In a groundbreaking medical advancement, the U.S. Food and Drug Administration has approved Amtagvi (lifileucel), a cellular therapy for treating melanoma that cannot be surgically removed or has spread to other parts of the body. This marks a significant milestone as the first cellular therapy for solid tumors, changing the landscape of cancer treatment.
An aggressive form of skin cancer, melanoma develops when pigment-producing skin cells grow uncontrollably. While it constitutes just 1% of all skin cancer cases, it accounts for many cancer-related deaths. A key risk factor for melanoma is exposure to ultraviolet light, commonly from the sun or tanning beds. Early detection makes it easier to treat; if left unchecked, the cancer can metastasize, spreading throughout the body.
"Unresectable or metastatic melanoma is a severe condition that can be fatal," explained Dr. Peter Marks, the director of FDA's Center for Biologics Evaluation and Research. "The approval of Amtagvi represents the culmination of years of scientific and clinical research, leading to a novel T cell immunotherapy for patients with limited treatment options."
The treatment involves extracting and replicating immune cells—specifically T cells—from a patient's tumor. The process starts with the removal of a portion of the tumor tissue, which is then taken to a lab. Here, the T cells are separated, cultivated, and prepared before being reintroduced to the patient as a single infusion dose. Unlike CAR T-cell therapies, Amtagvi's method uses T cells derived from the tumor itself rather than from the patient's circulating blood.
Melanoma treatments often include immunotherapy using PD-1 inhibitors, antibodies targeting specific proteins to help the immune system fight cancer. For melanomas linked to mutations in the BRAF gene, drugs targeting this gene may also be used. However, melanoma cases that progress despite these treatments present a high unmet medical need, one that Amtagvi aims to address.
Amtagvi received approval via the FDA's Accelerated Approval pathway, which permits drugs for severe or life-threatening conditions to be approved based on a surrogate endpoint likely to predict a clinical benefit. This allows for earlier patient access while the manufacturer continues trials to confirm the treatment's efficacy. Currently, a confirmatory trial is underway to verify the clinical benefits of Amtagvi.
Initial safety and effectiveness of Amtagvi were evaluated in a global clinical trial with over 70 patients. These participants had unresectable or metastatic melanoma that persisted despite at least one systemic therapy. Among the 73 patients treated, the objective response rate was 31.5%, including full tumor disappearance in some cases. Remarkably, nearly half of these patients maintained their responses without tumor progression or death at six, nine, and twelve months.
However, the treatment comes with potential risks. Patients might experience prolonged severe low blood counts, infections, cardiac issues, or respiratory and renal dysfunctions. Severe treatment-related complications can even be fatal. Common side effects include chills, fever, fatigue, rapid heartbeat, diarrhea, and others. Patients need close monitoring, and the treatment must be paused or stopped if severe symptoms appear.
This form of therapy was a long time in the making. Dr. Steven Rosenberg and his colleagues from the National Cancer Institute’s Surgery Branch pioneered TIL therapy in the late 1980s. The first clinical trials showed promise in reducing tumor size in advanced melanoma. Over the years, the process was refined, culminating in a research agreement with Iovance Biotherapeutics to develop the therapy further, leading to its eventual FDA approval.
The approval is a significant step in the mainstream adoption of cellular therapies for cancer. It shows that TIL therapy can be more accessible to patients, paving the way for similar treatments for other cancers. Unlike CAR T-cell therapies, TILs are collected from tumors and don't require genetic engineering, although they are expanded exponentially and combined with drugs to boost their cancer-fighting abilities.
Not quite ready to rest on its laurels, Iovance Biotherapeutics is already enrolling participants in trials combining lifileucel with pembrolizumab (Keytruda) to treat advanced melanoma initially. There are also promising signs of TIL therapy's effectiveness in treating lung, ovarian, and head and neck cancers.
While this approval is a joyous milestone for those battling melanoma, there are limitations. For instance, patients must be relatively healthy to undergo the treatment, which isn't always the case for those with advanced cancer. The method also involves high doses of chemotherapy before and after infusion, posing another challenge for weaker patients.
Dr. Alexander Shoushtari of the Memorial Sloan Kettering Cancer Center noted that the side effects seen during trials were consistent and predictable, mostly occurring within the first two to three weeks following treatment. No significant long-term side effects were observed, which may bode well for broader applications of TIL therapy.
The excitement surrounding this landmark approval is palpable. Dr. Rosenberg highlighted the potential of helping the immune system target and destroy tumors, including solid tumors responsible for most cancer deaths. With this foundational approval, there’s renewed optimism for the future of cellular-based immune therapies for cancer.