TLR1

A long research journey has finally paid off for Iovance Biotherapeutics, which last week won Food and Drug Administration approval of the first cell therapy to treat advanced melanoma. The clearance could also open the door for a new type of cancer immunotherapy.Iovances therapy, called Amtagvi, is built from a type of immune cells known as tumor-infiltrating lymphocytes, or TILs, which are collected directly from a tumor sample and fortified in a laboratory to better fight the cancer.Academic researchers have studied TIL therapy for decades, but scientific and regulatory factors slowed the technologys progress toward market, according to Jason Bock, head of the Cell Therapy Manufacturing Center and an expert on TIL therapy.This is the first cell therapy modality that has shown good results in solid tumors, he said.While CAR T-cell therapies can be powerfully effective in blood cancers, they havent performed as well in solid tumors. A one-time treatment, TIL therapy holds the potential to durably treat some of these solid tumors some treated patients have been cancer-free for a decade or more, Bock said.Jason Bock, CEO of Cell Therapy Manufacturing CenterPermission granted by CTMCAmtagvi will cost approximately $515,00 per patent before rebates and discounts. The FDA approved the therapy based on Phase 2 data, and is requiring Iovance confirm those results with a Phase 3 confirmatory trial. The drugs indication is limited to people with melanoma that cant be surgically removed or has spread, and was previously treated with other drugs.Others could follow Amtagvi, too. It will blaze this trail for others to follow on with enhanced next-generation products, said Bock. I think those will be where we really see some dramatic impacts of TIL in the overall treatment of solid tumors.Harnessing the immune systemEligible patients receive Amtagvi in select treatment centers, from where TILs are extracted and sent to a manufacturing center. There, they are isolated, grown and filtered before being sent back to the treatment center.The patient undergoes lymphodepletion to kill existing T cells before doctors infuse them with billions of the beefed-up cells, accompanied by a short course of high-dose Proleukin, an interleukin-2 product Iovance acquired in 2023. The IL-2 helps the infused cells transition from the controlled laboratory environment into the body, Bock said.Treatment can result in low blood counts, infection and other organ-related complications that can be serious risks the FDA highlighted in a black box warning. The accompanying IL-2 regimen can bring its own risks, too.[High-dose IL-2] carries its own toxicities and is a difficult treatment for patients to handle, Bock said.Companies developing second-generation TIL treatments are working on alternatives to IL-2, which could reduce side effects. The lymphodepletion process may also be problematic. In December, the FDA placed a clinical hold on an Iovance lung cancer trial after a patient died, potentially related to this process.A difficult development roadOne reason it took so long to bring a TIL treatment to market is due to one of its cancer-fighting strengths, Bock said.Unlike CAR-T -cells, which have to be engineered, the body naturally deploys TILs to infiltrate a tumors layers. The challenge is that TIL cells can get beaten down in the process, according to Bock, and the tumor evolves to avoid or repress them.They dont have the fortitude to contain the cancer. So, the goal [with TIL therapies] is to enhance and multiply them to turn them into an army capable of a successful attack, Bock said.TILs are polyclonal and can recognize many targets on cancer cells. While that makes them attractive as a treatment choice, it also created regulatory hurdles. The FDA had to hammer out a way to regulate this new kind of drug without a predefined target, Bock said.TILs in the pipelineSeveral other TIL treatments are currently in the pipeline. Many also target melanoma.In theory, though, TILs have the potential to work against a broad range of solid tumors. For the next generation to be effective in other cancers, better manufacturing methods will be needed, Bock said.While much of the work on TILs still happens in academic research centers, several companies such as Turnstone Biologics, Lyell and Instil Bio are testing second-generation TILs against targets including breast, colorectal and ovarian cancer. Iovance is studying its therapies in cervical cancer, non-small cell lung cancer, and head and neck squamous cell carcinoma.With Amtagvis approval, Bock predicts investment in TILs will surge, much like it did when the FDA approved the first CAR-T cell treatment.It's hard to be the first, but what's exciting is that after you're done with the first there's a trail there for others to build upon and improve upon, Bock said. '

