A Phase 2, Multicenter Study of Autologous Tumor Infiltrating Lymphocytes (LN 144/LN-145/LN-145-S1) in Patients With Solid Tumors

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Overview

• LN-145 (lifileucel; brand name Amtagvi) is an autologous tumor-infiltrating lymphocyte (TIL) therapy manufactured from a patient’s own resected tumor, expanded ex vivo, and reinfused after non‑myeloablative lymphodepletion and followed by high‑dose IL‑2 support. On February 16, 2024, lifileucel received U.S. FDA accelerated approval for adults with unresectable or metastatic melanoma previously treated with anti–PD‑1 therapy and, if BRAF V600–mutant, targeted therapy. Approval was based on objective response rate and durability of response. Continued approval may be contingent on confirmatory trials. (fda.gov)

Mechanism of action

• The specific mechanism of action of lifileucel is not fully defined; as a TIL product, it contains a heterogeneous mixture of tumor‑reactive T cells (primarily CD4+ and CD8+) expanded from the patient’s tumor and is intended to mediate anti‑tumor activity upon reinfusion. (fda.gov)

Efficacy

Melanoma (post–checkpoint inhibitor setting) - Pivotal single‑arm, multicenter study (C‑144‑01; cohorts within the recommended dose range): ORR 31.5% (95% CI 21.1–43.4); median time to response 1.5 months; median duration of response (DoR) not reached at data cutoff. (fda.gov) - Pooled analysis of consecutive cohorts (C‑144‑01 cohorts 2 and 4; n=153) by independent review committee: ORR 31.4% with complete responses in ~6%; median DoR not reached at analysis; median overall survival ~13.9 months in the heavily pretreated population. Longer‑term updates report durable responses with a substantial proportion ongoing beyond 18 months. (pmc.ncbi.nlm.nih.gov)

Non–small cell lung cancer (NSCLC; investigational) - Phase 2 multicenter study in metastatic NSCLC resistant to immune checkpoint inhibitors (n=28): ORR 21.4% (6/28) with responses observed even in PD‑L1–negative, low TMB, and STK11‑mutant tumors; two treatment‑emergent deaths were reported. (aacrjournals.org)

Cervical cancer (investigational) - Phase 2 C‑145‑04 (ASCO 2019): in 27 evaluable patients with recurrent/metastatic or persistent cervical cancer after prior therapy, ORR 44% (3 CR, 9 PR); median DoR not reached at 7.4‑month median follow‑up. Study uses the same lymphodepletion/IL‑2‑supported LN‑145 approach. (ascopubs.org)

Ongoing/confirmatory studies - A randomized phase 3 trial (TILVANCE‑301) is evaluating lifileucel plus pembrolizumab versus pembrolizumab alone in previously untreated advanced melanoma. (ascopubs.org)

Safety

• Boxed Warning: treatment‑related mortality; prolonged severe cytopenias; severe infection; cardiopulmonary and renal impairment. Administration must occur in an inpatient setting with intensive care capability. (fda.gov)
• Common adverse reactions (≥20%): chills, fever, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, alopecia, infection, hypoxia, and dyspnea. Grade ≥3 cytopenias are frequent (e.g., thrombocytopenia 78%, neutropenia 69%, anemia 58%). Serious adverse reactions leading to death have included severe infections, internal organ hemorrhage, acute renal/respiratory failure, and arrhythmia. The overall safety profile largely reflects effects of the lymphodepleting chemotherapy and high‑dose IL‑2. (fda.gov)
• In the NSCLC phase 2 study, adverse events were consistent with expectations for TIL therapy; two treatment‑emergent deaths (cardiac failure and multiorgan failure) were reported. (aacrjournals.org)

Further reading

• FDA accelerated approval notice for lifileucel (melanoma): https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma (fda.gov)
• Amtagvi (lifileucel) Prescribing Information (Feb 2024 PDF): https://www.fda.gov/media/176417/download (fda.gov)
• Pooled analysis in post‑ICI melanoma (C‑144‑01; J Immunother Cancer 2022): https://pmc.ncbi.nlm.nih.gov/articles/PMC9748991/ (pmc.ncbi.nlm.nih.gov)
• Phase 2 melanoma study (J Clin Oncol 2021): https://pubmed.ncbi.nlm.nih.gov/33979178/ (pubmed.ncbi.nlm.nih.gov)
• NSCLC phase 2 study (Cancer Discovery 2024): https://aacrjournals.org/cancerdiscovery/article/14/8/1389/746508/Lifileucel-an-Autologous-Tumor-Infiltrating (aacrjournals.org)
• Cervical cancer phase 2 (ASCO 2019 abstract): https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.2538 (ascopubs.org)
• Phase 3 TILVANCE‑301 design (ASCO 2023 abstract): https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.TPS9607 (ascopubs.org)

