Study: Adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TILs) is more effective in patients who have not been treated with checkpoint inhibitors than in those who have undergone one or more therapies.
Iovance Chief Medical Officer Dr. Friedrich Graf Finckenstein (Iovance)
Adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TILs) is more effective in patients who have not been treated with checkpoint inhibitors than in those who have undergone one or more therapies, according to research reported in Clinical Cancer Research (CCR).
The findings correlate with those from Iovance Biotherapeutics, which, along with the National Cancer Institute (NCI), funded the study under a cooperative research and development agreement. This suggests that TILs should be used much earlier in cancer therapy, perhaps even as a first-line treatment.
At the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting in June, Iovance presented data from a multi-center Phase II study of TIL cell therapy lifileucel involving a cohort of 66 patients who progressed after immune checkpoint inhibitors, or anti-PD-1 therapy. That data showed a 34.6 percent response rate and median duration of response that had not yet been reached at 33.1 months of median study follow-up. In that same set of patients, earlier intervention with TIL following initial progression on anti-PD-1 therapy was also associated with longer duration of response. Specifically, the duration of response to its lifileucel TIL therapy doubled for every six-month decrease in the cumulative duration of prior anti-PD-1 therapy.
Initially, “as we looked at the correlation of endpoints, including response rate and duration in the context of prior therapy, we didn’t see a direct correlation with prior anti-PD-1 therapy,” Iovance Chief Medical Officer Dr. Friedrich Graf Finckenstein, M.D. told BioSpace. “Interestingly, however, as we looked more deeply at the data, we saw that the duration of time treated with prior anti-PD-1 therapy was associated with duration of response after TIL therapy.
“In a way, that makes sense. You might very well see a response in a patient despite prior anti-PD-1 therapy, but the ability of TILs to do their job over a longer duration of time may be impacted. That’s the hypothesis,” Finckensetin said.
The CCR paper by Dr. Stephanie Goff of the NCI at the National Institutes of Health, “literally describes the experience with TILs over 20 years,” he pointed out, including the time before checkpoint inhibitors were available.
Goff studied 226 patients between 2000 and 2020. She reported an objective response rate (ORR) of 56% among patients who had never received anti-PD-1 therapy, and 24% among the 34 patients who had received anti-PD-1 therapies before being treated with TILs. Likewise, for patients who had never received MAPK inhibitors and then were treated with TILs, the ORR was 60%, but only 21% for those who had been treated with MAPK inhibitors first.
Progression-free survival was affected similarly. For anti-PD-1 treatment naïve patients treated with TIL therapy, median progression-free survival time was 6.5 months but fell to 3.2 months among those with prior anti-PD-1 treatments. For those who had been treated with MAPK inhibitors and then TIL therapy, the results were worse. Median progression-free survival fell from 6.6 months in MAPK inhibitor-naïve patients to just 2.5 months for those who had been previously treated.
The reason, Finckenstein hypothesizes, has to do with the effect of checkpoint inhibitors on the immune system. Basically, he said, “They inhibit an inhibitory pathway.” There are many reasons why TILs could be most effective before treatment with checkpoint inhibitors. Possibly, he suggested, as one defense mechanism of the tumor is checked, or targeted, others become more important. Some of those may be important to TIL therapy. “This is something that requires additional research,” he emphasized.
“Goff’s findings validate our findings at Iovance,” Finckenstein said. “The data suggests physicians should start a patient on TIL therapy as early as possible.” In practice, that implies starting TIL therapy as soon as a patient fails the first checkpoint inhibitor therapy.
To determine the validity of that approach, Iovance is studying whether TILs should, in fact, be administered first as part of a combination regimen in checkpoint-inhibitor-naïve patients. “TILs are administered as a one-time treatment, and checkpoint inhibitors are administered multiple times, so we are studying the benefits of starting a patient on TIL therapy and then treating them with checkpoint inhibitors,” he said.
That trial is still enrolling for metastatic melanoma among checkpoint-inhibitor-naïve patients. It combines TIL followed by pembrolizumab. Seven patients have been treated. “Early data suggests the response rate may be additive,” Finckenstein said. “We’ve seen an 86% response rate. Three had complete responses and three had partial responses. That’s highly encouraging, especially given the 30 to 40% response rate for pembrolizumab alone and the 50% response rate for TILs alone in this setting.”
Additionally, Iovance is looking at ways to make the TILs more potent. “One way is to combine them with other therapies (as with the above trial). Another is to make them more potent by selecting certain sub-populations of TILs, or by inactivating PD-1 signaling while maintaining their polyclonality.
“We’re also exploring ways to optimize manufacturing to shorten the manufacturing time,” Finckenstein said. Manufacturing of autologous TIL cells currently takes six-to-eight weeks in academic centers. Iovance does it in 22 days for its Gen2 TILs and in only 16 days for its Gen3 TILs.
