Lifileucel approval the start of a ‘glorious future’ for cell therapy in solid tumors
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It took more than 35 years for tumor-infiltrating lymphocytes, which Steven A. Rosenberg, MD, PhD, and colleagues first reported on in 1988 for the treatment of advanced melanoma, to progress enough to gain FDA approval.
Some may believe the realization of decades of work would be the perfect swan song for the 83-year-old Rosenberg, who received the American Association for Cancer Research Award for Lifetime Achievement in Cancer Research this month.
Not Rosenberg, however.
As physicians, researchers and patients celebrated the FDA approval for lifileucel (Amtagvi, Iovance Biotherapeutics) in February, Rosenberg had long started work on the future of tumor-infiltrating lymphocytes (TILs).
“I’m very excited about this approach to treating cancer," Rosenberg, 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. “I see it as the approach most likely to result in significant improvements in the future.
“In many ways, I feel like we’re just getting started now in the application of cellular therapy to the common cancers that result in 90% of all cancer deaths — the solid epithelial cancers,” he added. “That’s the major challenge we now face. I think we have the tools to begin to develop substantial improvements. We have a talented team of scientists working on trying to improve it. It’s just the beginning of what I think is going to be a glorious future for cellular therapy.”
‘A dream come true’
Lifileucel is indicated for adults with unresectable or metastatic melanoma who had previously been treated with a PD-1 inhibitor and, if BRAF-positive, a BRAF inhibitor with or without a MEK inhibitor.
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.
The treatment regimen includes nonmyeloablative lymphodepletion to promote cell engraftment prior to TIL infusion. Recipients are then given up to six doses of interleukin-2 to promote TIL expansion and activity.
Results of a phase 2 trial showed a 31.4% (95% CI, 24.1-39.4) objective response rate with the agent.
“Once patients fail checkpoint blockade therapy with anti-PD-1, or the combination with other checkpoints, there’s nothing left,” James J. Mulé, IPhD, immunologist and associate center director of translational science at Moffitt Cancer Center, told Healio. “This therapy was shown to be effective in 30-plus percent of patients who had failed those treatments. There was nothing else available to them.”
“The nice thing about those responders — about half might maintain that response for years,” added George Ansstas, MD, associate professor at Washington University in St. Louis and leader of the solid tumor TIL program at Siteman Cancer Center.
A confirmatory trial is ongoing and could take a few years to generate the necessary data, Ansstas said.
Mulé worked with Rosenberg on TILs at the NIH in the 1980s and marveled at the “long journey” it took to help this patient population.
It began with ineffective radiation and chemotherapy. Surgery only worked in early stages of the disease. Then, a long period of stagnation occurred.
“A lot of various treatments were tried and uniformly failed in [patients with] stage IV metastatic cancer,” Mulé said.
Then, about a decade ago, immune checkpoint inhibitors and targeted therapy for individuals with the BRAF mutation gained FDA approval.
Immune checkpoint inhibitor response rates are between 30% to 40%, Mulé said, but patients who did not respond had no subsequent treatment option until TILs.
“It’s a dream come true that we all worked very hard over 30-plus years to get to that point [of approval],” he said. “Now, the challenge is how do we increase that [response rate] beyond 30%? And how do we take it to other tumor types?”
Applying TILs to other tumor types
Mulé joked he would not be around if it took another 40 years for more progress in TILs to be made.
Fortunately for him, that seems highly unlikely.
In the next 5 years, “I would expect it to have received approval for additional cancers in addition to melanoma,” Rosenberg said.
The floodgates may have opened with approval of lifileucel.
In melanoma research, Mulé noted studies looking into biomarkers that could help identify why certain patients respond to treatment and others do not.
“Then the question is, how do you generate TILs from tumors in patients who don’t respond to TILs?” he asked. “What is it about their tumors that are different from patients whose tumors give you a very good response? A lot of efforts are looking at genetic differences between those tumors, looking at the tumor microenvironment to [determine] whether there are differences in what immune populations are in those tumors.”
