Tumor-infiltrating lymphocytes show ‘dramatic’ results in metastatic melanoma
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More than 80% of patients with heavily pretreated metastatic melanoma experienced tumor shrinkage after receiving the adoptive cell therapy lifileucel, according to results of a phase 2 study.
The study — presented during the virtual American Association for Cancer Research Annual Meeting — was the first to examine the efficacy of tumor-infiltrating lymphocytes (TILs) for unresectable or metastatic melanoma in the post-PD-1 inhibitor era, according to Jason A. Chesney, MD, PhD, director of James Graham Brown Cancer Center and associate vice president for health affairs at University of Louisville.
“There is very little to offer these patients that has been shown to improve outcomes,” Chesney told Healio, adding that, to his knowledge, there are no FDA-approved therapies for second-line use after treatment with immune checkpoint inhibitors.
“As a practicing melanoma oncologist, these results are nothing short of dramatic and outstanding for this patient population,” he said. “It's transformative and not only gives patients hope, but the opportunity to live a long life.”
Lifileucel (LN-144, Iovance Biotherapeutics) is an adoptive cell therapy derived by isolating TILs from a resected portion of a patient’s tumor and multiplying them in a laboratory. The manufacturing process occurs at a centralized facility and takes 22 days, according to the researchers.
Chesney and colleagues presented results from cohort 2 of an open-label phase 2 study to determine the efficacy and safety of lifileucel among patients with unresectable metastatic melanoma. All participants experienced disease progression after receiving anti-PD-1 therapy, as well as BRAF/MEK inhibitors if they had BRAF V600-mutant disease.
The cohort included 66 patients (median age, 55 years; range, 20-79; 59% men) who received a mean 3.3 (range, 1-9) previous lines of therapy.
All patients previously received anti-PD-1/anti-PD-L1 therapy, and 80% previously received anti-CTLA-4 therapy.
The study regimen started with 1 week of nonmyeloablative lymphodepletion with 60 mg/kg IV cyclophosphamide and 25 mg/m2 fludarabine, followed by a single infusion of lifileucel. Patients then received up to six doses of interleukin (IL)-2 (600,000 IU/kg/dose) to promote TIL activity.
Efficacy as determined by the investigator-assessed objective response rate (ORR) served as the primary endpoint for the cohort 2 analysis. Secondary endpoints included safety and additional efficacy measurements.
Patients received a mean dose of 27.3 × 109 TIL cells.
Median follow-up was 28.1 months, with a data cutoff date of Dec. 14, 2020.
Results showed an objective response rate of 36.4%, with a complete response rate of 4.5%.
Forty-four percent of patients had stable disease after the regimen, for an overall disease control rate of 80.3%.
Median duration of response had not been reached (range, 2.2-35.2 months), which Chesney said indicates lifileucel induced “very durable responses.”
“The long game with many types of cancer is to turn it into a chronic illness. That means we don't need to eradicate the tumors; we need to just need to prevent the tumors from growing and spreading,” he told Healio. “This therapy clearly did that in our study population.”
Most toxicities were expected, related to lymphodepletion and hematologic in nature, Chesney said.
Grade 3 to grade 4 treatment-emergent adverse events occurred among 97% of patients and included thrombocytopenia (81.8%), anemia (56.1%), febrile neutropenia (54.5%), neutropenia (39.4%), hypophosphatemia (34.8%) and leukopenia (34.8%).
Two patients died during the study, one of intra-abdominal hemorrhage possibly related to TILs and one of acute respiratory failure deemed unrelated to TILs, according to the investigator’s evaluation.
“The TILs themselves are very safe,” Chesney told Healio.
However, he acknowledged “there is quite a bit of toxicity associated with high-dose IL-2,” which Chesney said has been well-established in previous studies because IL-2 is an FDA-approved treatment for stage IV melanoma.
“With that said, IL-2 can be given safely [to] patients who have adequate respiratory and cardiac function,” he said.
Although TILs remain investigational, they would represent perhaps the first option for late-stage melanoma that can improve patient outcomes if they receive commercial approval, Chesney said.
“This therapy is going to have a large, long-term impact on survival for our patients,” he said. “TILs are a very important treatment option for patients with stage IV melanoma after receiving therapy with immune checkpoint inhibitors. I believe the FDA is going to look favorably on these results."
