Perlmutter team recognized cancer-related peptides bound to their covalent inhibitors could act as an MHC marker that could be recognized by immune antibodies, then engineered antibodies to recognize these proteins and joined them with another antibody known to recruit natural killer (NK) cells to create a bi-specific antibody that destroyed tumor cells.
The results of this approach applied to two drugs—sotorasib and osimertinib—were published today in the AACR journal Cancer Discovery.
“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,” said 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.”
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. Sotorasib effectively blocks this activated signal to start, but cancer soon become resistant to the treatment.
In experiments with KRAS mutant cancer cell cultures, the team applied its approach, called HapImmune antibodies, and found they recruited T-cells and killed treatment-resistant cancer cells in which sotorasib attached to its target, KRAS p.G12C, and was displayed by MHCs. The teams then applied this approach to the drug osimertinib with similar results. Due to these two experimental successes the Perlmutter team believes their new bi-specific antibody approach shows broad potential to overcome immunotherapy resistance.
The current study also found that the team’s platform was effective against KRAS p.G12C mutant cells with different MHC types, also called human leukocyte antigen (HLA) supertypes. Usually, there is a strict pairing between MHC/HLA types and antibodies built to interact with certain T cells, which could potentially restrict the number of patients that could treated by this approach. The new study showed that the team’s antibodies recognize multiple MHC/HLA types, and so, in principle, could be deployed in 40–50 percent of the US patient population with tumors bearing KRAS p.G12C.
“Our results further show that the antibodies attach to drug molecules only when presented by MHCs on cells, and so could be used in combination with a drug,” says study co-corresponding author Benjamin G. Neel, MD, PhD, director of NYU Langone Health’s Perlmutter Cancer Center. “When used in combination with such antibodies, a given drug would only need to flag cancer cells, not fully inhibit them. This creates the possibility of using drugs at lower doses, potentially, for reducing the toxicity sometimes seen with covalent inhibitors.”
Follow up research will be to study this new therapeutic approach in live animals models, as well as more pairs of drugs and the disease-related protein fragments they target.