Note: As of October 7, 2025, lifileucel is FDA‑approved for melanoma as above; use in other tumor types remains investigational pending results of ongoing trials. (fda.gov)

Last updated: Oct 2025

Overview

LN-145-S1 (also called PD-1 Selected TIL) is an autologous tumor‑infiltrating lymphocyte (TIL) product being developed by Iovance Biotherapeutics as a next‑generation TIL therapy that selectively enriches for PD‑1–positive T cells from a patient’s tumor. It is being evaluated in multicohort phase 2 trials alongside other Iovance TIL products (lifileucel/LN‑144 and LN‑145) in melanoma, head and neck squamous cell carcinoma (HNSCC), and non‑small cell lung cancer (NSCLC). Publicly available human outcome data specific to LN‑145‑S1 have been reported to date in HNSCC (C‑145‑03, cohort 4); melanoma testing (IOV‑COM‑202, cohort 1B) has been described but without published response results as of October 7, 2025. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Product type: Autologous TIL therapy manufactured from a patient’s resected tumor, followed by non‑myeloablative lymphodepletion and a single TIL infusion with post‑infusion IL‑2 support. LN‑145‑S1 is distinguished by selecting PD‑1–positive TIL during manufacturing to enrich for tumor‑reactive clones. (jto.org)
• Rationale: PD‑1 expression on CD8+ TIL marks the patient‑specific repertoire of tumor‑reactive and neoantigen‑specific T cells in human tumors; selecting PD‑1+ TIL can enrich for tumor‑recognizing clones, and PD‑1–selected TIL products demonstrated superior antitumor activity versus bulk TIL in preclinical models. (pubmed.ncbi.nlm.nih.gov)

Efficacy

• Head and neck squamous cell carcinoma (C‑145‑03; phase 2, multicohort)

• Cohort 4 (PD‑1–selected TIL; LN‑145‑S1): 12 patients were treated; 2 achieved partial responses. Across all cohorts in the study (n=53), the objective response rate (ORR) was 11% (6/53), median duration of response was 7.6 months, and disease control rate (DCR) was 76%. (pubmed.ncbi.nlm.nih.gov)

• Melanoma (IOV‑COM‑202; phase 2, multicohort)

• Cohort 1B is designed to evaluate LN‑145‑S1 as a single agent in previously treated melanoma; as of October 7, 2025, no response outcomes for cohort 1B have been publicly reported. (jto.org)

Note: Other Iovance TIL cohorts (not PD‑1–selected) have reported activity in several tumors, but those results are not specific to LN‑145‑S1 and are not summarized here given the focus on PD‑1 Selected TIL. (jto.org)

Safety

• In C‑145‑03 (HNSCC), LN‑145/LN‑145‑S1 safety was consistent with the known toxicities of the lymphodepleting regimen and high‑dose IL‑2; no new safety signals specific to LN‑145‑S1 were identified in the report. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Phase 2 HNSCC TIL trial (includes LN‑145‑S1 cohort and outcomes): Efficacy and safety of one‑time autologous TIL cell therapy in recurrent/metastatic HNSCC (C‑145‑03). (pubmed.ncbi.nlm.nih.gov)
• Multicohort phase 2 design that includes LN‑145‑S1 (IOV‑COM‑202): Journal of Thoracic Oncology meeting abstracts outlining cohorts and manufacturing approach. (jto.org)
• Trial registry summary for IOV‑COM‑202 (NCT03645928). (cdek.pharmacy.purdue.edu)
• Foundational human data supporting PD‑1 as a marker of tumor‑reactive TIL: J Clin Invest 2014. (pubmed.ncbi.nlm.nih.gov)
• Preclinical demonstration of PD‑1–selected TIL efficacy: Cancer Research 2017. (aacrjournals.org)

If additional, indication‑specific results for LN‑145‑S1 (e.g., melanoma cohort 1B) are reported in the future, the efficacy and safety sections should be updated accordingly.

Last updated: Oct 2025

Inclusion Criteria

* Must have a confirmed diagnosis of malignancy of their receptive histologies: unresectable or metastatic melanoma Stage IIIC to IV (Cohorts 1A,1B and 1C), advanced, recurrent or metastatic HNSCC (Cohort 2A), or Stage III or Stage IV non-small cell lung cancer (Cohorts 3A, 3B, and 3C). Stage IV NSCLC with no actionable mutations (EGFR, ALK, ROS1) with effective targeted therapy (Cohorts 3D and 3E).

