Tumor-infiltrating lymphocyte therapy appears safe, effective in melanoma, cervical cancer
CHICAGO — Data from two trials evaluating the safety and efficacy of adoptive cell transfer with autologous tumor-infiltrating lymphocytes showed promising overall response rates for the treatment of advanced metastatic melanoma and cervical cancer, according to results presented at ASCO Annual Meeting.
The study data show that investigational therapy LN-144 (Lifileucel; Iovance Biotherapeutics) had a 38% overall response rate among patients with advanced metastatic melanoma. Investigational therapy LN-145 (Iovance Biotherapeutics) conferred a 44% ORR among patients with advanced cervical cancer.
Both trials used an identical treatment method that involve isolating a patient’s tumor-infiltrating lymphocytes (TILs) from a resected portion of their tumor, and then multiplying them in a laboratory. The manufacturing process takes 22 days.
Patients in both trials received lymphodepletion for 1 week with cyclophosphamide or fludarabine and were given up to six doses of interleukin-2 after the infusion of LN-144/LN-145.
“Taking the tumor out of the patient allows us to grow these lymphocytes to a far greater number,” Amod Sarnaik, MD, surgical oncologist with the Melanoma Center of Excellence at Moffitt Cancer Center and lead author of the LN-144 study, told HemOnc Today.
“These patients are treatment refractory, so their disease has progressed on the best FDA-approved treatments that are available,” he said. “Our treatment has a 38% response rate. You can walk around the ASCO exhibit hall and you are not going to find very many, if any, treatments that can match that response rate.”
There are few effective treatment options for patients with advanced cervical cancer, according to Amir Anthony Jazaeri, MD, vice chair for clinical research and the director of the Gynecologic Cancer Immunotherapy Program in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center.
“It’s nice to have a process that’s only 22 days, because these are patients with metastatic disease and if they wait too long, they can experience progression,” Jazaeri told HemOnc Today.
He explained that the entire process takes about 2 weeks, from the start of lymphodepletion, followed by TIL infusion, ending with adjuvant interleukin-2 therapy.
TILs for metastatic melanoma
In the phase 2, open-label, multicenter clinical trial, 66 patients (median age, 55 years; 59% men)with stage IIIC or stage IV metastatic melanoma were infused with cryopreserved lifileucel (mean cells infused, 27.3 × 109).
Patients had received a mean of 3.3 previous therapies (range, 1-9) before infusion, including PD-1 inhibitors (100%), CTLA-4 inhibitors (80%) and BRAF/MEK inhibitors (23%). Study patients also had a high baseline tumor burden (106 mm mean target lesion sum of diameters).
Median follow-up was 7.4 months.
Results showed an ORR of 38%, which included two complete responses, 23 partial responses and 28 patients with stable disease. The overall disease control was 80%.
ORR appeared nearly identical in the subgroups of patients with and without prior anti-CTLA-4 therapy (38% vs. 39%), and was 47% among patients with mutated BRAF and 35% among those with wild-type BRAF mutations.
Nine patients had progressive disease. The investigators noted that some patients had improved responses after a longer follow-up period.
The most common toxicities of any grade included thrombocytopenia (89.4%), chills (78.8%), anemia (66.7%), pyrexia (59.1%) and febrile neutropenia (54.5%). Sixty-three patients (95.5%) experienced grade 3 or grade 4 toxicities, and two patients died of grade 5 toxicities — researchers deemed one of these deaths, due to intra-abdominal hemorrhage, related to treatment.
Sarnaik explained why TIL therapy could succeed in solid tumors where chimeric antigen receptor T-cell therapy has failed.
“There has to be a target that the CAR can attack that is tumor-specific,” he said. “With TIL therapy, the target is not identified because it’s naturally occurring in the patient that we are amplifying. CAR T doesn’t work in solid malignancies because we haven’t yet identified a tumor-specific target.”
He added that, with TIL therapy, treatment toxicity occurs during the first few days after the infusion.
“With common-sense medicine and supportive care, there are very few toxicities to worry about after the 2-week period following treatment,” Sarnaik said.
“I think this will be practice-changing,” he said. “I expect this treatment to be FDA approved, and once we get FDA approval, the next step is to take these cells and genetically modify them in a manner similar to CAR T. The difference with our method is that the lymphocytes are genetically homed in on the tumor, which will result in more on-tumor and less off-tumor target effects.”
Potential paradigm shift for cervical cancer
The phase 2 multicenter study included 27 patients (median age, 45 years) with advanced cervical cancer who had at least one previous line of therapy who received an infusion of LN-145 as of May 14, 2019. Fifty-two percent of patients had metastatic disease, 37% had recurrent disease and 11% had persistent disease.
Patients received a median of 2.4 previous therapies that included platinum-based chemotherapy (100%), taxane-based chemotherapy (96%), VEGF inhibitors (82%), radiotherapy (74%) and PD-1/PD-L-1 inhibitors (15%).
Median follow-up was 7.4 months. Patients received a mean of 28 x 109 infused TIL cells.
The ORR was 44.4% for those who received LN-145, with three complete responses, nine partial responses and 11 patients with stable disease, for a disease control rate of 85.2%. Seventy-eight percent of patients showed a reduction in tumor burden.
Jazaeri compared this ORR with the 12% response rate observed for pembrolizumab (Keytruda, Merck) in the same patient population, which recently received FDA accelerated approval.
“This is really exciting data for these patients, who don’t have very good treatment options,” he told HemOnc Today.
The most common toxicities included any-grade chills (77.8%), anemia (55.6%), diarrhea (51.9%), pyrexia (51.9%) and thrombocytopenia (51.9%); nearly all patients (96.3%) experienced a grade 3 or grade 4 toxicity. There were no grade 5 toxicities.
“The results we are getting are very encouraging, and they could mean a paradigm shift in the treatment of women with metastatic cervical cancer after first-line chemotherapy,” Jazaeri said. – by Drew Amorosi
Sarnaik A, et al. Abstract 2518. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Jazaeri AA, et al. Abstract 2538. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Sarnaik reports stock and other ownership interests in Merck; a consultant/advisory role with B4CC; institutional research funding from Genentech, Iovance Biotherapeutics and Provectus; and patents on compositions and methods for improving TILs for adoptive cell therapy (No. 61/955,970 and No. 61/973,002 [institutional]). Jazaeri reports honoraria from Gerson Lehrman Group; consultant/advisory roles with Almac Group, Aravive and Genentech/Roche; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Immatics, Iovance Biotherapeutics and Pfizer; and travel, accommodations and paid expenses from AstraZeneca/MedImmune. Please see the studies for all other authors’ relevant financial disclosures.