First engineered T-cell therapy put to the test in solid tumors
An immune-boosting therapy similar to therapies that save lives in advanced blood cancers has now been used to treat a patient with metastatic synovial sarcoma, a rare, aggressive soft tissue cancer.
[Full disclosure: This story has personal resonance. I was diagnosed with stage III synovial sarcoma in the summer of 2009. After nearly a year of treatment with preoperative inpatient chemotherapy and radiation, followed by limb-sparing surgery and three postoperative inpatient chemotherapy cycles—interrupted by infections, dangerously low white blood cell levels, and a whole-body exfoliating dermatitis—I have been in remission ever since. I hope that I will never need the therapy described here, but I’m grateful that’s it available for others with this rare cancer with a high propensity for recurrence and metastasis.]
In August 2024, the US Food and Drug Administration (FDA) gave accelerated approval to afamitresgene autoleucel (afami-cel; tradename Tecelra), the first engineered T-cell construct designed for the treatment of a solid tumor. Afami-cel is approved for the treatment of adults with inoperable (unresectable) or metastatic (widespread) synovial sarcoma who were previously treated with chemotherapy, have specific immune profiles, and whose tumors harbor an antigen (treatment target) known as MAGE-A4.
Synovial sarcoma is a soft-tissue sarcoma, a type of rare cancer with an estimated annual US incidence of 1 or 2 cases for every 1 million people, according to the National Cancer Institute. Approximately one-third of all cases occur in person younger than 30 years of age. The word “synovial,” meaning “relating to joints,” is a bit misleading, as the tumors tend to occur near joints of the extremities but not typically within joints. Synovial sarcomas may also form in soft tissues in the lungs or abdomen.
“Synovial sarcoma is a particularly devastating type of cancer, affecting many patients in the primes of their lives with poor prognosis for those who fail first-line treatment. Despite this outlook, in the last decade we have seen no new, effective treatments become available to patients. TECELRA’s one-time infusion treatment provides a much-needed option to patients with unresectable or metastatic synovial sarcoma, offering a novel therapeutic approach to treatment as well as a new found sense of hope for patients and their loved ones,” said Mihaela Druta, MD, a medical oncologist and vice chair of the sarcoma department at Moffitt.
The FDA’s approval of afami-cel for commercial use was based on the results of the SPEARHEAD-1 clinical trial. In the trial, afami-cel was associated with significant tumor shrinkage in 17 of 44 patients (39%) with metastatic synovial sarcoma who had previously received chemotherapy. This percentage, known in medical parlance as the objective response rate (ORR), compares favorably to an approximately 22% ORR with chemotherapy as the first line, or choice, of treatment for advanced or metastatic synovial sarcoma.
The first patient to receive the one-time infusion after its approval was treated at the Moffitt Cancer Center in Tampa, Florida, afami-cel’s manufacturer, Adaptimmune, announced in a press release.
Until the development and commercial approval of afami-cel, therapies that exploit the patient’s own T cells to attack cancer had not been successful for treatment of tumors in solid organs, due to a variety of factors that include difficulty in identifying targets; immune suppression in the tissues surrounding the tumor (known as the tumor microenvironment); the limited ability of T cells to infiltrate solid tumors; and side effects caused by the treatment attacking non-tumor tissues.
Whether afami-cel will be successful in its first use as a commercially approved cancer drug remains to be seen.
How engineered T-cell receptors (TCR) work
Although we don’t recommend trying this at home, here, in a nutshell, is a recipe for making a TCR therapy such as afami-cel:
Extract some disease-fighting white blood cells—T cells—from the bloodstream of a person with cancer.
Give that person chemotherapy to clear the bloodstream of immune cells and make room for new ones.
Meanwhile, treat the harvested T cells by modifying a T-cell receptor (docking site) to recognize a protein target inside cancer cells in that person’s tumor and grow (expand) the population of altered cells in the lab.
Return the boosted T cells to the patient via an intravenous infusion where they will, ideally, attack and shrink, or even completely eliminate, the tumor.
Life-saving therapy
TCR targets proteins within cancer cells, whereas it’s close cousin, CAR T-cell therapy, uses a similar technology to target proteins on the surface of cancer cells.
T-cell engineering, which falls under the category of cellular immunity, is a complex and costly but often life-saving treatment for persons with certain cancers for whom all other options have been tried and failed. The greatest and only successes thus far have been with CAR-T cell therapy in patients with blood cancers such as leukemia, lymphoma, and multiple myeloma.
The first adult to receive CAR T-cell therapy was Bill Ludwig, a man with advanced chronic lymphocytic leukemia (CLL) who was enrolled in a clinical trial at the University of Pennsylvania in 2010. Ludwig, who had no remaining treatment options, lived cancer-free for 11 years after receiving the therapy, but died from Covid-19 during the pandemic.
The first childhood patient to receive the treatment, Emily Whitehead, was 5 years old in 2010 when she was diagnosed with acute lymphoblastic leukemia. Following two relapses after conventional chemotherapy failed to work, she underwent CAR T-cell therapy, and has been in remission ever since.
Synovial sarcoma facts
In more than 90% of cases the tumors are caused by a characteristic gene translocation in which a gene on one chromosome combines abnormally with a gene on a different chromosome, resulting in a fusion of the genes SYT and SSX, and creation of an abnormal fusion protein. It’s unknown how the translocation occurs, but it is thought to be related to genetic abnormalities, radiation exposure, or exposure to chemicals, notably dioxin, the chief constituent of the defoliant known as Agent Orange that was widely used by the US in the Vietnam War.
Because the tumors are aggressive and have the propensity to recur and to metastasize, or spread, to the lungs or other parts of the body, surgery to remove the primary tumor, with wide surgical margins to ensure it is all removed, is essential for offering patients the best chance of cure. In many cases, patients may require amputation of an affected limb if the tumor is extensive or recurs after surgery.
Synovial sarcomas are one of the few sarcoma types known to be sensitive to chemotherapy. In some specialty sarcoma centers larger tumors may be treated with a combination of preoperative chemotherapy and radiation to shrink the tumor and improve chances for complete surgical removal, followed by postoperative chemotherapy to knock down any residual cells that may have escaped the primary tumor in an attempt to prevent metastasis.
This article was corrected to emphasize that afami-cel is a TCR therapy and not a CAR T-cell therapy, as originally stated.
Neil Osterweil is an award-winning medical journalist with more than 40 years of experience reporting on medicine and health care.