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Innovative Biotechnology Fuses Targeted and Immune Therapies to Kill Treatment-Resistant Cancer Cells

New biotechnology combines targeted and immune therapies to kill treatment-resistant cancer cells.

Targeted therapies specifically bind to and inhibit cancer-causing proteins, but cancer cells can rapidly evolve to counter their action. A second class of drugs, immunotherapies, uses the immune system to attack cancer cells. However, these agents often cannot “see” the disease-causing changes that occur inside cancer cells that appear normal from the outside.

Now, a new study identifies a strategy to overcome these limitations, based on various insights. The research was led by scientists from the Perlmutter Cancer Center at NYU Langone Health.

First, the research team realized that certain targeted drugs, called “covalent inhibitors,” form stable links inside cancer cells with the disease-related proteins they target. They also knew that once inside cells, proteins are naturally broken down and presented as small fragments (peptides) on cell surfaces by major tissue compatibility complex (MHC) molecules. After binding to the MHC, the peptides are recognized as foreign by the immune “surveillance” system if they are sufficiently different from the body’s naturally occurring proteins.

Mutated KRAS-Driven Lung Cancer Cells

Mutated KRAS-driven lung cancer cells (purple) in a genetically engineered mouse lung cancer model. Credit: NCI/University of Utah

Although tumor cells often develop ways to evade immune surveillance, the researchers speculated that a cancer-related peptide target tightly bound to its covalent inhibitor could act as a “flag” displayed by the MHC, which can be recognized by immune proteins called antibodies. The team then engineered such antibodies and combined them with another antibody known to “recruit” T lymphocytes, the “killer cells” of the immune system, to create “bi-specific” antibodies that destroy tumor cells.

“Even when genetic and other changes prevent targeted therapies, they often bind to their target proteins in cancer cells, and this linkage can be used to tag these cells for immunotherapy attack,” said co-author Shohei Koide, PhD. “Moreover, our system conceptually has the potential to increase the efficacy of any cancer drug for which the combination can be demonstrated by MHCs when added to the drug’s disease-related target.” Koide is a professor in the Department of Biochemistry and Molecular Pharmacology and a member of the Perlmutter Cancer Center at NYU Langone.

The first KRAS-blocking drug, called Sotorasib (Lumakras), was granted accelerated approval by the FDA on May 28, 2021. Under approval, sotorasib can be used to treat people with disseminated non-small cell lung cancer (NSCLC). near (locally developed) or distant locations (metastatic) in the body

It was released online today (October 17). Cancer DiscoveryThe new study, a journal of the American Association for Cancer Research, 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 binding to a modified form of the protein KRAS, called p.G12C, in which a glycine building block is mistakenly replaced by a cysteine. This change causes the KRAS protein switch to “stuck in on” and signal abnormal growth. Sotarasib effectively blocks the onset of this active signal, but cancer cells quickly become resistant.

In experiments with KRAS mutant cancer cells grown in a dish (cell cultures), the team’s HapImmuneWB antibodies were recognized, recruited T cells, and resulted in the killing of treatment-resistant lung cancer cells, where sotorasib binds to its target KRAS p.G12C and is imaged by MHCs. The team also developed prototypes that “see” the drug ibrutinib when it binds, as well as bi-specific antibodies that bind to a “marked” peptide with osimertinib, a drug that targets an altered epithelial growth factor receptor seen in other lung cancers. The researchers say BTK has achieved its goal, demonstrating the technology’s “wide potential”.

Usage Screen

The work revolved around the process by which proteins inside human cells are broken down and replaced as part of their normal life cycle. Alongside this cycle, an inspection system works, in which protein fragments are delivered to the surface of a cell. T cells examine these displayed complexes and may notice, for example, when a cell displays viral proteins for a sign that the cell has been infected with a virus. T cells then direct the killing of virally infected cells.

On December 18, 2020, the FDA approved osimertinib (TAGRISSO) for adjuvant therapy after tumor resection in patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations.

In some cases, the immune system can recognize cells with cancerous changes in them by the proteins they show on their surfaces. However, because cancer-causing proteins arise from normal proteins, the differences between cancerous and normal parts are often very slight, the system has difficulty distinguishing them. Even when patients develop T cells that can see these small differences, tumors respond with mechanisms designed to “run out” of anti-tumor cells. In trying to counteract these mechanisms, the team’s key finding was that among the proteins displayed by MHCs are fragments that carry drugs that are taken up by cells and can be targeted by antibodies.

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. Often there is a strict match between MHC/HLA strains and antibodies raised to interact with certain T cells, potentially limiting the number of patients that can be treated with this approach. The new study showed that the team’s antibodies recognize more than one type of MHC/HLA and therefore could, in principle, be deployed in the 40-50 percent of the US patient population with tumors carrying KRAS p.G12C.

“Our results also show that antibodies bind to drug molecules only when presented on cells by MHCs and can therefore be used in combination with a drug,” says Benjamin G. Neel, MD, Director of NYU. Langone Health’s Perlmutter Cancer Center. “When used with such antibodies, a particular drug should only mark cancer cells, not block them completely. This creates the possibility of using potentially lower doses of the drug to reduce the toxicity sometimes seen with covalent inhibitors.”

Going forward, the research team plans to examine their platform in live animal models and use more drug pairs and disease-related protein fragments they target.

Reference: “Creation of MHC-restricted neoantigens by covalent inhibitors that can be targeted by immune therapy” Oct 17, 2022 Cancer Discovery.
DOI: 10.1158/2159-8290.CD-22-1074/709728

Along with Koide and Neel, the study was led by Kiyomi Araki, Akiko Koide, James Hayman, Padma Akkapeddi, and Injin Bang, as well as first authors Takamitsu Hattori and Lorenzo Maso from the Perlmutter Cancer Center. The work was supported by National Institutes of Health grants R21 CA246457, R21 CA267362, R01 CA248896, as well as Perlmutter Cancer Center Support grant P30CA016087.

Hattori, Maso, S. Koide, A. Koide, and Neel are listed as inventors of patents pending on the work. NYU has entered into a research and options agreement with ATP Research and Development to develop these inventions and potentially establish, license, and commercialize a startup company co-founded by Neel and S. Koide. Neel owns shares in Northern Biologics, LTD, Navire Pharma; and Lighthouse Therapeutics, which holds equity and receives advisory fees from Arvinas, Inc., Recursion Pharma, and the GLG group. It also receives research funding from Repare Therapeutics. S.Koide is a co-founder and a stakeholder in Revalia Bio; and Puretech Health receives research funding from Argenx BVBA and Black Diamond Therapeutics. These relationships are managed in accordance with NYU Langone’s policies.

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