Adoptive transfer of tumor-infiltrating lymphocytes (TIL) is effective in melanoma and selected solid tumors, but its potential in pancreatic ductal adenocarcinoma (PDAC) remains largely unexplored. We report a 39-year-old male with metastatic PDAC involving lung, peritoneal, liver, and lymph node who received three sequential infusions of TIL expanded ex vivo with IL-2/IL-15/IL-21 from a lung metastasis. Each infusion followed low-dose lymphodepletion and IL-2 support. The patient achieved stable disease after the first infusion and a partial response after the second along with reductions in serum CA19-9. Genome sequencing revealed substantial inter-tumoral heterogeneity, with mutations in ITGB2, C1QTNF3, CDK9, TMEM200C, FHOD1 and ZZZ3 impacting TIL infiltration and clinical response. RNA-seq showed that responding lesions were enriched for inflammatory and tumor-specific programs, displayed enrichment of T-cell activation transcripts and had reduced infiltration of cancer-associated fibroblasts. TCR sequencing confirmed the robust infiltration of TIL-derived CD8+ clonotypes, while functional assays demonstrated a polyclonal recognition of patient-derived somatic mutations and cytotoxicity against autologous tumor lines. Single-cell TCR mapping further validated the dominance of tumor-specific CD8+ clonotypes in responding lesions. This case demonstrates the feasibility and immunological activity of TIL therapy in PDAC, while underscoring the impact of spatial tumor heterogeneity on therapeutic outcomes.

BackgroundOral mucositis/stomatitis is a common adverse event during cancer treatment that can disrupt oral functioning and adherence to treatment. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, has shown promise in treating solid tumors. It has been associated with oral mucositis/stomatitis in clinical trials for breast and lung cancer (TROPION program). Currently, there is a lack of formalized guidelines for managing Dato-DXd-associated oral mucositis/stomatitis. The present study employed a modified Delphi approach to establish expert consensus on preventing, diagnosing, monitoring, and treating oral mucositis/stomatitis secondary to Dato-DXd and to improve patient care and clinical outcomes.Materials and MethodsA four-stage modified Delphi study engaging 15 oncology experts from Europe and Canada was used to establish consensus on managing Dato-DXd-induced oral mucositis/stomatitis in lung and breast cancer patients. Experts were selected based on their roles as investigators in Dato-DXd clinical trials, including but not limited to TROPION-PanTumor01, TROPION-Lung01, TROPION-Lung05, and TROPION-Breast01, and their experience managing cancer treatment-associated oral mucositis/stomatitis. The Delphi process included an initial meeting, two anonymized surveys, an in-person consensus meeting, and virtual one-to-one sessions for absentees.ResultsExpert consensus was reached on recommendations for managing Dato-DXd-associated oral mucositis/stomatitis, and experts highlighted the importance of establishing guidance to improve patient quality of life and clinical outcomes. Key recommendations included prophylactic dexamethasone mouthwash, patient education, and behavioral changes. Early detection through self-checks and monitoring was emphasized, and recommended treatment strategies were tailored to oral mucositis/stomatitis severity. Treatment recommendations included dose modifications and discontinuation for severe cases.ConclusionsThis study offers expert guidance on managing Dato-DXd-associated oral mucositis/stomatitis, filling a crucial gap in patient care. Ongoing efforts to generate Dato-DXd-specific data will facilitate the creation of standardized, evidence-based protocols to improve patient safety and treatment outcomes.

Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has demonstrated consistent clinical efficacy in treating advanced melanoma and other "hot" tumors. However, it has shown limited success in "cold" tumors like glioblastoma. We present the successful treatment of a rapidly progressing glioblastoma patient with TILs expanded using a defined cytokine combination of IL-2, IL-15, and IL-21. The patient received lymphodepletion with cyclophosphamide one day pre-TIL infusion, followed by a single dose of IL-2 post-transfer. Complete tumor regression was observed after two TIL infusions administered two weeks apart. The TIL products were enriched for CD8+ T-cells and demonstrated specific lysis of the autologous tumor cell line. Transcriptomic analysis of tumor biopsies post-TIL infusion revealed increased expression of genes associated with immunological synapse formation and T-cell effector function, correlating with the patient's clinical outcome. T-cell receptor (TCR) next-generation sequencing of the infused TILs and post-treatment tumor biopsies confirmed the infiltration and expansion of TIL-derived clonotypes within the tumor microenvironment. CD8+ T-cell clonotypes exhibited robust tumor migration and expansion, while CD4+ T-cells showed limited tumor infiltration. In conclusion, TILs expanded with IL-2/IL-15/IL-21 represent a promising therapeutic approach for glioblastoma, overcoming traditional challenges posed by the tumor microenvironment and achieving significant clinical outcomes.

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) can achieve durable responses in patients with metastatic cancers, but the long-term clonal dynamics after multiple administration and synergy with checkpoint blockade remain understudied. We present a longitudinal case study of a patient with treatment-refractory metastatic prostate cancer that achieved complete and durable tumor remission over 5-years after multiple TIL infusions and anti-PD-1 therapy. We performed longitudinal high-throughput T-cell receptor (TCR) sequencing on blood and tumor samples collected over five years to track the persistence and dynamics of TIL-derived and endogenous clonotypes. TIL-derived clonotypes exhibited sustained persistence in blood, with notable clonal expansions correlating with reduced repertoire diversity, increased clonality, and observed clinical response. Multiple TIL administration increased the patient exposure to the therapy, improving its pharmacokinetics profile over time. The third TIL infusion was followed by pembrolizumab administrations, which coincided with the re-expansion of TIL-derived clonotypes and emergence of novel clones. Serial tracking revealed clonotype stability for up to five years post-treatment. Our findings provide insights into the long-term persistence and reactivation of TIL-derived immunity and illustrate the potent synergy between adoptive transfer and PD-1 blockade by enhancing both infused and endogenous tumor-reactive T cell responses, and supporting the integration of longitudinal immunogenomic monitoring in personalized immunotherapy.

Introduction of immune checkpoint inhibitors (ICI) has improved overall survival (OS) for advanced non-small cell lung cancer (NSCLC). However, responses differ greatly amongst patients. Additional radiotherapy (RT) may promote tumor-specific immunity and synergize with ICI to improve tumor control. The multicenter phase II FORCE trial evaluated safety and efficacy of nivolumab with additional palliative radiotherapy (5 × 4 Gy) as clinically indicated in pre-treated metastatic non-squamous NSCLC (group A, n = 41), including pretreated patients without an indication for radiotherapy in a parallel cohort as real-world controls (group B, n = 60). With an objective response rate (ORR) of 8.3

