Josh Friedman , 2025-04-24 12:32:00
April 24, 2025
5 min read
Key takeaways:
- The addition of pembrolizumab to TIL therapy improved response rates among individuals with metastatic gastrointestinal cancers.
- Government cuts are “slowing down” further research, a researcher said.
A novel approach to tumor-infiltrating lymphocyte therapy yielded higher response rates among patients with metastatic gastrointestinal cancers than prior strategies, according to results of a phase 2 trial.
The addition of pembrolizumab (Keytruda, Merck) to tumor-infiltrating lymphocytes (TILs) more than tripled the number of responders, from about 8% to nearly 24%.
“Research rarely moves in a straight line,” Steven A. Rosenberg, MD, PhD, senior investigator in NCI’s Center for Cancer Research, chief of the NCI Surgery Branch and professor of surgery at Uniformed Services University of Health Sciences and George Washington University School of Medicine and Health Sciences, told Healio.
“Most things you try don’t work but, when we find things like this that do work, that gives us a hook onto what we can then pursue next,” he added. “We’re working around the clock trying to develop new treatments. I think they’re going to continue to improve.”
‘Motivation to improve’
Lifileucel (Amtagvi, Iovance Biotherapeutics) became the first FDA-approved TIL therapy in February 2024. It garnered approval for treatment of adults with unresectable or metastatic melanoma.
Lifileucel is an adoptive cellular therapy derived by isolating TILs from a resected portion of a patient’s tumor and multiplying them in a laboratory for subsequent reinfusion into the patient.
Rosenberg, who first reported on TILs for advanced melanoma in 1988, has continued his research of TILs in other tumor types.
“Melanomas have very large numbers of mutations because they’re the result of UV irradiation exposure that can cause these mutations,” Rosenberg said. “When we tried to apply this to the common solid, epithelial cancers, these TILs did not work.”
That prompted Rosenberg and other researchers to investigate different TIL approaches.
Healio previously reported on a novel way Rosenberg and colleagues used TILs for treatment of metastatic colorectal cancer.
They took a gene-encoding receptor found in a TIL and used a retrovirus to insert it into normal lymphocytes. In all, 42.9% of the limited cohort achieved partial responses.
“I make rounds every day on patients,” Rosenberg said. “When I walk into a patient’s room who’s responding, there’s joy. The family’s laughing and happy. Everybody is in good spirits. Then I walk into the next room, and the treatment hasn’t worked. The patient is in tears. Their family doesn’t know what to do because they have no way to deal with all of this. There’s a lot of motivation to improve.”
Methods
Rosenberg and colleagues conducted an evolving, single-arm phase 2 trial of TILs in metastatic gastrointestinal cancer.
They included 91 patients aged 18 to 72 years with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers. Participants had a variety of malignancies, including upper and lower gastrointestinal cancers, early-onset colorectal cancer, hepatopancreatobiliary cancer, pancreatic adenocarcinoma and cholangiocarcinoma.
All participants received chemotherapy for lymphodepletion and high-dose interleukin-2 to promote TIL expansion and activity.
Response to therapy served as the primary endpoint. Safety served as the secondary endpoint.
‘Hot on the trail’
The first cohort of 18 patients (median age, 49 years; range 37-63; 50% women) received unselected TILs that had not been screened for anti-cancer activity.
None responded.
A second cohort of 39 patients (median age, 52 years; range, 37-69; 62% women) received TILs that had been screened for their ability to recognize neoantigens.
Results showed a response rate of 7.7% (95% CI, 2.7%-20.3%) in this group. Duration of response ranged from 8 months to more than 70 months.
“We developed techniques to try to identify the lymphocytes that are attacking these solid cancers that actually recognize the cancer,” Rosenberg said. “It turns out there were only about one in a thousand of them. When we developed techniques to grow higher frequencies of those cells, for the first time we started seeing responses in patients with the common cancers.
“The first patient we treated with these selected cells had previously received cells that were not selected,” Rosenberg added. “She didn’t respond [to the unselected cells]. We then gave her the selected anti-cancer cells, and she did respond. She had widespread disease in her lungs and in her liver, and she’s now completely disease-free 12 years later.”
However, Rosenberg described the 7.7% as “not nearly enough.”
When researchers evaluated the second cohort, they found the TILs had high levels of PD-1 cell death.
They added pembrolizumab — a PD-1 inhibitor — to counteract that effect and gave the combination therapy to 34 more patients (median age, 50 years; range, 25-71; 53% men).
Nearly one-quarter (23.5%; 95% CI, 12.4%-40%) had an objective response. Duration of response ranged from 4 to 42 months.
Objective responses among cohorts occurred among patients with cholangiocarcinoma, pancreatic cancer and colon and rectal cancers.
In addition to those responders, another eight patients had a tumor reduction of at least 30% at their first follow-up.
“The excitement is that we’re not attacking just individual types of cancers,” Rosenberg said. “Because we’re attacking the mutations, we potentially can treat any cancer that has mutations.”
Grade 3 or worse adverse events occurred in all patients due to chemotherapy aimed at the depletion of inhibitory lymphocytes prior to treatment, and 30% experienced severe adverse events.
One person died from adenoviral hepatitis, which researchers attributed to treatment. Additionally, 9.6% of patients had to deescalate care.
Among patients who received pembrolizumab, 24% had grade 3 or worse adverse events and 5.9% had serious adverse events.
“This is the first paper to describe a trial of the use of TIL immunotherapy for the treatment of the common solid, epithelial cancers,” Rosenberg said. “We’re now hot on the trail of trying to improve this immunotherapy, and we have multiple different approaches that we’re working on in the laboratory that we intend to translate into patients.”
Government ‘slowing down’ research
Further evaluations of the data revealed ways to potentially increase response.
“There was a statistically significant difference between responders and nonresponders based on the number of antigen-reactive CD4 cells, not CD8, although we generally give both. That was one important clue that we’re working on,” Rosenberg said. “The second is the number of antigens that we target has a profound impact on the likelihood of having a response. When we could target three or more [antigens], response rates were over 40%. We’re working on ways now to identify additional targets and lymphocytes that can target those.”
The genetic engineering of TIL to improve their effectiveness is also being pursued, as well.
However, government cutbacks were “slowing down” research, Rosenberg said but that is improving.
Healio previously reported that HHS planned to lay off 20,000 employees.
“We were able to continue work, but restrictions on personnel hiring and difficulties in ordering new materials existed” Rosenberg said “but they are being corrected now that we have a new NIH director.”
For more information:
Steven A. Rosenberg, MD, PhD, can be reached at sar@mail.nih.gov.