Another strategy under investigation involves inducing TILs in tumors that do not produce them. “[Researchers] are looking at oncolytic viruses, which they say turn a cold tumor into a hot tumor, to determine whether that maneuver will generate TILs that you can then [harvest] from the tumor, expand and give back to patients,” Mulé said.
Ansstas discussed research into moving TILs up in the treatment regimen with checkpoint inhibitors, or the best combination with TILs in the latter stages of treatment to improve response.
“One of the thoughts is, for example, adding PD-L1 and LAG3 — other immune checkpoint inhibitors that could really activate these TILs,” Ansstas said. “We need to investigate what is suppressing these T cells, and see what immune checkpoint inhibitors are being expressed, and try to target [them].”
Multiple studies are being conducted into the impact of TILs on other cancers outside of melanoma.
Ben Creelan, MD, thoracic oncologist at Moffitt Cancer Center, co-authored a paper published in Nature Medicine in 2021 about a phase 1 trial using TILs for metastatic lung cancer. The study had 13 evaluable patients, and of those, three had confirmed responses and 11 saw a decrease in tumor burden.
“That really was the first evidence that you could take TILs beyond melanoma and show good response in a subset of patients with non-small cell lung cancer,” Mulé said. “Again, these were patients who had failed all other treatments.”
Mulé also mentioned work by another colleague at Moffitt, Shari Pilon-Thomas, PhD, an immunologist evaluating use of TILs in bladder cancer, and another researcher’s work in women with cervical cancer.
“We do know that you can use T cells to identify antigens on the solid cancers in up to 80% of all patients with metastatic solid cancers,” Rosenberg said. “We’ve published the effective treatment of patients with breast, cervical, colon or liver cancers.”
Whether TILs can be effective treatment for solid tumors is a question asked and answered in the affirmative, according to Rosenberg. The expansion of TILs as a treatment modality faces another obstacle, he added.
“The challenge now is in figuring out ways to generate cells of sufficient reactivity with sufficient proliferative capacities that will mediate tumor regression in a larger percentage of patients,” he said.
Currently, about 15% to 20% of patients with the metastatic solid cancers respond in clinical trials Rosenberg and colleagues have conducted, he said.
“The cause of the cancers were originally mutations that existed in the DNA of patients,” Rosenberg said. “When I say that 80% of patients develop in vitro cellular responses against their own cancer, those are often very minor responses — one out of every 1,000 tumor-infiltrating lymphocytes in the solid cancers have the recognition capacity to mediate rejection of those tumors. Identifying those rare subpopulations growing them and maintaining the kinds of properties necessary to mediate tumor rejection are the real challenges we face right now.”
The opportunity exists to attack multiple diseases with this therapeutic approach.
“Because we are attacking the products of the very mutations that gave rise to the cancer and have developed in the patient during cancer growth — and virtually all cancers have these mutations — this is a kind of approach that’s potentially applicable across multiple different cancer histologies,” Rosenberg said.
Nervous optimism
Ansstas, like Rosenberg and Mulé, is optimistic about the future of TILs.
He also said he is “nervous.”
Several of Ansstas’ patients have expressed their excitement for TILs, and rightfully so, but it will take time to get them treatment.
Washington University is one of 25 to 30 centers that will administer the therapy, but it likely will not start for 6 to 8 weeks, he said.
Ansstas has concerns about accommodating enough patients when Washington University begins.
“It’s almost one center for every two states,” he said. “Half of patients with melanoma will respond very well to immune checkpoint inhibitors. What is the number of patients [who do not respond] in two states that one center can accommodate upfront? Over time, I’m pretty sure we’re going to have more centers that could accommodate this treatment, but the first influx is going to be huge.
“As much as I’m excited that we have an option, I’m anxious if I’m going to be in a position on prioritizing treatment for patients. For example, if we have 12 patients, and we can only accommodate four, we need to run these patients internally and select the best fit for it, but that creates some intense pressure on us, because we know all 12 could be potential patients, but now we’re selecting the best who might benefit from the treatment.”
Lifileucel is not a treatment for “all comers,” Ansstas emphasized.
The adverse effects of TILs themselves are minimal “because they are reacting against mutations that exist in the cancer and not in normal tissues,” Rosenberg said. “There are no on-target, off-tumor toxicities.”