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown remarkable efficacy in treating melanoma and other "hot" tumors characterized by high tumor mutation burden (TMB), a biomarker increasingly recognized for predicting immunotherapy success in solid tumors. However, gliomas show no clear correlation between TMB and immunotherapy efficacy due to the immunosuppressive tumor microenvironment, defective antigen presentation and the restrictive blood-brain barrier, hindering the effectiveness of immunotherapy. We report the successful treatment of a rapidly progressing high-TMB glioblastoma patient with TILs expanded using a defined cytokine cocktail comprising IL-2, IL-15, and IL-21. The therapeutic regimen included lymphodepletion with a single dose of cyclophosphamide prior to TIL intravenous infusion followed by a single dose of IL-2 post-infusion. Remarkably, complete tumor regression was achieved following two TIL infusions administered two weeks apart. Sequential cranial MRI showed complete tumor remission 22 days after the second infusion, with biopsies of the tumor showing complete necrotic tissue transformation. The TIL products were enriched for CD8 T-cells with high IFNg production and CD107a expression. They exhibited dose-dependent, specific cytolytic activity against autologous tumor cell lines but not against an autologous EBV-transformed B-cell line, the allogeneic glioblastoma cell lines U-373 and DBTRG05, or the unrelated Daudi B-cell lymphoma cell line. After TIL infusion, peripheral blood T-cells exhibited TCR downregulation, indicating activation, alongside with increased numbers of effector memory CD8 T-cells and CD4 Th1 and Th17 subtypes, while terminally differentiated CD8 T-cells decreased. A surge in serum IL-6 and sIL-2R levels was seen after each TIL infusion, confirming the strong systemic T-cell activation. Hematological analyses revealed persistent lymphopenia despite the use of reduced conditioning regimen. Surgical tumor samples collected before and after TIL infusions were analyzed by whole-exome sequencing (WES), RNA-seq and T-cell receptor (TCR) next-generation sequencing. WES revealed a high mutation burden (>10/Mb) across all samples, including mutations on EGFR, TP53 and BRCA1/2. Transcriptomic analysis of post-infusion tumor biopsies demonstrated enhanced expression of genes associated with immunological synapse formation and T-cell effector function, in line with the observed clinical response. TCR sequencing demonstrated that TIL-derived CD8 T-cells effectively infiltrated the tumor tissue and were strongly associated with tumor clearance. Hyperexpanded clonotypes within the tumor indicated robust TIL expansion in vivo, highlighting the significant contribution of TIL-derived CD8 T-cell proliferation to tumor control. CD4 T-cells, despite presenting greater TCR diversity than CD8 T-cells within the infused product, showed limited infiltration. This case highlights the potential of TILs expanded with IL-2/IL-15/IL-21 to overcome the challenges of glioblastoma’s immunosuppressive microenvironment, achieving significant clinical outcomes. These findings support the exploration of optimized TIL-based therapies as a viable treatment strategy for glioblastoma and other "cold" tumors. Lucas C M Arruda, Julia Karbach, Dragan Kiselicki, Hans-Michael Altmannsberger, Evgueni Sinelnikov, Dirk Gustavus, Hans Hoffmeister, Akin Atmaca, Elke Jäger. Tumor-infiltrating lymphocytes-derived CD8 clonotypes infiltrate the tumor tissue and mediate tumor regression in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB370.

BACKGROUND:Although immune checkpoint inhibitors (ICIs) form the cornerstone of first-line treatment for non-small cell lung cancer (NSCLC), the challenge remains to improve patients' long-term outcomes. Eftilagimod alfa (efti) activates antigen-presenting cells, triggering T cell activation and a sustained immune response. Prior studies combining efti with an ICI, pembrolizumab, have shown encouraging efficacy, especially in PD-L1 low (tumor proportion score [TPS] 1-49%) and negative (<1%) tumors. TACTI-004 is a global double-blinded, randomized, placebo-controlled phase III study investigating efti plus standard-of-care (SoC: pembrolizumab plus chemotherapy) in first-line NSCLC, regardless of PD-L1 expression (TPS 0-100%). PATIENTS AND METHODS:About 756 participants with squamous or non-squamous first-line NSCLC, not amenable to EGFR/ROS1/ALK-targeted therapy, will be randomized to receive either efti plus SoC or placebo plus SoC. The dual primary endpoint is progression-free survival and overall survival. Key secondary endpoints include objective response rate, duration of response and safety. Participants will receive 30 mg efti subcutaneously every 2 weeks (q2w) for 24 weeks, then q3w and pembrolizumab 200 mg intravenously q3w, both for up to 2 years. Chemotherapy choice will be histology-dependent. CONCLUSIONS:TACTI-004 will evaluate whether efti can mitigate resistance to ICIs when added to SoC in NSCLC, irrespective of PD-L1 tumor status. CLINICAL TRIAL REGISTRATION:www.clinicaltrials.gov identifier is NCT06726265.

Objectives: Canakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy. Materials and methods: CANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel. Results: A total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2-12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5-13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76-1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3-4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (>= 10 mg/L) CRP levels. There was no association with treatment arm. Conclusion: Adding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy.

