NEW YORK – In the two weeks since the US Food and Drug Administration granted accelerated approval to Adaptimmune's Tecelra (afamitresgene autoleucel) — marking the second-ever commercially available autologous cell therapy for a solid tumor indication — oncologists and drugmakers have become further energized about the future cell therapy landscape.
"This approval allows other developers to know this is possible," said Edwin Choy, the director of Massachusetts General Hospital's sarcoma oncology program. "It's kind of like when we first broke the four-minute mile, and now everyone is running faster than four minutes. I'm hoping this is the lead that starts the avalanche."
The FDA approved Adaptimmune's autologous T-cell receptor (TCR) T-cell therapy Tecelra for patients with MAGE-A4-expressing synovial sarcoma and the human leukocyte antigen types HLA A*02:01P, HLA A*02:02P, HLA*02:03P, or HLA*02:05P. The autologous therapy's approval comes six months after Iovance's autologous tumor-infiltrating lymphocyte therapy Amtagvi (lifileucel) netted FDA approval for advanced melanoma, the very first autologous cell therapy approved for a solid tumor indication.
Even though it's the second autologous cell therapy approved for a solid tumor, Adaptimmune views Tecelra as a first-in-class therapy on account of its manufacturing process. Unlike Amtagvi, which involves expanding patients' own immune cells ex vivo and reinfusing them unmodified as a one-time treatment, Tecelra involves ex vivo engineering.
"Tecelra is the first engineered cell therapy for a solid tumor [and] the first medicine in its class," Adaptimmune CEO Adrian Rawcliffe said on a conference call to discuss the firm's second-quarter financial results on Monday. "It's also the first new treatment option for synovial sarcoma in over a decade."
After Adaptimmune harvests patients' immune cells, the firm engineers them to target the major histocompatibility complex (MHC) peptide MAGE-A4 that appears on the surface of patients' sarcoma cells. The approach is different from targeted therapies that directly bind to cell surface antigens. Instead, with Tecelra, patients' T cells are engineered to go after the molecules that present those tumor antigens to T cells. Adaptimmune designed the approach to get around one of the major challenges to developing cell therapies for solid tumors: finding a target unique to cancer cells that isn't expressed on healthy tissue.
"There are lots of reasons why it's harder to treat solid tumors with cell therapies than lymphoma or leukemia or other hematologic malignancies," Choy said. "So the fact that so many of our patients are benefiting from this is a huge step forward."
A 'wonderful tool,' but not a cure
In the clinical trial that led to Tecelra's approval, SPEARHEAD-1, 44 patients with inoperable or metastatic synovial sarcoma whose tumors met both the MAGE-A4 and HLA-typing eligibility criteria received a single dose of engineered TCR T cells. In the analysis that the FDA used to approve Tecelra, which involved an independent review committee, the overall response rate was 43.2 percent and the median duration of response was six months.
"The way I think of this treatment is that it gives patients several important months to spend with their family and friends and get some extra time to live that they may not have had if this product did not exist," Choy said. "I think it's a wonderful tool to help prolong synovial sarcoma, but I don't see it as being curative. Patients will still ultimately have disease progression within several months of getting this product."
Going forward, Choy is hoping that the fact there are now two commercially approved cell therapies on the market will incentivize other researchers and industry players to work at developing new iterations of these therapies to further improve patient outcomes, both in synovial sarcoma and other indications.
"We first have to figure out why cancers develop a resistance to an effective T-cell therapy," he said. "Are the T cells themselves dying off or no longer being effective? Are the tumor cells mutating and figuring out ways to survive the T-cell pressure? There's a lot of science that we still haven't figured out that we need to."
Now that there's evidence of a possible commercial pathway for these therapies — that is, a clear return-on-investment opportunity since others have paved the way — others in the field could be motivated to invest in answering these questions, Choy hopes.
For its part, Adaptimmune is already looking to expand its TCR T-cell therapy into new patient populations and indications. On a recent conference call to discuss Tecelra's approval, Adaptimmune informed investors and analysts that it's already planning to submit a rolling biologics license application (BLA) with the FDA in 2025 for letetresgene autoleucel, or lete-cel, an autologous TCR T-cell therapy that's similar to Tecelra but targets the NY-ESO-1 antigen on cancer cells instead of MAGE-A4. The firm has been evaluating lete-cel in synovial sarcoma and myxoid/round cell liposarcoma patients in the Phase II IGNYTE-ESO trial.
Choy believes the approach could work beyond sarcoma, too.
"The product doesn't know sarcoma exists," he said. "Any tumor that expresses the target could potentially be amendable to this treatment."
Biomarker-restricted eligibility
When the FDA approved Tecelra, it also approved two assays as diagnostics to test patients for eligibility: Agilent Technologies' MAGE-A4 IHC 1F9 PharmDx as a companion diagnostic to select MAGE-A4-positive synovial sarcoma patients and Thermo Fisher Scientific's HLA-A-typing test, SeCore CDx, to identify patients with the specified HLA types for Tecelra therapy.
According to Adaptimmune, these are already widely available tests, so the firm doesn't expect a heavy lift in getting patients the proper testing they need to determine Tecelra eligibility.
But actually ensuring that all patients who could benefit from Tecelra receive the tests is a different story, Choy said.
"This is paradigm shifting in that a diagnosis of synovial sarcoma should come with [this testing]," he said. "At this point, everyone with a synovial sarcoma should also know whether or not their tumor expresses MAGE-A4 … and have HLA-A*02."
Importantly, this immune phenotype is enriched in patient populations of White, European descent, which, by default, limits the diversity of the patient population eligible for Tecelra.
"The company decided to design their product using this HLA subtype in order to capture as large of a population in the United States as possible," Choy said. "But patients with other ethnicities are less likely to have HLA-A*02."
Indeed, 89 percent of the patients who received Tecelra in the SPEARHEAD-1 cohort that led to the Tecelra approval were White and 96 percent had the HLA-409 A*02:01P type.
Choy, who was an investigator on Tecelra's clinical trials, noted that patients were turned away frequently due to their HLA type, saying that only about half of people who have a MAGE A4-expressing synovial sarcoma also have the HLA type that makes them eligible for Tecelra.
"In addition to expanding to other indications with MAGE-A4 expressing tumors, it would be great to see other products designed that can target MAGE-A4 in the presence of other HLA subtypes," he said.
Although Adaptimmune emphasized during its investor call that its top focus in the near term is getting its newly approved therapy to eligible patients who need it, Adaptimmune Chief Medical Officer Elliot Norry said in an interview this spring that it is the firm's "absolute desire" to move beyond just HLA-A*02.