* Cohorts 1A, 1D, 2A, 3A, 3D and 3E: If previously treated, patients must have progressed on or after most recent therapy and must not have received ICIs as part of one of the counted lines of prior therapy. Patients must have radiologically documented disease progression while receiving or after the completion of the most recent prior treatment. Patients may have received up to 3 prior systemic anticancer therapies (except for Cohort 3A, where patients whose tumors harbor actionable mutations may have received up to 4 prior systemic therapies). Patients in Cohort 1D may have had no prior therapy for advanced disease. Patients in Cohorts 3D and 3E may have had no prior systemic therapy for Stage IV disease.

* Cohorts 1B, 1C, 3B, and 3C: Unresectable or metastatic melanoma patients in Cohorts 1B or 1C must have previously received systemic therapy with a PD-1 blocking antibody. NSCLC patients in Cohort 3B must have previously received systemic therapy with any ICI (except for those patients with known oncogene driver mutations that are sensitive to targeted therapies) as part of 1 - 3 prior lines of therapy. NSCLC patients in Cohort 3C must have previously received 1 line of ICI monotherapy. No other systemic therapy for metastatic disease is allowed. Prior chemoradiation and/or chemotherapy in the adjuvant and/or neoadjuvant settings are allowed.

* Must have at least 1 resectable lesion

* Must have remaining measurable disease as defined by RECIST 1.1 following tumor resection

* Must be ≥ 18 years at the time of consent for Cohorts 1A, 1C, 1D, 2A, 3A, 3B, 3C, 3D and 3E. Patients must be ≥ 12 years at the time of consent for Cohort 1B. Enrollment of patients \> 70 years of age may be allowed after consultation with the Medical Monitor.

* Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an estimated life expectancy of ≥ 6 months.

* Patients of childbearing potential or those with partners of childbearing potential must be willing to practice an approved method of birth control during treatment and for 12 months after their last dose of aldesleukin, 4 months after their last dose of pembrolizumab, 5 months after their last dose of ipilimumab or nivolumab, or nivolumab-relatlimab; 6 months after the last dose of carboplatin; 14 months after the last dose of cisplatin; and 6 months after the last dose of pemetrexed, paclitaxel, or nab-paclitaxel, whichever occurs later.

Exclusion Criteria

* Patients with melanoma of uveal/ocular origin.

* Patients who have a history of allogeneic organ transplant or any form of cell therapy involving prior conditioning chemotherapy within the past 20 years. Patients being retreated with TIL, as part of this study are not excluded.

* Patients who have symptomatic, untreated brain metastases or history of leptomeningeal metastases.

* Patients who are on systemic steroid therapy \> 10 mg/day of prednisone or other steroid equivalent. Patients receiving steroids as replacement therapy for adrenocortical insufficiency at ≤ 10 mg/day of prednisone or other steroid equivalent may be eligible.

* Patients who are pregnant or breastfeeding.

* Patients who have an active medical illness(es), which in the opinion of the Investigator, would pose increased risks for study participation

* Cohort 1A, 1D, 2A, 3A, 3C, 3D and 3E patients may not have a medical history of autoimmune disorders (including pneumonitis) requiring treatment or active management.

* Patients who have received a live or attenuated vaccination within 28 days prior to the start of treatment

* Patients who have any form of primary immunodeficiency

* Patients with a history of hypersensitivity to any component of the study drugs to be administered in the pertinent cohort(s).

* Patients who have a left ventricular ejection fraction (LVEF) \< 45% or who are New York Heart Association Class II or higher. A cardiac stress test demonstrating any irreversible wall movement abnormality in any patients ≥60 years of age or in patients who have a history of ischemic heart disease, cardiac chest pain, or clinically significant atrial and/or ventricular arrhythmias.

* Patients with respiratory dysfunction or history of smoking are excluded if not meeting either of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) \> 0.7 or FEV1 \> 50%.

* Patients who have had another primary malignancy within the previous 3 years

* Participation in another interventional clinical study within 21 days prior to the initiation of treatment.

* Patients in Cohorts 1D, 3D, or 3E who previously received adjuvant or neoadjuvant ICI(s) for non-metastatic disease and had an immune-related AE(s) requiring systemic steroid treatment or discontinuation of immune checkpoint inhibitor therapy.