Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma

Abstract

Purpose: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.

Methods: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.

Results: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.

Conclusion: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.

Trial registration: ClinicalTrials.gov NCT02360579.

Conflict of interest statement

Amod A. SarnaikHonoraria: Physicans' Education ResourceConsulting or Advisory Role: B4CC, Iovance Biotherapeutics, Guidepoint Global, Defined Health, Gerson Lehrman GroupResearch Funding: Provectus, Genentech, Iovance BiotherapeuticsPatents, Royalties, Other Intellectual Property: Compositions and methods for improving tumor-infiltrating lymphocytes for adoptive cell therapy, filed March 20, 2014 US Patent Application No. 61/955,970 and second Application No. 61/973,002Travel, Accommodations, Expenses: Iovance Biotherapeutics Omid HamidHonoraria: Bristol Myers Squibb, Novartis, Sanofi/Regeneron, PfizerConsulting or Advisory Role: Amgen, Novartis, Roche, Bristol Myers Squibb, Merck, Aduro Biotech, Akeso Biopharma, BeiGene, Genentech, GlaxoSmithKline, Immunocore, Incyte, Janssen, NextCure, Regeneron, Sanofi, Seattle Genetics, Tempus, Zelluna, BioAtla, Idera, PfizerSpeakers' Bureau: Bristol Myers Squibb, Novartis, Sanofi/Regeneron, PfizerResearch Funding: Bristol Myers Squibb, Genentech, Immunocore, Incyte, Merck, Merck Serono, Novartis, Pfizer, Roche, Amgen, CytomX Therapeutics, Iovance Biotherapeutics, NextCure, GlaxoSmithKline, Arcus Biosciences, Aduro Biotech, Akeso Biopharma, Exelixis, Moderna Therapeutics, Regeneron, Sanofi, Seattle Genetics, Torque, Zelluna, Bioatla, Idera Nikhil I. KhushalaniStock and Other Ownership Interests: Bellicum Pharmaceuticals, Mazor Robotics, Amarin Corporation, Asensus SurgicalHonoraria: SanofiConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/PfizerResearch Funding: Bristol Myers Squibb, Merck, Novartis, GlaxoSmithKline, HUYA Bioscience International, Amgen, Regeneron, Celgene, Replimune Karl D. LewisHonoraria: Array BioPharma, Iovance BiotherapeuticsConsulting or Advisory Role: Array BioPharma, Merck, Roche, Regeneron, Sanofi, Iovance BiotherapeuticsResearch Funding: Roche/Genentech, Merck, Array BioPharma, Incyte, Nektar, Iovance Biotherapeutics, Bristol Myers Squibb, Kartos Therapeutics, OncoSec, Regeneron, Alkermes, Neon Therapeutics, Ultimovacs, Senhwa Biosciences, Replimune, AmgenTravel, Accommodations, Expenses: Merck, Roche/Genentech, Regeneron, Neon Therapeutics, AlkermesUncompensated Relationships: Roche/Genentech, Regeneron Theresa MedinaConsulting or Advisory Role: Bristol Meyer Squibb, Iovance BiotherapeuticsResearch Funding: Merck, Replimune, Bristol Myers Squibb, Iovance Biotherapeutics, Nektar, Immunocore, Checkmate Pharmaceuticals, BioAtla Harriet M. KlugerConsulting or Advisory Role: Nektar, Celldex, Iovance Biotherapeutics, Merck, Immunocore, Array BioPharma, ElevateBio, Instil Bio, Clinigen Group, Shionogi, Bristol Myers SquibbResearch Funding: Merck, Bristol Myers Squibb, ApexigenTravel, Accommodations, Expenses: Apexigen Sajeve S. ThomasSpeakers' Bureau: BMS, Merck, Genentech, Ipsen, Amgen, Pfizer, Novartis Evidio Domingo-MusibayHonoraria: RegeneronConsulting or Advisory Role: Sanofi/Regeneron, Castle BiosciencesSpeakers' Bureau: Sanofi/RegeneronResearch Funding: Clinigen Group, Iovance Biotherapeutics, Nektar Anna C. PavlickConsulting or Advisory Role: Bristol Myers Squibb, Merck, Regeneron, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Merck, Millennium, Regeneron, Replimune Eric D. WhitmanConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, Castle Biosciences, Novartis, Eisai, PfizerSpeakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Castle Biosciences, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Castle Biosciences, Genentech/Roche, Amgen, TRACON Pharma, AstraZeneca/MedImmune, Provectus, Oncolys BioPharma, Iovance Biotherapeutics, Dynavax Technologies, OncoSec, Toray Industries, Array BioPharmaPatents, Royalties, Other Intellectual Property: Nerve monitoring dissection device, Lighted Polyhedral surgical retractor Salvador Martin-AlgarraConsulting or Advisory Role: MSD Oncology, Sanofi, Regeneron, AstraZenecaSpeakers' Bureau: Bristol Myers Squibb, MSD Oncology, AstraZeneca, Novartis, Roche, Sanofi/RegeneronTravel, Accommodations, Expenses: Pierre Fabre, Roche, MSD Oncology Pippa CorrieHonoraria: Novartis, Merck Sharp & Dohme, Pierre Fabre, Bristol Myers SquibbConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Incyte, Pierre Fabre, Roche, MicrobioticaSpeakers' Bureau: Merck Sharp & Dohme, Novartis, Bristol Myers SquibbResearch Funding: MSD, Bristol Myers Squibb, Novartis, Array BioPharma, Celgene, Halozyme, Iovance Biotherapeutics, LillyTravel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme Brendan D. CurtiHonoraria: Clinigen Group, NektarConsulting or Advisory Role: MerckResearch Funding: Bristol Myers Squibb, Galectin Therapeutics, Clinigen GroupPatents, Royalties, Other Intellectual Property: Biomarkers for OX40 