Abstract
Findings from two phase II trials indicate that tumor-infiltrating lymphocyte therapy may prove an effective option for advanced melanoma and cervical cancer. The treatment was well tolerated, with durable responses seen even in patients whose disease was refractory to standard treatment.
For patients with advanced melanoma or cervical cancer whose disease is refractory to standard treatment, tumor-infiltrating lymphocyte (TIL) therapy may merit a closer look, according to two ongoing multisite phase II trials. Findings were presented during the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL, in June.
The studies, innovaTIL-01 and innovaTIL-04, are evaluating two autologous cell therapies—lifileucel/LN-144 and LN-145 (Iovance Biotherapeutics), respectively. Enrolled patients have a tumor lesion resected for TIL harvesting; the cells are then massively expanded in number at a central facility, aided by high amounts of IL2, as well as allostimulation with donor-derived irradiated feeder cells. After this 22-day process, the TILs are cryopreserved and can be infused at patients' convenience, explained principal investigator Amod Sarnaik, MD, of Moffitt Cancer Center in Tampa, FL.
Unlike chimeric antigen receptor (CAR) T cells, “these TILs aren't really manipulated in any way,” Sarnaik added. “The idea is that because they've previously trafficked into the tumor, hopefully they can do so again after in vitro expansion.”
Sarnaik reported results from 66 patients with advanced melanoma who had all relapsed on immune checkpoint blockade and, where appropriate, BRAF/MEK inhibitors (J Clin Oncol 37, 2019 [suppl; abstr 2518]). Nearly half (44%) also had brain or liver metastases. The objective response rate (ORR) to lifileucel was 38%, including two complete responses. Another 42% experienced stable disease, and the median duration of response (DOR) has not been reached.
“This is pretty much unmatched when compared with any other treatment we've seen for melanoma following progression on anti–PD-1 therapy,” Sarnaik observed.
Among 27 patients with metastatic cervical carcinoma refractory to the standard of care—chemotherapy, VEGF-targeted agents, and radiation—the ORR with LN-145 was 44.4%, including three complete responses (J Clin Oncol 37, 2019 [suppl; abstr 2538]). Stable disease was seen in another 40.7%, and the median DOR has not been reached.
“These are striking results so far,” said principal investigator Amir Jazaeri, MD, of The University of Texas MD Anderson Cancer Center in Houston. “We need longer follow-up to see how the DOR translates to progression-free survival, but I think this is pretty exciting for a difficult-to-treat population.”
In both studies, most toxicity issues were due to patients receiving preparatory regimens of lymphodepleting chemotherapy as well as six doses of IL2 to spur TIL growth in vivo. “There were some cases of febrile neutropenia and chills right after TIL infusion,” Sarnaik said; otherwise, lifileucel and LN-145 were well tolerated.
Ignacio Melero, MD, PhD, of Clínica Universidad de Navarra in Pamplona, Spain, suggested that in cases of melanoma progression after lifileucel, the investigators might want to consider re-treating these patients with checkpoint inhibitors. “It makes sense, because once TILs have been engrafted, the rules of the game could be different” in the tumor microenvironment, he said.
“A tumor's immune responsiveness is certainly dynamic, and any therapeutic intervention could change it in some way,” agreed Tara Mitchell, MD, of the University of Pennsylvania in Philadelphia. Overall, lifileucel and LN-145 appear “really impressive,” she said, showing significant promise in solid tumors, where CAR T cells have been more disappointing than not.
“I think many clinicians are convinced that the efficacy is there” with TIL therapy, Mitchell added, but because its potential has so far been reported anecdotally, studies such as Iovance's are “a big step forward in demonstrating that this technology is feasible and more broadly accessible.”
Therapies involving tumor-infiltrating lymphocytes (shown above with other immune cells) have demonstrated effectiveness in patients with certain cancers who have relapsed despite receiving immune checkpoint blockers.
The innovaTIL-01 trial is enrolling 75 more patients to support lifileucel's FDA registration. Meanwhile, LN-145 has received the agency's fast track and breakthrough therapy designations, Jazaeri said, and “considering that pembrolizumab [Keytruda; Merck] was approved for PD-L1–positive cervical cancer based on an ORR of just 14%, I think our data, although early, could be registration-enabling.” –Alissa Poh
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