Early Study Shows Promise for Genetically Modified TILs in Advanced Melanoma

Rodabe Amaria, MD

Treatment with tumor infiltrating lymphocytes (TILs) engineered to express the transforming growth factor-β (TGF-β) dominant negative receptor (DNR) and nerve growth factor receptor (NGFR) showed some signs of activity and very little added toxicity for patients with metastatic melanoma following prior treatment with a checkpoint inhibitor, according to findings from a pilot study presented at the 2017 World Congress of Melanoma.

In the small phase I study, the initial disease control rate (response plus stable disease) following infusion of the TILs was 86% in 7 heavily pretreated patients with metastatic melanoma. The duration of response was limited, with 2 patients having a response lasting longer than 6 months.

"This is one of the first studies to use gene-modified TILs in metastatic melanoma patients. Before this, there had been just a couple other studies treating just a handful of patients," said investigator Rodabe N. Amaria, MD, Department of Melanoma Medical Oncology, Division of Cancer Medicine.

The TIL manufacturing process was broken into 2 steps, starting with 4 to 6 weeks of patient and laboratory procedures. In the lab, tumors were fragmented and cultured with IL-2, until there were at least 40 million T cells available. After this, the cells were cryopreserved or used fresh. Prior to infusion of the TILs, patients were checked to see if they could undergo treatment with high-dose IL-2, which was followed by hospital admission 8 days prior to infusion.

During these checks and hospitalization, the T cells underwent a rapid expansion protocol to grow the millions of cells into potentially billions, Amaria noted. During this phase, TGF-β and NGFR were transduced using a retroviral vector. Prior to infusion, patients underwent 7 days of lymphodepleting chemotherapy, consisting of cyclophosphamide and fludarabine. After infusion of the TILs, high-dose IL-2 was administered to promote T cell persistence and activation.

At the time of the analysis, the pilot study had enrolled 7 patients with melanoma. The average age of patients was 52 years (range, 29-68) and all had stage IV M1C disease. The average number of prior therapies was 4 (range, 3-6), and all patients had received a prior PD-1 inhibitor, including 3 who received ipilimumab and nivolumab. All but 1 of the patients had normal LDH levels.

Overall, by immune-related response criteria (irRC), 1 patient experienced a partial response, with 5 having stable disease at the time of the assessment. One patient developed progressive disease following treatment with the TILs. "We used irRC; so, although most patients are having some reduction of tumor, they are labeled stable disease until they get to the minus 50% threshold," noted Amaria.

The durability of response was not consistent across all patients who showed signs of stable disease. Overall, 2 patients (29%) showed signs of a persistent response lasting longer than 6 months. For 1 of these patients, a consistent drop in tumor burden, which was close to 90%, was seen out to 17 months. Additionally, "Three patients had an initial response and then progression at the 3-month time point," Amaria said.

Overall, there was no increase in toxicity observed following the infusion of the TILs, said Amaria. The adverse events reported were primarily associated with the lymphodepletion, which included anemia and thrombocytopenia. Both of which required transfusions. There was also a low level of febrile neutropenia. Following infusion with the TILs, there were also expected toxicities related to treatment with high-dose IL-2.

The TILs used in the trial were administered in 3 parallel groups, including TILs transduced with TGF-β, NGFR, or un-transduced. This method of administration allowed for each patient to be their own control, Amaria said. Based on this approach, additional translational research is planned to uncover an optimal TIL construct using detection of RNA levels by Nanostring.

"Translational work is ongoing to identify if our responders showed improved persistence of TGF-β DNR TIL over the NGFR TIL," added Amaria.

In other trials, without modification for TGF-β and NGFR, TILs have shown moderate benefits for treating patients with melanoma. In findings from 74 patients treated between 2007 and 2017 at the MD Anderson Cancer Center, the ORR was 42% with the TILs and high-dose IL-2, this was comprised of 8 CRs and 23 PRs.

Declines in response were seen following checkpoint inhibition, with ORRs around 30%. These were also seen in other trials exploring TILs, Amaria noted. In an NCI study, the ORR was 25% following prior anti—PD-1 therapy. In another study, conducted by Lion/Iovance, the ORR was 29% for anti–PD-1 refractory patients.

"There are many potential reasons for why this might be," she said. "We know that in order to get some sort of a response to TILs, the T cells have to persist and stay around, and there can be very immunosuppressive effects in the tumor microenvironment. Melanoma can secrete soluble factors that inhibit T cell function, like TGF-β."

The phase I study continues to enroll participants at the MD Anderson Cancer Center. The trial has an enrollment goal of 15 patients. Additionally, translational work will continue to find an optimal TIL construct (NCT01955460).

Amaria RN, Haymaker C, Forget M-A, et al. TGF-β dominant negative receptor (TGF-DNRII) and NGFR-transduced tumour infiltrating lymphocytes (TIL) and high dose interleukin-2 (IL-2) in patients (pts) with metastatic melanoma (MM). Presented at: 2017 World Congress of Melanoma; October 18-21, 2017; Brisbane, Australia. Presentation SMR04-1.

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"We haven't had any major issues with this," said Amaria. "We are able to treat patients on our own melanoma unit, patients don't need to get transferred to the ICU. Overall, this is a very safe protocol."