Guidelines: Toxicity management vital with tumor-infiltrating lymphocytes
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Key takeaways:
- Clinicians should have a low threshold for stopping interleukin-2 when treating with tumor-infiltrating lymphocytes.
- Patients with poor cardiac, lung or kidney function may not be candidates for TIL therapy.
Clinicians treating patients with tumor-infiltrating lymphocytes should closely monitor toxicities associated with interleukin-2 and halt administration of the drug if necessary, according to the first guidelines regarding the therapy.
The recommendations, published in Journal for ImmunoTherapy of Cancer, provide guidance from patient selection through the end of treatment with tumor-infiltrating lymphocytes (TILs).
“This is a unique data set that comes from many investigators who have used TILs before — kind of our collective experience and knowledge and resources we developed,” Adam J. Schoenfeld, MD, thoracic oncologist at Memorial Sloan Kettering Cancer Center, told Healio. “My hope is that for those who are developing new TIL programs or ones that are just getting started, these [guidelines] will help them so they don’t have to make the same mistakes that we did when we all started.”
Lifileucel (Amtagvi, Iovance Biotherapeutics), for treatment of adults with advanced melanoma, became the first TIL therapy to gain FDA approval in February.
Numerous trials are starting or ongoing across the country evaluating TIL therapy in melanoma as well as other cancers, including advanced or metastatic non-small cell lung cancer; recurrent, metastatic or persistent cervical carcinoma; head and neck squamous cell carcinoma and breast cancer, according to background information provided by the guidelines’ authors.
The international TIL Working Group developed the guidelines as “expert consensus recommendations” to provide clinicians and researchers with information to help better serve patients.
Administration of IL-2
Interleukin-2 (IL-2) helps TILs multiply and attack tumors.
However, many of the toxicities associated with TIL therapy stem from IL-2, including fever, rigors, hypotension, shortness of breath, pulmonary edema, oliguria and neurotoxicity, the authors wrote.
“Before this, those who had experience with IL-2 had been giving it as a primary modality of treatment, so giving it without TIL,” Schoenfeld said.
IL-2 is an approved therapy for certain individuals with melanoma and kidney cancer but used much higher doses as a stand-alone treatment compared with a maximum of six doses used to promote the expansion of TILs, he added. The old high-dose approach to IL-2 could lead to severe toxicity among recipients.
“The toxicity tended to be transient, but it could be serious and life threatening,” Schoenfeld said. “[With TILs], it’s a totally different mindset. We’re not giving IL-2 as the primary treatment. It’s really to help stimulate the TILs and help them grow, and no one knows how much is the right dose to give.”
Schoenfeld noted responses have been seen with fewer than six doses, sometimes even none. Therefore, clinicians should have a low threshold for stopping IL-2.
“There’s no correlation between the amount of IL-2 and outcomes for this product,” he said. “If you run into toxicity, there’s no known benefit of pushing beyond, and there is known toxicity.”
Management of lymphodepletion
Nonmyeloablative lymphodepletion reduces competition in the tumor microenvironment, allowing TILs to be more effective.
The TIL regimen starts with high-dose of cyclophosphamide — more than what is used in chimeric antigen receptor T-cell therapy — and that can cause cytopenia for multiple weeks, as well as other toxicities.
Patients receive lymphodepletion, then the TILs, and then IL-2. They do not have a lot of time to recover between lymphodepletion and the IL-2 regimen, and the stacking of treatments can cause increased toxicity.
“Patients are going to get IL-2, and that causes capillary leak syndrome,” Schoenfeld said.
“The patient’s fluid status during the lymphodepletion is really important. Planning ahead to try to get them back to their baseline weight and fluid status so that they’re not volume overloaded after the lymphodepletion process is really key,” he added. “If you don’t give them appropriate drugs to help diuresis and help urinate out these fluids, then by the time they get the high dose IL-2, it could leak into their lungs and cause respiratory issues, pulmonary edema. It’s very important to watch their weight their fluid status very carefully.”
Patient selection
TILs could be a transformative therapy for many individuals, but they will not be for everyone.
The toxicities associated with lymphodepletion and IL-2 limit who can benefit.
Schoenfeld said patients must have sufficient cardiac, lung and kidney function.
The performance status is “critical as well,” he said. “Patients who spend most of the day seated, lying down in bed or who are bed bound would not be good candidates for this treatment.”
TILs probably would not be a good option for individuals with rapidly progressing disease because the process takes about 2 months.
Patients also need to have a tumor that can be resected to generate TILs from.
Future considerations
Schoenfeld stressed these guidelines stem from clinical trial results. As TILs are used in the real world, more data must be collected.
“Things are very different when they’re done in a trial versus in the approved setting,” he said. “We need to look at the outcomes and the safety profile of this in that setting, and based upon that, actually come up with more individualized guidelines for different populations. This is approved for a specific population, but I’m sure it will also get used and explored in other settings — in melanoma, too.”
The TIL Working Group designed these guidelines to be universal, across multiple cancer types, but future results could cause them to recommend changes.
Schoenfeld hopes more studies research how much lymphodepletion and/or IL-2 is necessary for patients to have success. Trials have already began involving engineered and modified TILs, which could have a role in reducing treatment-related toxicity.
“Right now, we don’t engineer them at all, but if you modify [TILs] so that they have co-stimulation, you potentially won’t need the high-dose IL-2 and can lower some of the other requirements, like the lymphodepletion — maybe even how much tissue you need to make the product,” Schoenfeld said. “If you make them a more super-charged or enhanced product, that might eliminate the need for some of the toxic components of the therapy. Those trials are just getting underway in melanoma and lung cancer.”
For more information:
Adam J. Schoenfeld, MD, can be reached at schoenfa@mskcc.org.
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