Background: Despite advances in frontline therapy, most patients (pts) with adv/met NSCLC experience progression, and later-line chemotherapy with docetaxel-based regimens has limited benefit. Dato-DXd is an antibody-drug conjugate composed of a TROP2 directed monoclonal antibody covalently linked to a highly potent cytotoxic payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. This is the first report of results from TROPION-Lung01 (NCT04656652), a randomized, global, open-label, phase 3 study comparing the efficacy and safety of Dato-DXd vs docetaxel in pts with adv/met NSCLC with or without actionable genomic alterations (AGAs).

COVID-19 primarily affects the respiratory system. What comes after the disease is now a greater concern for the scientific world. It is remarkable for causing endocrine organ involvement, particularly in the adrenal glands. However, its effect on the adrenal gland has not been fully elucidated. A case of primary adrenal insufficiency after COVID-19. A 31-year-old female patient who presented with complaints of weakness, anorexia, nausea, recent onset of vomiting, dizziness, and low blood pressure for two months was admitted to the outpatient Department of Endocrinology and Metabolism. After discharge, the patient had routine follow-ups, and here we present the information on the first and seventh month after discharge. The patient was diagnosed with primary adrenal insufficiency with cortisol <0.054 g/dL and adrenocorticotropic hormone >1200 pg/mL in the laboratory. In the non-contrast computed tomography taken in the adrenal protocol, the stem and leaves of both adrenal glands are significantly thinned and appear atrophic, the right adrenal gland is hardly distinguished. Hydrocortisone was started. All complaints were resolved within a week, except hyperpigmentation, which was resolved six months later after treatment. Our study support adrenal gland involvement due to COVID-19, further research is needed to obtain data on damage mechanisms.

Background BNT116 is an intravenously administered RNA-lipoplex therapeutic cancer vaccine comprising six RNAs each encoding a tumor-associated antigen (TAA) frequently expressed in non-small cell lung cancer (NSCLC). Here, we report preliminary results from patients with advanced unresectable or metastatic NSCLC (ECOG 0–2) receiving BNT116 monotherapy with optional addition of cemiplimab. Methods LuCa-MERIT-1 is a first-in-human, open label, Phase I trial with cohorts to confirm the dose of BNT116 alone or as combination therapy with cemiplimab, docetaxel, and/or carboplatin/paclitaxel (21-day cycles). The first six BNT116 doses are administered once weekly during Cycles 1 and 2 and three-weekly from Cycle 3 onwards. The cohort reported here will confirm the dose of BNT116 as monotherapy. Cemiplimab may be added from cycle 3 if tumor samples exhibit PD-L1 expression (tumor proportion score ≥1%). Patients’ prior therapies must have included a PD-1/PD-L1 inhibitor, a platinum-based chemotherapy regimen as well as one other systemic therapy. The objectives are to determine safety (dose limiting toxicities [DLTs] in Cycle 1; treatment-emergent adverse events [TEAEs]), and clinical activity (RECIST v1.1). Tumor and blood samples will be used for biomarker analysis. Results As of 01 March 2023, 18 patients (median age 65 years) have received BNT116 in the reported cohort (n=13 monotherapy only; n=5 cemiplimab added after Cycle 3). Most (16/18 [89%]) had received ≥3 prior therapy lines. All patients experienced ≥1 TEAE, and most TEAEs were grade 1–2 (table 1). TEAEs (incidence rate ≥5%) include pyrexia (n=12 [67%], grade 1–3), chills (n=9 [50%], grade 1–2), and vomiting (n=5 [28%], grade 1–2). Pyrexia and chills were considered treatment-related TEAEs for BNT116. Serious TEAEs were observed in 5/18 (28%) patients (grade 2 pneumothorax [n=1] or pyrexia [n=1], grade 3 fatigue [n=1] or pneumonia [n=1], and grade 4 acute kidney injury [n=1]). The latter grade 4 TEAE occurred during safety follow-up after trial treatment termination and was considered as unrelated to treatment with IMP. No DLTs or deaths under treatment were observed. Ten of 18 patients were evaluable for clinical activity (n=5 monotherapy only; n=5 cemiplimab added after Cycle 3). Of these, 6/10 had stable disease and 4/10 had progressive disease. The median duration of disease control was 1.53 months. Conclusions In this trial, BNT116 was generally well tolerated with an expected safety profile as monotherapy and in combination with cemiplimab. Updated safety and clinical activity data will be presented along with additional biomarker data (TAA expression, PD-L1 expression, cytokines, tumor markers). Acknowledgements LuCa-MERIT-1 is funded by BioNTech SE. The authors would like to acknowledge Nick Fulcher and Andrew Finlayson (BioNTech SE) for medical writing support. Cemiplimab was provided by Regeneron Pharmaceuticals, Inc. Trial Registration EudraCT: 2021–004739-94, ClinicalTrials.gov: NCT05142189. Ethics Approval This study was reviewed and approved by the institutional review boards of the participating institutions.

