In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.
The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies that utilize T cells collected from the patient’s blood.
The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.
“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” said Jason Alan Chesney, MD, PhD, of the James Graham Brown Cancer Center at the University of Louisville (Ky.)
He presented the new data at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT008).
Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.
However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the clinical research division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.
The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.
“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
Patient-derived product
Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, where the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.
Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2.
Details from clinical trial
At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The had received a mean of 3.3 prior lines of therapy. All patients had received prior anti–PD-1/PD-L1 agents; 53 had received a CTLA4 inhibitor; and 15 had received a BRAF/MEK inhibitor.
These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.
In all, 24 patients (36.4%) had an objective response, 3 patients had a complete response, and 21 had a partial response. There were 29 patients who had stable disease and 9 who progressed. Four patients had not undergone the first assessment at the time of data cutoff.
After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to more than 35.2 months.
Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.
The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.
All patients experienced at least one adverse event of any grade. All but two patients experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy and one from acute respiratory failure deemed not related to TILs.
The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, hypophosphatemia, and lymphopenia.
“The adverse-event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloablative depletion regimen and IL-2,” Dr. Chesney said.
The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.