Perspective
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Kim Margolin, MD
TIL cell therapy for advanced melanoma — an immunogenic and chemotherapy-resistant malignancy with only one druggable pathway — has a long track record and is now experiencing a renaissance. TIL therapy emerged soon after high-dose IL-2 and autologous IL-2-stimulated peripheral blood-derived effector cells were studied at the NCI, which found that IL-2 alone was as beneficial as with ex vivo-expanded cells. This study — performed by a biotechnology-sponsored, non-NCI and multi-institution group — used unselected TILs and traditional lymphodepletion with cyclophosphamide and fludarabine, as well as post-TIL high-dose IL-2 to maintain TIL cells’ survival, expansion and cytotoxicity.
Investigators at the NCI are working on melanoma and several other malignancies to identify the most active TIL phenotype to select for enrichment, the most important immunogenic epitopes on-tumor and the most reactive TIL cells. They also are trying to create a patient-specific vaccine and to identify the most predictive biomarkers that could lead to overall better outcomes by enriching their strategy for the cells, patient characteristics and tumor features with the highest likelihood of benefit.
It is critical that today’s commercial production of TILs for melanoma start by faithfully replicating the most promising results from the NCI’s Surgery Branch. Thereafter, the results of the Surgery Branch’s current focus on patient-specific neoantigens (predominantly from UV-induced mutational damage to the tumor genome) and TIL subsets with the most potent and antigen-specific cytotoxicity may also be reproduced and then taken into new directions — including the use of emerging cytokines — that might lead to even safer regimens and better patient outcomes.
As the landscape continues to change and new therapies join the armamentarium against advanced melanoma, the benefit of TIL therapy will need to be continually examined and improved through the intensive study of patient, tumor and therapy factors that interact to determine outcomes.
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Philip D. Greenberg, MD
This multicenter study addresses a critical issue that has limited the availability of TIL therapy and the interpretation of previous studies. The results show TIL therapy can be performed with cell generation at a centralized facility with the required technical expertise and then dispersed to multiple centers for use in treatments.
It also shows that TILs can be successfully generated from tumors that are resected from visceral organs, in addition to lymph nodes or skin/subcutaneous sites.
The toxicity observed in this study was significant although generally manageable. There was a high level of grade 3 or grade 4 toxicities, and two patients died in the study of causes potentially related to the treatment regimen. However, toxicity associated with this treatment typically occurs earlier, within the first 2 weeks of therapy.
The tumor regressions observed in this study, as measured by ORR and complete response rate, were lower than previous reports from the NCI.
It also appears that efficacy was independent of CD4 or CD8 T-cell composition and the cell dose infused; however, the target cell dose and composition are not clear from the presented data.
Further study should focus on the identification of biomarkers in tumor or infiltrating cells to potentially predict success or failure. We also don't know if the high dose of IL-2 is needed after infusion, but we do know its role in toxicity.
It also would be interesting to see this broadened to more tumor types where it could be effective, along with post-infusion strategies being deployed, such as administering vaccines or checkpoint blockade to increase the therapeutic activity of TILs.
Reference:
Mehta GU, et al. J Immunother. 2018;doi:10.1097/CJI.0000000000000223.
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Roman Groisberg, MD
The response rate in this very heavily pretreated population of patients with metastatic melanoma was quite remarkable, with greater than 80% of patients having some amount of disease reduction.
Notably, the responding patient population was predominantly PD-1-refractory and had a best response of progressive disease to previous anti-PD-1 therapy. This is a particularly difficult population to treat, yet lifileucel was effective.
Additionally, the deepening responses over time suggest durability to these TILs, with potential for long-term response and hopefully a resulting “tail” to the survival curve. This is further boosted by the notably few deaths among patients who achieved a response to therapy.
Lifileucel is becoming an exciting option for patients with melanoma that is refractory to treatment with immune checkpoint inhibitors. However, given the initial toxicity during lymphodepletion and IL-2 administration, lifileucel likely will remain out of reach for older patients and those with underlying cardiopulmonary comorbidities. Considering this initial toxicity, as well as the need for specialized care, lifileucel is unlikely to replace checkpoint inhibitors as the category 1 front-line option for metastatic melanoma.
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Chesney JA, et al. Abstract CT008. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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