British scientists who announced last week their discovery of a new type of cancer-killing T-cell have entered a partnership with a biotechnology company pioneering the use of Dark Antigens to developT-cell receptor (TCR)-based immunotherapies and off-the-shelf cancer vaccines. The resultthey hopewill be a one-size-fits-all cancer therapy.
Last Monday, scientists at Cardiff University in the UK announced they had identified a new type of killer T-cella T-cell clonethat recognized and killed multiple different types of human cancer, while ignoring healthy, non-cancerous cells. The discovery, researchers said, offers hope of a universal cancer therapy. The researchers reported in Nature Immunology that these T-cells attacked many forms of cancer from all individuals. The T-cell clone killed lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer.
Less than a week later, the Cardiff researchers have announced they will enter a partnership with Ervaxx to eventually bring their discovery to patients.
Cardiff University Professor Andrew Sewell
The Cardiff University T-cell modulation group, within the Division of Infection and Immunity, studies all areas of T-cell biology including T-cell genetics, molecular biology, protein chemistry, crystallography and cell biology. The group aims to understand the genetic, biochemical and cellular mechanisms that govern T-cell responses in human diseases, such as HIV, EBV, tuberculosis autoimmunity and cancer.
Professor Andrew Sewell with Research Fellow Garry Dolton
Ervaxx is a UK biotechnology company based in London and Oxford, which is pioneering a new approach to developing targeted immunotherapies for treating and preventing cancer. These immunotherapies, including T-cell therapies, are based on new cancer targets (Dark Antigens) that derive from the dark matter of the genome, which are generally silenced in normal tissue but can become selectively activated in cancer.
T-cell therapies for cancer are the latest paradigm in cancer treatments. Current therapies include CAR-T and TCR-T, where immune cells are removed, genetically-modified and returned to a patients blood to seek and destroy cancer cells. Current therapies are personalized to each patient, target only a few types of blood cancer and have not been successful for solid tumors, which make up the vast majority of cancers.
In contrast, the newly discovered cell attaches to a molecule on cancer cells called MR1, which does not vary in humans.So not only would the treatment work for most types of cancer, said Professor Andrew Sewell, an expert in T-cells and a lead author on the study from Cardiff Universitys School of Medicine, but the same approach could be applied in all patients. It is hoped that the approach might eventually be applied as an almost instant off-the-shelf treatment.
The use of HLA-agnostic T-cell receptors has the promise to transform the treatment of common solid tumors that are presently incurable, said Carl June, MD, in reference to the Cardiff research. A leading expert in the delivery of successful T-cell therapies, June is a professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and the director of the Center for Cellular Immunotherapies and of Translational Research in the Abramson Cancer Center of the University of Pennsylvania. As with organ or bone marrow transplants, previously identified cancer-specific T-cells have been suited only to small sections of the population who share specific tissue types, making it difficult to identify and treat the most appropriate patients. This new T-cell appears not to have these limitations, and if this is borne out in clinical testing, and the approach is shown to be safe and efficacious, it could represent a real advance for the field. We need to cure cancer and not turn it in to a chronic disease.
June studies various mechanisms of lymphocyte activation that relate to immune tolerance and adoptive immunotherapy for cancer and chronic infection. According to the Parker Institute, his research team published findings in 2011, which represented the first successful and sustained demonstration of the use of gene transfer therapy to treat cancer. Clinical trials utilizing this approach, in which patients are treated with genetically engineered versions of their own T-cells, are now underway for adults with chronic lymphocytic leukemia and adults and children with acute lymphoblastic leukemia. Early results in that group show that 90 percent of patients respond to the therapy, and more recently, trials of this approach have begun for patients with other blood cancers and solid tumors including pancreatic cancer, mesothelioma and the brain cancer glioblastoma. In 2017, it became the United States first FDA-approved personalized cellular therapy for the treatment of cancer.
Still, Sewell cautioned people from becoming overly optimistic too soon about Cardiffs findings. He said while the scientists discovery is potentially game-changing, an actual universal cancer therapy could be years away.I would really like to stress that we have not cured a patientour results were all laboratory based, albeit with patient T-cells and cancer cells. Clearing cancer in a culture dish and clearing it in a patient are two very different things.
When Cardiff researchers injected the new immune cells into mice with a human immune system and a human blood cancer line, the cancers cells were cleared to a level seen with CAR-T cells in the same mouse model, Sewell said. The group further demonstrated that equipping T-cells of skin cancer patients with the new receptor induced them to destroy not only the patients own cancer cells, but also other patients cancer cells in the laboratory, he said.
Cardiff researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognizes and kills most human cancer types, while ignoring healthy cells, Cardiff reported in a press release. This TCR recognizes a molecule present on the surface of a wide range of cancer cells as well as in many of the bodys normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.
