After more than a decade devoid of therapeutic advancements, a first-in-class T cell receptor therapy could be on the immediate horizon for synovial sarcoma patients.
Adaptimmune Therapeutics—and synovial sarcoma patients—are lined up for a monumental moment. After more than a decade without any new treatments, a one-time, first-in-class cell therapy is waiting in the wings for possible FDA approval this weekend.
Based in Philadelphia, Adaptimmune’s core purpose has been to launch the first engineered T cell receptor (TCR) therapy into the world, CEO Adrian Rawcliffe told BioSpace. The company’s lead candidate, afamitresgene autoleucel (afami-cel), was submitted for FDA approval in January and assigned a PDUFA date of Aug. 4.
If approved, afami-cel would be “transformative” for patients with metastatic synovial sarcoma, Rawcliffe said. One-third of patients diagnosed with the rare, aggressive soft tissue cancer are younger than 30, and synovial sarcoma spreads in half of all patients. In patients with metastatic disease, the five-year survival rate is just 20%.
Currently, first-line therapy for synovial sarcoma patients is anthracycline-based chemotherapy, which Rawcliffe said is often called “the red devil” because of its color and serious side effects. While half of patients experience a response to chemotherapy, it has low durability, with 80% or more of patients relapsing within a year, he said. After that, practitioners are simply trying to keep the cancer at bay with radiation and surgery.
“There really is no standard of care for second-line [treatment] because, honestly, nothing works yet,” Rawcliffe said.
Afami-cel could change all of that. According to Rawcliffe, TCR therapy has the potential to be a “highly effective therapy” in the second-line, metastatic, advanced setting.
A T Cell Option for Solid Tumors
If approved, afami-cel will be the first engineered TCR therapy on the market. In 2022, Immunocore’s Kimmtrak got the greenlight from the FDA as a “first-in-class TCR therapeutic” for the treatment of uveal melanoma. However, Kimmtrak and afami-cel are not the same class of therapy.
Kimmtrak is a bispecific protein that binds to a T cell and a cancer cell, bringing them together, explained Sandra D’Angelo, a sarcoma oncologist at Memorial Sloan Kettering and lead investigator on afami-cel’s pivotal SPEARHEAD-1 trial. Afami-cel, by contrast, is an autologous cell therapy made from the patient’s own T cells, which have been engineered to target melanoma-associated antigen A4 (MAGE A4).
An engineered TCR is more comparable to the process involved with the CAR T cell therapies now on the market, where T cells are removed from the patient and genetically modified before being reinfused. While CAR T therapies have been successful in treating blood cancers, solid tumors have presented a stumbling block for “a number of different reasons,” D’Angelo told BioSpace, adding that she has seen evidence that TCR therapy could prove more effective.
In SPEARHEAD-1, the overall response rate for patients with metastatic or unresectable synovial sarcoma was 39%. Median overall survival was around 17 months for those in the trial, compared to historical survival data of less than 12 months for patients who had received two or more prior lines of therapy. Two years after the one-time afami-cel treatment, 70% of responders are still alive.
Side effects of afami-cel included cytopenia, a lowering of blood counts, which D’Angelo attributed to the chemotherapy given in preparation of the cell therapy. The most common adverse event observed was cytokine release syndrome (CRS), inflammation in the body related to receiving the T cells. This phenomenon was short-lived, with most events considered grade 1, and patients were successfully treated with rheumatoid arthritis drug tocilizumab.
D’Angelo compared afami-cel to the last drug approved for synovial sarcoma in 2012, pazopanib. On average, she said, the latter works for three to six months, and the tumor shrinkage rate is roughly less than 10%. With afami-cel, there is a 40% tumor reduction with a durable benefit of well over a year. “Generally speaking, it offers a better quality of life,” D’Angelo said.
Rawcliffe agreed that although quality of life was not a metric used in the study, anecdotal evidence from patients showed a true value and benefit compared to existing therapies. For patients experiencing round after round of debilitating therapy, a one-off treatment is “transformational,” he added.
Manufacturing Is Key
Though differing in mechanism of action from CAR T cell therapies, all cell therapies share one key challenge—manufacturing, Rawcliffe said. “Can you make it consistently and effectively for the volumes of patients that you anticipate at launch?”
Adaptimmune has taken significant steps to invest in its internal manufacturing. This choice was important, Rawcliffe said, for its ability to control the supply of the product to each patient. All doses of afami-cel administered in the SPEARHEAD-1 trial were manufactured in-house by Adaptimmune in its Navy Yard facility in Philadelphia. That same facility and staff will be involved in the launch if afami-cel is approved.
As a rare form of cancer, the market for synovial sarcoma is small. Adaptimmune believes there are around 400 patients in the U.S. who would be eligible for treatment with afami-cel each year, and Rawcliffe feels confident about the company’s ability to maintain supply all the way up to “peak sales” of the cell therapy.
Market Impact
Peak sales are expected to be around $400 million for Adaptimmune’s two synovial sarcoma-targeting candidates, afami-cel and lete-cel, said Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas. Lete-cel is currently about two years behind afami-cel and expected to be the company’s next launch, he told BioSpace.
Even if afami-cel is approved on Aug. 4, however, analysts are not anticipating revenue from the product until the third or fourth quarter of 2025, Suvannevejh said. This is due to the complexities of cell therapy.
Rawcliffe acknowledged the market potential is “not huge” for the company’s synovial sarcoma franchise but said he hopes the transition from a research-based to a commercial company with cash flow will help fund the rest of the pipeline, which focuses on larger population indications like ovarian and head and neck cancer.
D’Angelo, who led the first TCR therapy study back in 2014, is excited to see the first successful treatment potentially cross the finish line.
“It’s a new way to approach cancer care,” she said. “[Afami-cel] is a one-time treatment and infusion and limits the need for ongoing therapy. . . . It’s an exciting time for patients that qualify for the therapy.”
