Jefferson Health oncologist Jennifer Johnson had exhausted all the standard treatment options for her 49-year-old patient with esophageal cancer, who was likely to die within months.
Surgery, chemotherapy, radiation, and immunotherapy had kept the Northeast Philadelphia woman alive for six years after her diagnosis, but no longer were enough to stop her cancer from spreading.
Johnson knew her patient needed something novel. She recalled a presentation several years prior at a conference for head and neck cancers, where a doctor discussed an experimental treatment called T-cell receptor (TCR) therapy.
This type of cancer immunotherapy works by engineering the immune system to fight cancer, and falls into the same family of treatments as CAR-T, or chimeric antigen receptor (CAR) T cell therapy, an approach pioneered at the University of Pennsylvania that has revolutionized treatment for blood cancers.
She thought TCR therapy’s clever approach could work against solid tumors, where CAR-T had not been effective.
“I just remember sitting in the room and watching him present, thinking, I’m gonna use that one day,” the oncologist and cancer researcher recalled.
As it would happen, the approach was being tested in a phase II clinical trial at Rutgers Cancer Institute against tumors just like her patient’s: metastatic cancers driven by a virus called human papillomavirus 16. One of the most common strains, HPV16 causes roughly half of cervical cancer cases worldwide, as well as cancers of the head and neck area, anus, and genitals.
Cases that reach the metastatic stage like Johnson’s patient often run out of treatment options. Whether T-cell receptor therapy would work was unknown, but the alternatives were expected to fail.
“Anything that you might offer them would definitely not be expected to make their cancer go away completely and do it for a long time,” said Christian Hinrichs, the oncologist and scientist heading the trial whose presentation Johnson saw.
But interim results from the first half of the trial showed improvement in six out of 10 patients, whose tumors at least partially shrank. And two of them had no evidence of cancer after treatment.
Johnson’s patient, Maria Pascale, was one of the two whose promising early results were presented at a medical conference and highlighted in a research abstract in the Journal for ImmunoTherapy of Cancer in November.
She arrived at the health system in New Jersey in the summer of 2024 in such poor health that her lungs were starting to collapse.
The therapy has enabled her to celebrate two birthdays, start martial arts classes, reunite with old friends visiting from Argentina, and see her 23-year-old son get engaged.
“Imagine the wedding, then later the grandkids, I’m always thinking about [that],” she said.
What is a T-cell receptor therapy?
In the immune system, T cells act as frontline defenders against viruses, bacteria, and other threats.
Sometimes, these cells aren’t great at their jobs.
In the face of cancer, T cells can become exhausted over time, and fail to recognize invaders or mount attacks.
The idea behind immunotherapy is to transform these regular immune cells into cancer-fighting super-soldiers.
The Rutgers approach, an engineered TCR therapy, involves collecting T cells from a patient’s blood and genetically engineering them to better target a cancer cell for attack.
Afterward, the scientists grow more of the enhanced T cells in the lab and infuse them back into the patient.
The “prototype” for this style of therapy is CAR-T, a treatment that has saved tens of thousands of lives since the first FDA approval in 2017. Scientists have not yet been able to replicate the therapy’s success in blood cancers in solid cancers, although some early stage trials have shown potential.
TCR therapy is thought to be more promising against the latter cancer type — which is what’s being treated in the Rutgers trial — due to differences in the way the engineered T cells identify cancer cells.
CAR-T therapy uses what’s called a chimeric antigen receptor, a protein that recognizes a cell as cancer based on what’s on the outside of the cell.
It’s like knowing you’re at your friend’s house because of a specific doormat or set of house numbers on the exterior.
TCR therapy uses what’s called a T-cell receptor, which can recognize cancer cells based on what’s inside the cell.
It’s like knowing you’re at your friend’s house because you can see your friend inside.
Sometimes cancer cells have more unique identifiable elements on the outside, but other times they don’t. Imagine if multiple houses had the same doormat.
“That target would be on other cells that aren’t cancer cells and cause lots of toxicity,” said Carl June, the pioneering cancer scientist at Penn who developed the first FDA-approved CAR-T therapy and was not involved in the Rutgers trial.
That’s been the problem that’s held back CAR-T’s use in solid tumors.
