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T-Cell Therapies

The concept of using the human immune system to fight cancer has been around for more than 100 years, but it wasn’t until several years ago that scientists were able to bring this sort of treatment to patients. Blincyto, Amgen Inc.’s cancer drug first approved by the Food and Drug Administration in 2014, combines these two concepts in a one-two punch against cancer. It is the Thousand Oaks company’s first so-called first BiTE treatment, a trademarked name that stands for bispecific T-cell engager, an antibody-like protein that brings together a tumor cell and T-cell, or T lymphocyte, in hopes that the T-cell will kill the intended target. In Blincyto’s case, that intended target is leukemia. A company named Micromet in Rockville, Md., developed BiTE technology for nearly a decade before it was acquired by Amgen in 2012 for $1.16 billion; the acquisition gave Amgen the biotech to bring Blincyto to market two years later. In the last year, Blincyto has received regulatory approvals in the U.S. and Europe to expand its potential patient population. The treatment has worked so well that Amgen was able to introduce the new immunotherapy to patients before the traditional Phase III of clinical trials was completed. “We did ultimately complete the third, definitive phase, but we were able to do that after the drug had already reached the market,” Dr. Elliott Levy, head of global development for Amgen, told the Business Journal. “It was reviewed and approved in what I think was at the time a record time for the FDA, about 90 days. Typically, their review cycles are at least eight months, and 12 months is more typical.” Antibody variations Blincyto is seen as a “smaller opportunity” for revenue, or under $1 billion in peak sales for Amgen, according to a January 2019 report from Morningstar. But it could prove to be more useful than what analysts expected, given the adaptability of bispecific antibodies. “All kinds of possibilities exist when you have an antibody that binds to two different targets,” Levy explained. “There are almost limitless numbers of constructs that you can envision. It doesn’t have to be exactly like a normally occurring antibody.” The BiTE platform is built on more than 100 years of research. Creating a protein, or an antibody-like protein, to bring together two targets in the body first appears in scientific literature around 1985. Researchers ran with that idea and applied it to targeting cancer cells in the 1990s. Blincyto had total sales of $230 million, according to Amgen’s annual report. While that’s a small number compared to the company’s top-sellers Enbrel and Neulasta, at $5 billion and $4.5 billion respectively, Blincyto increased sales 31 percent last year, buoyed by three new regulatory approvals in the U.S. and Europe. Amgen, the No. 1 company on the Business Journal’s list of Bioscience Companies with 5,220 employees, believes its success with Blincyto is a good indicator that other BiTE treatments may get fast approvals. “We’re very interested in advancing the technology. The BiTEs we have today are a very specific protein structure. We’ve introduced one variation into that structure in order to make it more stable so it can be administered intermittently, say every week or every other week,” Levy said. “We’re experimenting with other variations on the protein framework. … We find them quite exciting. They give us the possibility to address a wider variety of cancers than we can today.” Cost questions CAR-T cells, another cancer immunotherapy in the works by Amgen and other companies, harnesses the immune system in a different way to fight cancer as well as a multitude of other illnesses. Chimeric antigen receptor T-cells, or CAR-T cells, are harvested from the patient and then genetically modified to bind to and kill the cancer cells, according to Levy. Atara Biotherapeutics is headquartered in South San Francisco, but last year it opened a facility in Thousand Oaks to manufacture CAR-T cells. The company ranks No. 12 on the Business Journal’s list with 217 local employees. Amgen and venture capital firm Kleiner Perkins Caufield & Byers created Atara in 2012 with licensed Amgen technology. The process of harvesting and modifying can take up to a month to produce cells, but sometimes doctors can develop them ahead of time so patients won’t have to wait. The CAR-Ts are living cells too and may last longer in the patient’s system than BiTEs. “The BiTEs and CAR-Ts both harness the power of the immune system – since BiTEs are proteins, they’ll last for a little while and then the dose may need to be repeated,” said Chris Haqq, chief scientific officer for Atara Biotherapeutics. “CAR-T cells seem to last for a long time. Because they’re living, they can grow inside the patient when they’re received and then in that way they can give a durable effect.” “The CAR-T cells seem to be quite potent, and that has created a great deal of interest,” added Amgen’s Levy. “On the other hand … they are very costly to make, and then they are also very costly to administer, usually requiring an extended hospital stay in an intensive care unit.” CAR-Ts on average cost $450,000, compared to $178,000 for Blincyto, according to indications from Amgen at the time of its launch. Amgen provided the Business Journal with an updated wholesale acquisition cost, or the price cited for drug distributors, of $106,922. For Atara, other T-cell immunotherapies such as tab-cels aim to fill the void when it comes to cost and timeliness. Tab-cels are marketed as a treatment for patients with the Epstein-Barr virus as an “off-the-shelf” T-cell. “CAR-Ts have an engineered receptor inside of them that recognizes the target, whereas our tab-cel actually uses the natural T-cell receptor to target the virus EBV on the surface of a lymphoma cell,” Haqq added. Atara’s facility in Thousand Oaks has a whole library of T-cells from different donors that can be shipped to patients that have EBV-associated tumors. It appears that the effectiveness of BiTEs and CAR-Ts depends on where the patient is with treatment. In some cases, an oncologist may start with one treatment and segue into another. “We’re quite interested in combining BiTEs with other promising therapies like the PD1 inhibitors,” said Levy. “There is reason to believe that the technology will combine well with other therapeutic approaches to cancer, including immunotherapeutic approaches. We’re starting to see some very preliminary data on those combinations which is encouraging, but still quite early.” In addition to combining immunotherapies, BiTE and CAR-T developers are working on how the same technology can be applied to other cancers and illnesses. So far, Amgen has started testing for BiTEs that target lung cancer, prostate cancer, and other kinds of leukemia and lymphoma. Amgen has seen responses in six different tumor types with this technology, Levy said. Atara has developed the first CAR-T to target a solid cancer. Once trials are completed, the company plans to use the T-cells to treat patients with breast cancer, mesothelioma, ovarian cancer, pancreatic cancer and lung cancer. Immunotherapy buzzwords like BiTEs and CAR-Ts have the oncology world at the edge of its seat – those close to research and development expect these therapies to take their place next to traditional oncology treatments such as chemotherapy, radiation and surgery. “They are really pioneering advances for medicine,” said Haqq. “I think they’re both going to become widely adopted … based on the effectiveness and value of the therapy to patients. Immunotherapies like these could become a new whole branch of medicine.”

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