Engineering a patient’s immune cells into cancer treatments works for treating blood cancers, but has fallen short in solid tumors—until now. An Iovance Biotherapeutics treatment employing a different type of cell has won accelerated FDA approval for advanced melanoma, marking the first product approval of any cell therapy for a solid tumor. The regulatory decision announced Friday covers melanoma in adults whose cancer cannot be surgically removed or has spread following treatment with an immunotherapy or a targeted cancer therapy. The cell therapy of San Carlos, California-based Iovance, known in development as lifileucel, will be marketed under the brand name Amtagvi. Amtagvi, a one-time treatment, is made from a type of cell called a tumor-infiltrating lymphocyte, or TIL. The body produces TILs to fight cancer, and they are found in the tumor. The Iovance cell therapy is made by surgically removing a small piece of a patient’s tumor and isolating TILs from that sample. Those TILs are multiplied in a lab, then shipped back to the hospital for infusion into the patient. The TIL manufacturing process is similar to that of CAR T-therapies, which are made by harvesting and multiplying a patient’s T cells. One key difference is what happens in the lab. CAR T-treatments are engineered to go after a target on the surface of a cancer cell. TILs don’t need this engineering step because they already have the ability to recognize a patient’s cancer cells. Amtagvi’s Clinical Trial Results The FDA based its approval on the results of an open-label, single-arm Phase 2 clinical trial. Participants had advanced melanoma that was previously treated with at least one systemic therapy, including a type of immunotherapy called a checkpoint inhibitor, and if positive for a BRAF mutation, a BRAF inhibitor. The main goal was to measure the objective response rate and the duration of response. Of the 73 patients who received Amtagvi within the recommended dosing range, the overall response rate was 31.5%. The median duration of response was not reached. Results were published in in 2022 in the Journal for ImmunoTherapy of Cancer. The most common adverse reactions reported from the clinical trial included chills, fever, fatigue, faster than normal heart rate, and diarrhea. Amtagvi’s label carries a black box warning that the treatment can lead to death. In the clinical trial, treatment-related mortality was 7.6%. Adverse reactions associated with these deaths included severe infections, internal bleeding, kidney failure, respiratory failure, and abnormal heart rhythm. Patients may experience prolonged and severe cytopenia, which is a low levels of certain blood cells. The risk of heart and kidney injury are also flagged in the boxed warning. CAR T-therapies also carry black box warnings, with the main complications risks being an excessive immune response called cytokine release syndrome and neurotoxicity. Fred Vogt, interim Iovance CEO and the company’s president and general counsel, noted that Amtagvi was not associated with either of these complications risks. FDA approval of CAR T-therapies came with Risk Evaluation Mitigation Strategies (REMS), programs to manage the risks associated with treatment. “The [Amtagvi] black box is pretty good, we think it’s much better than what the CAR T’s have,” Vogt said during a Friday conference call. “It doesn’t have a REMs, first and foremost, like the CAR T’s do. It’s got boxed warnings essentially for known risks, from the lymphodepletion and the IL-2 therapies that we provide.” Lymphodepletion, a key step in all cell therapies, involves using chemotherapy to reduce levels of a patient’s immune cells to improve the survival chances of the cell therapy. IL-2 refers an engineered version of a protein that stimulates an immune response. In the clinical trial, treatment with Amtagvi was followed by aldesleukin, an IL-2 therapy whose uses include the treatment of metastatic melanoma. In the Amtagvi treatment regimen, aldesleukin’s role is to activate the TILs’ anti-tumor activity. Aldesleukin also has risks: Its label includes a black box warning of a potential complication called capillary leak syndrome, leading to low blood pressure and low levels of the protein albumin in the blood. This complication can lead to life-threatening organ damage. Because aldesleukin is a key part of the Amtagvi treatment regimen, Iovance last year acquired global rights to Proleukin, an IL-2 product from Clinigen. Iovance paid £166.9 million (about $207.2 million) up front for the product’s rights. The acquisition agreement puts Clinigen in line for milestone payments and royalties from sales. Premium Pricing for the First TIL Cell Therapy Iovance set a $515,000 wholesale price for Amtagvi, which is higher than the $373,000 to $475,000 price range for currently available CAR T-therapies. The company will make the TIL therapy at its Philadelphia manufacturing facility. Together with a nearby contract manufacturer, the company says it has