responseTravel, Accommodations, Expenses: Agonox Jose LutzkyConsulting or Advisory Role: Castle Biosciences, Iovance Biotherapeutics, Replimune, RegeneronResearch Funding: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Immunocore, Regeneron, Replimune, Vyriad Jeffrey S. WeberStock and Other Ownership Interests: CytomX Therapeutics, Biond Biologics, Protean Biodiagnostics, NeximmuneHonoraria: Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Amgen, Roche, Celldex, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Takeda, Moderna Therapeutics, Jounce Therapeutics, Kirin Pharmaceuticals, Regeneron, Idera, OncosecConsulting or Advisory Role: Celldex, Bristol Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Jounce Therapeutics, Moderna Therapeutics, Kirin Pharmaceuticals, Protean Biodiagnostics, Idera, OncosecResearch Funding: Bristol Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche, Novartis, NextCure, Moderna TherapeuticsPatents, Royalties, Other Intellectual Property: Named on a patent submitted by Moffitt Cancer Center for an IPILIMUMAB biomarker, named on a patent from Biodesix for a PD-1 antibody biomarker, named on a patent for 41BB induced TIL by Moffitt Cancer CenterTravel, Accommodations, Expenses: Bristol Myers Squibb, GlaxoSmithKline, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis James M. G. LarkinHonoraria: Eisai, Bristol Myers Squibb, MSD, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Pierre Fabre, EUSA Pharma, Achilles Therapeutics, AstraZeneca, Boston Biomedical, Ipsen, Imugene, Incyte, iOncologi, Merck Serono, Nektar, Vitaccess, Kymab, SecarnaConsulting or Advisory Role: Eisai, Bristol Myers Squibb, MSD, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Pierre Fabre, EUSA Pharma, Achilles Therapeutics, AstraZeneca, Boston Biomedical, Ipsen, Imugene, Incyte, iOncologi, Merck Serono, Nektar, Vitaccess, Secarna, KymabResearch Funding: Pfizer, Novartis, MSD, Bristol Myers Squibb, Achilles Therapeutics, Roche, Nektar, Covance, Immunocore, AVEOTravel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Boston Biomedical, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono Wen ShiEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsTravel, Accommodations, Expenses: Iovance Biotherapeutics Toshimi TakamuraEmployment: Iovance Biotherapeutics Inc Madan JagasiaEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsConsulting or Advisory Role: Kadmon Harry QinEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance Biotherapeutics Xiao WuEmployment: Iovance BiotherapeuticsStock and Other Ownership Interests: Iovance BiotherapeuticsTravel, Accommodations, Expenses: Iovance Biotherapeutics Cecile ChartierEmployment: Iovance BiotherapeuticsLeadership: Iovance BiotherapeuticsPatents, Royalties, Other Intellectual Property: PCT/US2019/059598 for Expansion of TILs Utilizing AKT Pathway Inhibitors. PCT/US2019/012729 for Processes for Generating TIL Products Enriched for Tumor Antigen-specific T-cells. PCT/US2019/029286 for Gene Editing of Tumor Infiltrating Lymphocytes and Uses of Same in Immunotherapy. PCT/US2019/065892 for Methods of Expanding Tumor Infiltrating Lymphocytes Using Engineered Cytokine Receptor Pairs and Uses Thereof. PCT/US2019/012733 for Processes for Generating TIL Products Enriched for Tumor Antigen-Specific T-Cells. PCT/US2020/013095 for System and Methods for Monitoring Adoptive Cell Therapy Clonality and Persistence. PCT/US2020/063767 for Processes for the Production of Tumor Infiltrating Lymphocytes (TILs) and Methods of Using the Same. PCT/US2020/057135 for Gene Editing of Tumor Infiltrating Lymphocytes and Uses of Same in Immunotherapy. One patent application is nonpublic, for which Iovance declines to furnish any informationTravel, Accommodations, Expenses: Iovance Biotherapeutics Friedrich Graf FinckensteinEmployment: Adverum, Iovance Biotherapeutics, Roche/GenentechLeadership: Iovance BiotherapeuticsStock and Other Ownership Interests: Roche/Genentech, Bristol Myers Squibb, Johnson & Johnson, Iovance Biotherapeutics, AdverumTravel, Accommodations, Expenses: Iovance Biotherapeutics, Roche/Genentech Maria FardisEmployment: Iovance Biotherapeutics, Acerta PharmaLeadership: Iovance Biotherapeutics, Acerta PharmaStock and Other Ownership Interests: Iovance Biotherapeutics, Acerta Pharma, Gilead Sciences, AbbVie, Kartos TherapeuticsPatents, Royalties, Other Intellectual Property: Iovance Biotherapeutics, Acerta PharmaTravel, Accommodations, Expenses: Iovance Biotherapeutics, Acerta Pharma John M. KirkwoodConsulting or Advisory Role: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Elsevier, Amgen, Checkmate Pharmaceuticals, Harbour BioMed, Istari Oncology, OncoSec, Scopus BioPharma, PfizerSpeakers' Bureau: Bristol Myers SquibbResearch Funding: Amgen, Bristol Myers Squibb, Castle Biosciences, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapeutics, Novartis, Merck Jason A. ChesneyResearch Funding: Amgen, Replimune, Iovance Biotherapeutics, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: University of Louisville US PatentsNo other potential conflicts of interest were reported.