Though there are various types of T-cells, Sewell said his interest is in killer T-cellsalso called cytotoxic T-cells. Killer T-cells are fascinating as they have the unique ability to see inside other body cells and scan them for anomalies he said. Conventionally, killer T-cells scan the molecular machines inside cells called proteins. A clever system presents bits of all the proteins inside each cell on its surface bound to molecular platforms called HLA [Human Leukocyte Antigen]. Normal, healthy body cells only present bits of normal proteins, and these are ignored by killer T-cells. If a cell is, for instance, infected with a virus, then it will contain some proteins of viral origin and bits of these will be displayed on the surface of the infected cell. Killer T-cells can recognize these protein fragments as foreign. This activates the killer T-cell to destroy the infected body cell and all its contents, including the virus. In this sense, killer T-cells act as a sophisticated seek and destroy weapon.
T-cells attacking cancer.
When cells become cancerous, they change the expression of some proteins and some proteins mutate, Sewell explained. These changes can also be detected by killer T-cells. Successful cancers go to great lengths to hide from killer T-cells, he said. We know that cancer often exploits the safety checkpoints that are built into T-cells to prevent them causing inflammation or autoimmunity. These checkpoints can be thought of as T-cell brakes, and successful cancers are often good at applying these brakes. Recent development of new drugs called checkpoint inhibitors prevents the application of these brakes and can result in complete clearance of some cancers in some people. Research that led to the discovery of checkpoint inhibitors was awarded the Nobel prize for Physiology or Medicine in 2018.
Sewell said the Cardiff teams discovery could mean exciting opportunities for pan-cancer, pan-population immunotherapies not previously thought possible. The research was funded by the Wellcome Trust, Health and Care Research Wales and Tenovus.
Until now, Sewell said, nobody knew this cell existed. He said the teams hypothesis is that the T-cell works by interacting with a molecule called MR1 which, in turn, flags up the distorted metabolism in a cancer cell.
Now that we know that these types of cells exist, we can actively look for others that work by a similar mechanism. Indeed, we have already found similar broadly tumoricidal, HLA-agnostic killer T-cells that see cancers via different surface molecules. The molecules targeted by these cells were also discovered using the CRISPR library approach. CRISPR gene editing has been a real game-changer.
Sewell said the next step will begin with safety testing on further healthy human cell lines in the laboratory. History has shown, he said, that some T-cells could attack things we dont want them to. We have already demonstrated that our new T-cell does not respond to 20 healthy cell types, he said. The human body has many more cell types than this so, as best we can, we need to rule out that this T-cell does not attack any further healthy human cell types. The new MR1-binding receptor has a natural sequence isolated from a healthy donor and thus the likelihood that it will attack healthy tissue is unlikely.
In any event, Sewell said it is important for people to acknowledge that this discovery has not been tested outside of the laboratory and not yet in human beings. It is impossible to reconstitute a whole human body as individual cell types in the laboratory, so after passing an accepted level of safety testing in this way, the next step is a first-in-man trial Sewell said. In order to minimize the risk, it is likely that the first time this type of T-cell is used in man, the T-cells will transiently [impermanently] express the relevant T-cell receptor and be given in low numbers, with escalation from there once safety is demonstrated. This way if there is any autoimmune attack it will be at low level and short-lived, so hopefully do minimal damage.
While Sewell hesitated at giving a timeline for when an actual universal cancer therapy or cure could be expected, he is hopeful that clinical trials may start in the next few years once further laboratory safety testing is completed.
The new collaboration to develop this recent discovery funded by Ervaxxwill support a multi-year research program with Sewells T-cell modulation group at Cardiff University focusing on the discovery and characterization of T-cells and TCRs reactive to cancer-specific antigens and ligands, including Ervaxx proprietary Dark Antigens.
The company has the right to advance resulting candidate T-cell/TCR-based immunotherapeutics and cancer vaccines through development and commercialization, Ervaxx stated in a press release.
Kevin Pojasek, Ervaxx CEO, said the collaboration with the Cardiff University research group shows early but enormous potential for the treatment of cancers. He said the partnership, which follows those with the University of Oxford, University of Cambridge and Johns Hopkins University School of Medicine, reinforces our ambition to collaborate with leading academic institutions and be at the cutting edge of the T-cell immunology field to drive the development of novel off-the-shelf cancer therapies.
In terms of the MR1 finding, when asked if it meant that some people are completely immune to cancer, Sewell said, Possibly. This immune cell could be quite rare, or it could be that lots of people have this receptor, but for some reason it is not activated. We just don't know yet, but we hope that this finding can be exploited and will pave the way for new cancer treatments.
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New Partnership Could Lead To An Almost Instant Off-The-Shelf One-Size-Fits-All Cancer Treatment - Forbes