the capacity to produce Amtagvi for “several thousand patients annually.” The current manufacturing process is 34 days, which is a comparable to the lengthy, multi-step manufacturing process for CAR T-therapies. Vogt said Iovance believes it can improve Amtagvi’s manufacturing timeframe. Jim Ziegler, executive vice president, commercial, said about 30 authorized treatment centers are now ready to collect and ship tumor tissue for Amtagvi manufacturing. He expects that number to grow to 50 centers within the next three months. Based on interactions with payers, Ziegler said Iovance expects coverage of Amtagvi will be similar to insurance coverage of approved CAR T-therapies. TIL therapy competition is coming. The Achilles Therapeutics pipeline includes a TIL therapeutic candidate currently in a Phase 1/2 clinical trial evaluating it in combination with a checkpoint inhibitor as a potential treatment for melanoma. Lyell Immunopharma has a TIL therapy in early clinical development in melanoma, colorectal cancer, non-small cell lung cancer (NSCLC), and other solid tumors. Instil Bio’s pipeline includes a TIL in Phase 1 development in NSCLC, ovarian, and kidney cancers. Instil’s former lead program had reached mid-stage clinical development in advanced melanoma, but that therapy was discontinued in late 2022 due to a pipeline reprioritization. Iovance is also testing Amtagvi in combination with the Merck checkpoint inhibitor Keytruda as a frontline treatment for melanoma. This Phase 3 study will serve as the confirmatory clinical trial required of the therapy’s accelerated approval. The Iovance pipeline also includes tests of Amtagvi—by itself and in combination with checkpoint inhibitors—in cervical cancer, NSCLC, and head and neck squamous cell carcinoma. Another Iovance TIL therapy, LN-145, has reached pivotal testing in NSCLC. This study was placed under an FDA clinical hold in late December due to a fatality potentially related to the therapy’s preconditioning regimen. Vogt said Iovance is working to resolve the clinical hold and hopes to have an update in a few weeks. Photo by Iovance Biotherapeutics

SAN DIEGO--( BUSINESS WIRE )--Excellos Inc., a cell therapy contract and development manufacturing organization (CDMO), today announced a new partnership with Vitalant, one of the nation’s largest nonprofit blood and biotherapies healthcare organizations. The strategic partnership includes an investment by Vitalant, and cell sourcing, testing and laboratory services. It also includes collaboration with the Vitalant Innovation Center, which provides scientific research and translational development expertise to bring new products and services to patients across the country. The strategic partnership is focused on supporting organizations to develop and deliver new cell therapies and addresses major challenges in bringing therapies to patients. Cell therapy development teams will now have access to larger and better geographically distributed donors that are well-characterized for aspects including metabolic and effector function profiles. This improves therapeutic potency and reduces manufacturing costs, while reducing clinical response variability. Commenting on the partnership, David Wellis, Ph.D., Chief Executive Officer of Excellos, said, “This is a great opportunity for Excellos to extend its collection network across the country and to collaborate with Vitalant in several areas, including testing services and research and development at their state-of-the-art Innovation Center. Additionally, Vitalant’s investment brings financial capital to accelerate the launch of new Excellos products and services, including donor characterization through our Excellos 360 platform.” “Through our partnership with Excellos and other innovators, Vitalant can leverage our unique capabilities and expertise to transform healthcare,” said Becky Cap, Vitalant’s Senior Vice President of Biotherapies. “We look forward to working with Excellos to help develop new technologies and therapies that improve patient access and outcomes.” About Vitalant Vitalant is one of the nation’s largest nonprofit blood and biotherapies healthcare organizations, providing hospitals and patients across the U.S. a safe blood supply, specialized laboratory services, transfusion medicine expertise and world-renowned research. Learn more about our healthcare solutions at vitalanthealth.org . About Excellos Excellos provides custom cGMP services to develop and manufacture cell therapies. Featuring proprietary cell characterization technologies, Excellos reduces variabilities in clinical responses and increases the probability of successful outcomes. Current applications support TIL-based therapies, autologous and allogenic CAR-T/NK therapies and TCR therapies. Customized services include donor recruitment, cell isolation, transduction, expansion and scale up GMP production. Learn more at www.excellos.com .