Supplementary Figure S1; Supplementary Table S1.

BACKGROUND:Eftilagimod alpha (efti) is a major histocompatibility complex class II agonist activating antigen-presenting cells which leads to greater systemic type 1 T helper response and more cytotoxic CD8+ T-cell activation. This phase I trial evaluated the administration of efti, a soluble lymphocyte activation gene-3 (LAG-3) protein, combined with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab in advanced solid tumors.PATIENTS AND METHODS:Patients with heavily pretreated metastatic solid tumors received intravenous avelumab (800 mg) combined with subcutaneously administered efti (6 or 30 mg) for up to 12 cycles, followed by avelumab monotherapy. The primary endpoint was the assessment of the recommended phase II dose (RP2D) of efti in combination with avelumab.RESULTS:Twelve patients with different tumor entities were enrolled (six patients in each cohort). During treatment, no dose-limiting toxicities occurred, and the severity of most adverse events was grade 1 or 2. In total, nine serious adverse events were documented, resulting in a fatal outcome in two cases, but none of them were assessed to be treatment related. Five patients (42%) achieved partial response. The median progression-free survival was 1.96 months and the median overall survival was not reached, with a 12-month survival rate of 75%.CONCLUSION:Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

IntroductionSmall cell lung cancer (SCLC) is a rapidly growing malignancy with early distant metastases. Up to 70% will develop brain metastases, and the poor prognosis of these patients has not changed considerably. The potential of checkpoint inhibitors (CPI) in treating recurrent (r/r) SCLC and their effect on brain metastases remain unclear.MethodsIn this retrospective multicenter study, we analyzed r/r SCLC patients receiving second or further-line CPI versus chemotherapy between 2010 and 2020. We applied multivariable-adjusted Cox regression analysis to test for differences in 1-year mortality and real-world progression. We then used interaction analysis to evaluate whether brain metastases (BM) and/or cranial radiotherapy (CRT) modified the effect of CPI versus chemotherapy on overall survival.ResultsAmong 285 patients, 99 (35%) received CPI and 186 (65%) patients received chemotherapy. Most patients (93%) in the CPI group received nivolumab/ipilimumab. Chemotherapy patients were entirely CPI-naïve and only one CPI patient had received atezolizumab for first-line treatment. CPI was associated with a lower risk of 1-year mortality (adjusted Hazard Ratio [HRadj] 0.59, 95% CI 0.42 to 0.82, p=0.002). This benefit was modified by BM and CRT, indicating a pronounced effect in patients without BM (with CRT: HRadj 0.34, p=0.003; no CRT: HRadj 0.50, p=0.05), while there was no effect in patients with BM who received CRT (HRadj 0.85, p=0.59).ConclusionCPI was associated with a lower risk of 1-year mortality compared to chemotherapy. However, the effect on OS was significantly modified by intracranial disease and radiotherapy, suggesting the benefit was driven by patients without BM.