The treatment strategy, known as neoadjuvant immunotherapy, is built on a compelling biological idea: rather than removing a tumor first and treating the patient afterward, clinicians can use the intact tumor itself as a training ground for the immune system. A tumor that has not yet been surgically disturbed still contains its full complement of cancer antigens, immune cells, and suppressive machinery. By activating immune responses inside that living tumor, physicians hope to generate a systemic anti-cancer army that can hunt down micrometastases already circulating in the body, cells that are invisible on scans but are often the seeds of later relapse.

The centerpiece of the Erlangen regimen was the TransCon TLR7/8 Agonist, an investigational drug built on a so-called transient conjugation technology platform. Toll-like receptors 7 and 8 are pattern-recognition sensors expressed by innate immune cells such as dendritic cells and monocytes. When these receptors are engaged, they trigger a cascade of signaling, classically through the NF-kB and interferon pathways, that transforms the tumor microenvironment from an immunologically cold, suppressive zone into an inflamed, antigen-presenting battlefield. Conventional TLR agonists, however, tend to flood the body quickly, causing systemic inflammatory toxicity that limits their usable dose. The TransCon approach wraps the active drug in a temporary linker that releases it slowly over days or weeks after injection, sustaining local immune activation inside the tumor while keeping blood concentrations low.

Because innate immune activation alone is rarely sufficient to eliminate established cancer, the trial combined the intratumoral agonist with a systemic partner. Patients were randomized 1:1 to receive either pembrolizumab, the widely used antibody that blocks the PD-1 checkpoint and releases the brakes on exhausted T cells, or TransCon IL-2 β/γ, an engineered long-acting version of interleukin-2 designed to preferentially expand and activate the cytotoxic T cells and natural killer cells that actually kill tumors, while avoiding the vasodilating and regulatory T-cell stimulating effects of unmodified IL-2. Each patient received two treatment cycles before undergoing standard surgical resection of the tumor.

The six patients, treated between April and December 2024 within the multicenter BelieveIT-201 phase 2 trial, had a median age of 63 years and a median follow-up of 81 weeks. The parent trial was terminated prematurely by its sponsor, Ascendis Pharma, for reasons unrelated to safety or efficacy, which is why the Erlangen cohort remained small. Three of the six patients achieved a major clinical response, meaning their tumors shrank substantially on clinical and radiographic assessment, two showed partial response, and one experienced progressive disease. On final pathological examination of the resected specimens, one patient had a complete response with no viable tumor remaining, one had a major pathological response, and four were non-responders.

Perhaps the most striking observation was a physical one. All three patients with major clinical responses developed sterile tumor-associated pseudoabscesses, fluid collections near the injection site that were inflamed but not infected. These lesions, the authors note, appeared in spatial proximity to where the TLR7/8 agonist had been delivered, suggesting that the drug was provoking a potent local immune reaction capable of liquefying tumor tissue without bacterial involvement. Such sterile inflammation is a visible signature of innate immune activation and may serve as a biomarker of drug activity in future studies.

Beneath the clinical surface, the tumors themselves were changing. The researchers performed immunohistochemical staining on paired samples taken before and after treatment, tracking markers including CD3 and CD8 for T cells and CD68 and CD163 for macrophage populations. The post-treatment tumors showed clear remodeling of the immune microenvironment, with increased T-cell infiltration that was most pronounced in the tumor center, the region typically most hostile to immune attack in untreated cancers. This shift from an immune-excluded or immune-desert phenotype toward a T-cell-inflamed state is precisely what combination immunotherapy is designed to achieve, and it provides a mechanistic explanation for the tumor shrinkage observed in half of the cohort.

Safety findings, however, temper the enthusiasm. All six patients underwent surgery, and postoperative morbidity was substantial: every patient experienced at least one grade III adverse event, and there was one postoperative death. Disentangling the contribution of the immunotherapy from the inherent risks of major oral and maxillofacial surgery in this small, descriptive cohort is impossible, and the authors are careful not to attempt it. Within the first year, two of the six patients experienced a progression-free survival event, one with progressive disease and one death. Encouragingly, after surgery none of the patients showed disease recurrence during follow-up.

The authors are explicit about the limits of their data. With only six patients, all analyses are purely descriptive, no inferential statistical testing was performed, and no conclusions can be drawn about efficacy or comparative tolerability between the pembrolizumab and TransCon IL-2 β/γ arms. The individual patient was the unit of analysis, and the premature termination of the parent trial means the full randomized comparison will never be completed as designed. What the report offers instead is a complete, consecutive single-center experience, an unfiltered look at how this treatment actually performed in real clinical practice, including the surgical complications that are often underreported in industry-sponsored trials.

Still, the study adds an important piece to one of the most active frontiers in oncology: intratumoral immunotherapy for head and neck cancer. The concept of turning a solid tumor into its own vaccine has gained momentum as long-acting formulations solve the pharmacokinetic problems that plagued earlier innate immune agonists. The consistent immune remodeling seen here, even in a handful of patients, supports the biological plausibility of the approach and justifies continued investigation in larger, properly powered trials. For patients with locally advanced oral cancer, whose treatment options have changed little in decades, the prospect of shrinking tumors before surgery, and potentially de-escalating the devastating operations that this disease demands, remains a goal worth pursuing with rigor and caution in equal measure.

Subject of Research: Neoadjuvant intratumoral TLR7/8 agonist combined with systemic immunotherapy for locally advanced oral squamous cell carcinoma

Article Title: Neoadjuvant combined immunotherapy with intratumoral TransCon TLR7/8 Agonist and systemic TransCon IL-2 β/y or pembrolizumab in patients with locally advanced oral cancer—a monocentric experience

Article References: Neoadjuvant combined immunotherapy with intratumoral TransCon TLR7/8 Agonist and systemic TransCon IL-2 β/y or pembrolizumab in patients with locally advanced oral cancer—a monocentric experience. (n.d.). https://doi.org/10.1007/s00262-026-04515-8

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04515-8

Keywords: oral squamous cell carcinoma, neoadjuvant immunotherapy, TLR7/8 agonist, TransCon IL-2 beta/gamma, pembrolizumab, tumor microenvironment, intratumoral injection, BelieveIT-201 trial, head and neck cancer, immunohistochemistry, sterile pseudoabscess, Ascendis Pharma