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A new approach to targeted immunotherapy developed by researchers at the Ludwig Center, Lustgarten Laboratory, and Bloomberg ~ Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center uses novel antibodies against genetically engineered proteins to target cancers.
The researchers focused their immunotherapy approach on alterations in the common cancer-related p53 tumor suppressor gene, the RAS tumor promoter oncogene, or T cell receptor genes. They also tested the therapy on cancer cells. in the laboratory and on animal tumor models. Their findings are reported in three related studies published March 1 in Science Immunology, Science and Science Translational Medicine.
Two of the three research studies – led by Jacqueline Douglass, MD, Ph.D. candidate at Johns Hopkins University School of Medicine and Emily Han-Chung Hsiue, MD, Ph.D., postdoctoral fellow at Johns Hopkins – report on a Precision medicine immunotherapy approach that specifically kills cancer cells by targeting fragments of mutant proteins presented as antigens on the surface of cancer cells.
Although common to all types of cancer, p53 mutations have not been successfully targeted with drugs. Genetic alterations in tumor suppressor genes have often resulted in their functional inactivation.
“Traditional drugs aim to inhibit proteins. Therefore, inhibiting an already inactivated tumor suppressor gene protein in cancer cells is not a feasible approach,” says Hsiue, lead author of the scientific paper. .
Targeted drug therapies have been most effective against oncogenes, but most RAS gene mutations have been notoriously difficult to target. Instead of drugs, the researchers decided to target these genetic alterations with newly developed antibodies.
Conventional antibodies require an antigenic target on the cell surface – most often a protein that looks like a foreign invader to the immune system. But proteins produced by mutant oncogenes and tumor suppressor genes are inside cells, beyond the reach of conventional antibodies. However, proteins are systematically broken down in cells, generating fragments of proteins called peptides.
“These peptides can be presented to the cell surface when complexed with human leukocyte antigen (HLA) proteins,” says Katharine Wright, postdoctoral fellow at Johns Hopkins University School of Medicine and lead author of the Science Immunology article. . “Mutated proteins in cancer cells can also be degraded and generate mutant peptides presented by HLA molecules. These mutant HLA peptide complexes serve as antigens and mark cancer cells as foreign to the immune system.”
Developing powerful antibodies that specifically recognize the amino acid difference between mutant proteins bound to HLA molecules is an extremely difficult task. To address this, the researchers used a five-step approach – combining cutting-edge research technologies such as mass spectroscopy, genetics, and X-ray crystallography that analyze cells at the molecular level – and immunological techniques to develop a therapeutic strategy that targets these antigens.
They have developed a therapeutic strategy in the form of bispecific antibodies, comprising a component that specifically recognizes cancer cells and another component that recognizes immune cells and brings cancer cells and immune cells together. In laboratory and animal tumor cell models, this resulted in the destruction of tumor cells.
“This therapeutic strategy depends on a cancer containing at least one p53 or RAS alteration and the patient having an HLA type that will bind to the mutant peptide to present it on the cell surface,” explains lead author Shibin Zhou Ph.D. , associate professor of oncology and director of experimental therapeutics for the Ludwig Center at Johns Hopkins and study leader.
Over the past five years, researchers have worked to overcome a variety of technical hurdles in an effort to develop antibodies that only recognize mutant cancer gene fragments and not normal cells. To prove that their antibody was specific to mutant antigens, the researchers used CRISPR (evenly spaced short palindromic repeats) technology on cancer cells to modify specific mutations in target genes or disrupt the HLA type responsible for peptide presentation. mutants. Bispecific antibodies did not drive T cells to cancer cells when these genetic manipulations were done.
In the Science Translational Medicine article, the researchers report that the powerful bispecific antibody approach they developed could also be used for the treatment of T-cell cancers. In animal models of T-cell cancers, the researchers have showed that their approach selectively kills cancerous T cells while sparing the majority of healthy T cells. An oncology researcher at Johns Hopkins University School of Medicine and lead author Suman Paul, MBBS, Ph.D., was inspired to conduct this study while treating a patient with this type of cancer.
“The patient had skin lesions so painful that the clothes were intolerable, and like other patients with this disease, had a grim prognosis,” says Paul, who emphasizes the need for better therapies.
“B-cell lymphoma immunotherapies have worked well with therapeutic agents such as CAR T cells and bispecific antibodies that kill both healthy and malignant B cells. These treatments targeting B cells are effective because humans can tolerate the loss of healthy B cells. But a treatment approach that depletes healthy and cancerous T cells would not work in T-cell cancer patients because healthy T cells are necessary for the human immune system to function properly. The erasure of healthy T cells as well as cancerous T cells would essentially result in a disease like AIDS. “
By targeting cancer-associated T cell receptors, the Science Translational Medicine study described a new strategy that killed cancerous T cells with the loss of only a small fraction of healthy T cells.
Another type of immunotherapy, called checkpoint inhibition, works well in patients whose cancer has already caught the attention of immune cells. Medicines called checkpoint inhibitors can successfully stimulate this immune response. Many cancers, such as pancreatic cancer and ovarian cancer, do not attract immune cells. However, these cancers very frequently contain RAS and / or p53 mutations, offering the opportunity for new forms of immunotherapy not dependent on natural immune responses, Zhou explains.
Researchers claim that one of the main advantages of this type of immunotherapy is that it has the potential to work widely on all types of cancer, provided the patient has the mutant p53 or RAS gene and a corresponding HLA type. , and that the therapeutic agent used should be relatively simple to produce.
“This is a commercially available reagent, not a therapy requiring manipulation of each patient’s own T cells, so it is a much easier product from a manufacturing standpoint. potentially be used for any patient who has the appropriate mutation and Type HLA, ”says Sandra Gabelli, Ph.D., associate professor of medicine at Johns Hopkins University School of Medicine and co-author of the study.
The researchers say the next steps are to see if the strategy can be applied to other genetic changes in p53, KRAS and other cancer driving genes.
“We intend to develop a large number of bispecific antibodies that would target such genes,” says Alex Pearlman, MD Ph.D. student and co-author of the three studies. “Although any individual bispecific antibody would target a small fraction of cancer patients, a series of antibodies would allow the treatment of many patients.”
Researchers are also concerned about off-target effects in which antibodies mistakenly bind to a similar target in vital tissue or organ, a side effect that has been seen in other types of immunotherapies. Resistance to treatment is another concern the research team will investigate, as such resistance often occurs in patients treated with any treatment, including immunotherapy.
These findings build on paradigm-shifting cancer genetic findings that emanated from the Ludwig Center lab, led by Bert Vogelstein, MD, Clayton professor of oncology and Howard Hughes Medical Institute researcher, and Kenneth Kinzler, Ph .D., Professor of oncology at Johns School of Medicine, Hopkins University. In 1989, Vogelstein’s team revealed that the p53 gene was the most commonly mutated gene in cancer. Mutations in the p53 gene are an important step in converting premalignant cells into cancer cells. As the first to reveal the genetic blueprint of cancer, the team at the Ludwig Center have shown that cancers result from the gradual build-up of genetic alterations in oncogenes and tumor-suppressor genes, starting with colorectal cancer. , then expanding their findings to a wide range of cancer types. .
Reference: Douglass J, Hsiue EH-C, Mog BJ et al. Bispecific antibodies targeting RAS mutant neoantigens. Sci. Immunol. 2021; 6 (57). doi: 10.1126 / sciimmunol.abd5515
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