The target in the Rutgers trial is a protein called HPV16 E7, found inside the cell. In tumors driven by the virus HPV16, it plays a key role in turning a cell into cancer.
“That’s like going after its Achilles’ heel,” June said.
Swarming the cancer
Pascale first arrived at Thomas Jefferson University Hospital in Center City in 2018 after suffering injuries in a car accident.
Doctors found a mass in the 43-year-old’s neck that turned out to be cancer.
Surgeons removed the mass, and she was fine until 2021 when doctors, including Johnson, found the cancer at the top of her esophagus.
They treated her with a combination of chemotherapy and radiation, which worked until March of 2022, when the cancer started appearing in Pascale’s lungs.
“All bets were off,” Johnson said.
Doctors gave Pascale chemotherapy and immunotherapy over the next couple of years, but in the spring of 2024, she developed an allergy to one of her chemotherapy drugs.
Around the same time, the cancer spread to the skin on Pascale’s back.
That’s when Johnson transferred her care to Hinrichs’ team at Rutgers.
Pascale started preparations for the treatment in July 2024, spending a couple weeks in the hospital.
The Rutgers team took T cells from her blood, gave her chemotherapy to knock her immune system down, and then transfused the engineered cells back into her body.
Within 48 hours, Pascale started feeling horrible.
“It was painful. It was my whole body, like I had pneumonia,” she said.
She had trouble breathing as the cells fought the cancer in her lungs. Hinrichs described it as “the T cells swarming the cancer,” leading to an inflammatory reaction.
The same thing occurred on her back. When Pascale’s sister came over, she saw one of the tumors in her skin was suddenly the size of a lemon.
Another one appeared red and felt like someone was burning a cigarette on her back.
The pain continued for three days, and then she felt well enough to go home. Pascale and her sister could see and feel the nodules on her back get smaller, until eventually they were gone.
Roughly five months later, Pascale’s scans showed no evidence of cancer. As of last month, a year and a half after she received the treatment, that was still true.
“What’s three days of pain compared with the opportunity that I have to live a lot of beautiful things with my family and friends?” Pascale said.
The future of the treatment
Hinrichs said his team is working to figure out why two of the patients, including Pascale and a patient with anal cancer, responded better to the treatment.
He cautioned that it’s too early to draw sweeping conclusions since the sample size is small. (Researchers will seek to recruit another 10 patients for the ongoing trial.)
The patients who had complete responses will need follow-up scans every few months to make sure their cancers have not returned.
It will still take years to finish evaluating safety and efficacy. Treatments tested in clinical trials often do not advance to become standard practice.
June, the Penn scientist, called the trial’s early results promising and noted that there weren’t any major safety problems reported.
Adverse effects seen in the trial were mainly those caused by the chemotherapy.
However, the drawback of using TCR therapy is that patients need a certain genetic background for it to work, June said. This is similar to how not every organ donor would be a good match for a recipient.
The genetic profile chosen for the Rutgers therapy is the most common in America. However, it is less common in Black and Asian people compared to white people.
Scientists hope it could one day be possible to manufacture the therapy with a warehouse approach, where TCR therapies that work across genetic backgrounds could be mixed and matched.
“It’s a practical issue that the drug companies face,” June said.
CAR-T, in comparison, can be used more broadly across different genetic backgrounds.
What matters most, since the treatment is expensive to make, is that the responses hold up over time, June said.
(The TCR therapy’s cost has not yet been set, Hinrichs said, since it is currently manufactured individually for each patient.)
“If they’re long lasting, then it’s really going to be a huge advance because nothing else works in the patients he’s treated,” June said.
At Jefferson, Johnson is cautiously optimistic about the treatment that has kept her patient alive.
If the therapy makes it through the rest of the trial process and proves effective, she hopes it could become “another thing in our armamentarium against this type of cancer.” (A type that doctors would hope to see less of since the introduction of the HPV vaccine in 2006.)
“I can’t tell you how wonderful it is to have a patient responding and living well when you saw things going the wrong way,” Johnson said.
Editor’s note: This story has been updated to clarify where the research has been presented and a reference to the prevalence of the genetic profile used in TCR therapy.