However, lymphodepleting regimens before treatment, and interleukin-2 used to populate the cells and keep them alive, do cause adverse events.
Common adverse events to lifileucel included chills, pyrexia, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia and dyspnea.
“You need patients to have good performance status — they need to have good functional status in terms of organs,” Ansstas said. “If they have any adverse event from interleukin-2, they might not be able to rebound fast. Fortunately, probably 70% to 80% of allcomers might fit these criteria.”
Ansstas expressed optimism regarding possible reduction of interleukin-2 in treatment.
“The full course I would say is toxic,” he said. “It does have side effects, though we are generating more data that give us more relief that this treatment will be more tolerable than what we expect, based on the fact that even if we cut short the number of interleukin-2 doses, we’ve seen that the benefit and the efficacy of the treatment was not compromised. Meaning, this now lowers the threshold for me as a screening physician. If I give a couple of doses of interleukin-2 and my patient has bad side effects, I feel comfortable holding off the four remaining doses. We’re not really forced to finish the full six treatments with high-dose interleukin-2.”
Ansstas also noted research into possibly replacing interleukin-2 down the road.
“There are some other companies utilizing the embedded interleukin-15 to avoid high-dose interleukin-2 post infusion,” he said.
The more patients able to undergo treatment increases the burden on manufacturing, though.
Research laboratories like the NCI can do it “readily,” Rosenberg said. Commercial companies, not so much.
“Virtually all commercial companies are based on distributing drugs in a vial that they can distribute easily around the country,” he said. “Here, with the use of cellular therapies, we’re developing a new drug for every patient. We’re using their own cells that either naturally have reactivity or are genetically engineered to have antitumor reactivity. These are new problems that need to be solved both at the basic scientific level as well as a level of regulatory approval.”
Cost is another hurdle.
Iovance announced lifileucel would cost $515,000, and the company’s belief is insurance would cover costs like it does for chimeric antigen receptor T-cell therapy, according to an NIH press release.
It is a large number, but one that could reduce financial burdens because it is a one-time therapy.
“It’s a lot of money that insurance might pay upfront, but if you think a bit about any other immune checkpoint inhibitors or target treatments, what is the monthly cost? And how many months will these patients be on treatment — or years?” Ansstas said.
Improvements in manufacturing could also lower costs over time.
Ansstas, Rosenberg and Mulé all believe these challenges can be overcome, and cellular therapy will grow into a foundational piece of cancer treatment along with surgery, radiation and chemotherapy.
“When it comes to immunotherapy, one of the most important findings that we’ve made in the last several years is an understanding of the targets of the immune system on the cancer,” Rosenberg said. “The fact that we can now, today, identify T cells that recognize a cancer in 70% to 80% of all patients with metastatic cancer holds substantial optimism for the ability to take advantage of that in developing new treatments. One of the advantages of cell therapy — it’s a living drug. When we inject those lymphocytes that can recognize the cancer, they expand thousands-fold in the first week or two after they are injected.
“I see immunotherapy playing a very important part of the future of cancer treatment in addition to the standard treatments,” he added. “I’m a surgeon, and probably 80% of people who can be cured of cancer today are cured by surgery. I don’t expect the current methods to be completely replaced, but I do see immunotherapy adding to treatment either in conjunction with other modalities or as a standalone treatment.”
References:
- Chesney J, et al. J Immunoother Cancer. 2022;doi:10.1136/jitc-2022-005755,
- Creelan BC, et al. Nat. Med. 2021;doi:10.1038/s41591-021-01462-y.
- NIH. First cancer TIL therapy gets FDA approval for advanced melanoma (press release). Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-amtagvi-til-therapy-melanoma. Published March 5, 2024. Accessed April 18, 2024.
- Rosenberg SA, et al. N Engl J Med. 1988;doi:10.1056/NEJM198812223192527.
For more information:
George Ansstas, MD, can be reached at gansstas@wustl.edu.
James J. Mulé, IPhD, can be reached at james.mule@moffitt.org.
Steven A. Rosenberg, MD, PhD, FAACR, can be reached at sar@mail.nih.gov.
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