In a remarkable advancement for cancer immunotherapy, a multi-institutional clinical investigation has demonstrated the potential of autologous tumor-infiltrating lymphocyte (TIL) therapy to stabilize metastatic head and neck squamous cell carcinoma (HNSCC). Conducted primarily through the UNC Lineberger Comprehensive Cancer Center along with 21 additional research sites across the United States, the phase 2 clinical trial marks one of the first instances where a single administration of TILs has yielded meaningful disease stabilization in patients with advanced and treatment-resistant HNSCC. This development offers renewed hope for a patient population that, until now, had limited therapeutic options and generally poor prognoses.
Autologous TIL therapy is an immunotherapeutic approach that leverages the patient’s own immune system to combat malignant cells. TILs are lymphocytes naturally present within a tumor, harboring the innate capability to recognize cancer-specific antigens. The therapeutic process involves surgically extracting these lymphocytes from tumor biopsies, expanding them ex vivo to quantities often reaching into the hundreds of millions, and infusing them back into the patient. This infusion aims to augment the immune response by saturating the body with highly active, tumor-specific lymphocytes capable of targeting and dismantling cancer cells more effectively than the patient’s unassisted immune system.
The impetus for this trial stems from earlier observational studies indicating that higher levels of TILs within tumors correlate with improved disease-free survival rates among HNSCC patients. This established an immunological rationale for enhancing TIL presence therapeutically, particularly within the context of recurrent or metastatic disease where conventional therapies—such as chemotherapy, radiation, and surgery—have often failed. The phase 2 trial enrolled 53 patients categorized into four distinct treatment arms, which allowed for a comparative assessment of various TIL formulations. These included non-cryopreserved TILs, cryopreserved lifileucel—an FDA-approved T-cell therapy previously validated in metastatic melanoma—non-cryopreserved lifileucel, and a cryopreserved TIL therapy enriched for PD-1 positive cells. PD-1 is an immune checkpoint receptor commonly expressed on T cells, acting as a marker for tumor-reactive lymphocytes.
Participants in the study predominantly consisted of males, with a median age of 57 years, suffering from late-stage metastatic HNSCC. The median duration of treatment exposure was approximately 17.9 months, and the median response to therapy lasted 7.6 months, though some patients experienced disease stabilization for nearly two years. Impressively, 64% of patients across the cohorts achieved stabilization of cancer progression—a benchmark that, until this study, had been elusive for this clinical population. The median overall survival was reported to be 9.5 months, a figure that notably surpasses existing outcomes for similar patient groups who have exhausted standard care options.
Side effect profiles were consistent with expectations for TIL-based therapies, which can prompt systemic inflammatory responses due to lymphocyte activation. The most prevalent non-hematologic adverse events included chills, experienced in 60% of patients, hypotension in 53%, and fever in 47%. Hematologic toxicities manifested as thrombocytopenia and anemia, with incidences of 74% and 53%, respectively. These side effects, while notable, were generally manageable with supportive care. The trial’s safety data reinforce the feasibility of administering TIL therapies to this fragile cohort without incurring unacceptable toxicity.
Robert L. Ferris, MD, PhD, who led the investigation while at UPMC Hillman Cancer Center and subsequently analyzed the findings as executive director at UNC Lineberger, underscored the significance of the outcomes. Ferris highlighted that these patients usually have limited life expectancy due to aggressive disease and prior treatment failures. The approximate nine-month extension in survival attributable to TIL therapy represents a meaningful clinical breakthrough, underscoring the importance of immunotherapeutic strategies in refractory solid tumors.
Despite these encouraging results, Ferris and colleagues acknowledged challenges inherent to the therapy’s broader applicability. The relatively small patient populations in each treatment arm limited the ability to perform direct statistical comparisons, emphasizing the necessity for larger, randomized controlled trials to comprehensively ascertain efficacy. Furthermore, questions remain regarding the optimization of TIL manufacturing—whether fresh or cryopreserved cells yield superior clinical outcomes—as well as the identification of synergistic combination regimens that could potentiate anti-tumor effects while mitigating immune evasion.
Of particular interest is the enrichment for PD-1 positive TILs, leveraging the understanding that these cells bear markers of prior tumor engagement and potential exhaustion. Modulating this population through adjunctive therapies, such as immune checkpoint inhibitors, might amplify the therapeutic durability of TIL infusions. Exploring these combinations could usher in a new paradigm in HNSCC treatment, providing not just disease stabilization but meaningful regression and long-term remission.
Head and neck squamous cell carcinoma remains a significant clinical challenge worldwide, accounting for approximately 3.6% of all new cancers in the United States, with nearly 60,000 diagnoses anticipated in 2025 alone. The notoriously aggressive nature of metastatic HNSCC, combined with frequent resistance to chemo- and radiotherapies, underscores the urgency of novel immunotherapies. The present study’s findings affirm the potential of individualized cell-based immunotherapies to fill this critical therapeutic void.
Underlying the trial’s success was a collaboration with Iovance Biotherapeutics, the manufacturer of lifileucel, ensuring access to cutting-edge cell manufacturing technologies. Lifileucel’s prior approval for metastatic melanoma provided a precedent for its adaptation in HNSCC, and the current findings could expand the therapeutic indications for this biologic agent. Moving forward, the results pave the way for subsequent large-scale studies designed to evaluate TIL therapy head-to-head against current standards of care, possibly reshaping treatment algorithms within oncology.
As the field of cancer immunotherapy evolves, the implications of TIL therapy extend beyond head and neck cancers. Enhancing the precision of adoptive T-cell therapies, optimizing cell culture conditions, and refining patient selection criteria hold promise for improving outcomes across various malignancies. This trial stands as a landmark step, illuminating the path toward harnessing the patient’s own immune system to tackle some of the most intractable cancers known to medicine.
In summary, the phase 2 clinical trial of autologous TIL therapy in recurrent and metastatic head and neck squamous cell carcinoma offers a compelling narrative of hope and scientific rigor. With the therapy demonstrating a tangible survival benefit and manageable safety profile, the findings invigorate the quest for personalized immunotherapies. Future research is expected to focus on combination modalities, refined manufacturing processes, and randomized trials that will ultimately define the clinical utility of TIL therapy in oncology practice.
Subject of Research: People
Article Title: Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma
News Publication Date: 24-Aug-2025
Web References:
https://jitc.bmj.com/lookup/doi/10.1136/jitc-2025-011633
Image Credits: UNC Lineberger Comprehensive Cancer Center
Keywords: Cancer, Immunology, Cancer immunology, Immunotherapy, Head and neck cancer, Lymphocytes