Figures

FIG 1.

Change in tumor burden of target lesions, response by subgroup, and response assessment in individual patients. (A) Waterfall plot depicting BOR as assessed by investigator and the best change from baseline in the SOD of the target lesions (per RECIST v1.1 criteria) in the FAS. A change of −100% from baseline is presented for CR assessment that includes lymph node lesions that resolved to 30% reduction in the SOD of the target lesions. Three patients had no post-TIL assessments because of early death. One patient had no post-TIL assessment because of start of new anticancer therapy before day 42.

FIG 2.

(A) The Kaplan-Meier curve for DOR in confirmed responders who achieved a PR or better. The DOR is measured from the time point at which the initial measurement criteria are met for a PR or CR, whichever occurred first, until the first date that PD or death occurred. (B) The Kaplan-Meier curve for OS in the full analysis set. OS was defined as the time (in months) from the start date of lifileucel infusion to death because of any cause. Patients who were alive at the time of data cutoff had their event times censored on the last date of their known survival status. The median OS was 17.4 months (95% CI, 11.0 to NR), with 1-year OS of 58% (95% CI, 45 to 69). CR, complete response; DOR, duration of response; NR, not reached; OS, overall survival; PD, progressive disease; PR, partial response.

FIG 3.

AEs over time. The distribution of onset of AEs starting from lifileucel infusion until 6 months postinfusion is shown. A TEAE was defined as any AE with onset after start of lifileucel through day 30 postinfusion. All occurrences of AEs were counted if a patient experienced a new onset of the same AE at different timepoints. If multiple records were reported on the electronic case report form because of toxicity grade decrease of the same AE that had not resolved, then the event was counted once with the highest grade reported. Overall, 24 AEs were reported post month 6 until data cutoff date, which are not shown in the histogram. No SAEs related to lifileucel were reported post month 6. AE, adverse event; D, day; M, month; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TIL, tumor-infiltrating lymphocytes.