Background Metastatic melanoma resistant to immune checkpoint inhibitors remains difficult to treat, and while adoptive tumor-infiltrating lymphocyte (TIL) therapy has shown durable responses, its reliance on lymphodepleting chemotherapy and high-dose interleukin (IL)-2 causes toxicity that may limit patient eligibility. The dual-cytokine-armed oncolytic adenovirus igrelimogene litadenorepvec (TILT-123) was administered with TILs in the TUNINTIL trial (trial registration: NCT04217473) in patients with metastatic melanoma resistant to immune checkpoint inhibitors, without lymphodepleting chemotherapy or IL-2 post-conditioning. This study presents a correlative immunological analysis of the phase I TUNINTIL trial evaluating TILT-123 in combination with TIL therapy.Methods The TUNINTIL trial was a first-in-human, open-label, dose-escalation, multicenter, multinational phase I trial. 17 patients with checkpoint-inhibitor-resistant metastatic melanoma received up to six intratumoral TILT-123 injections followed by TIL infusion, without lymphodepleting chemotherapy or IL-2 post-conditioning. Systemic immune profiling (serum proteomics, flow cytometry, interferon-γ ELISpot assay), intratumoral immune cell–cell profiling (multiplex immunofluorescence, H&E, adenovirus E1a immunohistochemistry), quantitative PCR, and neutralizing antibody responses were assessed at defined time points through the trial, with survival follow-up updated to March 2026. Response criteria were evaluated using Response Evaluation Criteria in Solid Tumors V.1.1 and positron emission tomography-based criteria. Statistical analyses included Kaplan-Meier survival with log-rank tests, Mann-Whitney U tests, Pearson correlation, and receiver operating characteristic/area under the curve analysis for biomarker cut-off determination.Results Tumor biopsy analyses revealed an early innate immune activation marked by natural killer-cell expansion and cytotoxic gene upregulation, followed by increased intratumoral T-cell infiltration. This occurred without lymphodepleting chemotherapy or post-conditioning IL-2. Intratumoral viral DNA was detectable in a subset of patients. The enrichment of CD27+CD28+ memory-precursor CD8+ T cell was associated with favorable clinical outcomes. Elevated monocytic myeloid-derived suppressor cells and angiogenic/inflammatory cytokines following combination treatment were associated with disease progression, highlighting the role of immunosuppressive myeloid subsets as potential mediators of therapeutic resistance. Additionally, correlative analysis in pooled TILT-123 cohorts identified serum epidermal growth factor as a candidate biomarker for stratifying and monitoring patients.Conclusions These findings provide mechanistic insights into TILT-123 combined with TIL therapy and propose future directions for biomarker-guided clinical studies.Trial registration number NCT04217473.

Limited DNA sequencing data on lung cancer (LC) patients are available from Eastern Europe where male smoking is commonest in Europe. As sequence analysis is the prerequisite for targeted therapy we provide such data from Czechia (CZ). Additionally, we present novel sequencing data for adenocarcinoma subtypes. Panel sequencing data on 1218 adenocarcinoma patients were available from a single histology laboratory for 2016 to 2024. The highest variant frequencies were observed for KRAS (51.6 %), EGFR (18.8%) and TP53 (16.3%). Commonest types of variants were codon 12 mutations for KRAS, exon 21 L858R for EGFR and V600E BRAF. EGFR variants were more common in females (25.3% vs 11.5%). KRAS mutations were frequent in males (56.9 % vs 46.9%), as were PIK3CA mutations (3.8% vs 1.9%). KRAS mutations were frequent in patients diagnosed below 70 years, whereas EGFR, PIK3CA and MET alterations were frequent in patients above age 70 years. As stage distinctions, high prevalence of KRAS mutations was found in early stage tumors (II and IIIA) and of TP53 mutations in stages IIIB and IV. As to adenocarcinoma subtypes, lepidic type showed a high frequency of EGFR variants. We could show differential distribution of gene variants by sex, diagnostic age, stage and subtype of adenocarcinoma. The data are in line with current literature that targeted treatment is being applied for selected LC patients in CZ. It can be expected that LC patients benefit from therapeutic and other clinical improvements, which however do not reduce the primary importance of anti-smoking campaigns.

The oncolytic adenovirus TILT-123 (Ad5/3-E2F-d24-hTNFA-IRES-hIL2, igrelimogene litadenorepvec) has demonstrated favorable safety profiles in phase 1 clinical trials in patients with advanced solid tumors (these trials were registered at ClinicalTrials.gov: NCT04695327, NCT05271318, and NCT04217473). In this study, we analyzed the serum proteome of patients treated with TILT-123 monotherapy using mass spectrometry, focusing on samples collected during the initial intravenous administration phase. Functional and correlative analyses revealed that IGLV8-61-encoded natural immunoglobulin M (IgM) was associated with reduced neutralizing activity and improved clinical outcomes, as assessed by positron emission tomography imaging and overall survival. Single-cell B cell receptor sequencing enabled profiling of the circulating antibody repertoire and detection of IGLV8-61-expressing clones. Recombinant expression of antibody sequences from a responding patient with a history of hyperlipidemia yielded three pentameric natural IgMs capable of binding both TILT-123 and anionic modified low-density lipoprotein. Further characterization revealed that the IgMs significantly enhanced transduction and promoted cell killing in vitro across multiple cell lines. Blocking studies demonstrated transduction was influenced by Fc receptors pIgR and FcμR. Cross-trial comparisons indicated dyslipidemia as a common feature among responders. Collectively these findings show that dyslipidemia -associated natural IgM enhances the therapeutic efficacy of TILT-123, via antibody-dependent enhancement. These findings may have broader implications for other oncolytic viruses, an emerging class of tumor immunotherapies.

Background:Classification of lung adenocarcinoma into subtypes is relatively recent and not universally practiced. Consequently, large representative studies describing clinical outcomes are rare, failing to pervasively present the advantages of subtyping, which might potentially improve treatment and survival. Although many related studies have been published, few of them include large patient numbers of unselected adenocarcinoma subtypes, which has probably resulted in discrepant results. We describe the situation in Sweden with the largest study on a European population with a focus on survival. Methods:Patient data were obtained from the Swedish Cancer Registry from 2005 to 2021, accounting for 1,418 patients, less than 5% of the reference group 'adenocarcinoma not otherwise specified (NOS)'. All reported adenocarcinoma patients were included from the cancer registry, with complete national coverage of patients and pathological verification of diagnoses. Non-parametric survival estimates were calculated using the Kaplan-Meier method and testing for linear consistency using Weibull modelling. Results:Survival was generally better for women compared to men and this was most prominent for early-stage cancers. Female 5-year survival decreased in order, lepidic [59%, 95% confidence interval (CI): 55-65%], papillary (51%, 95% CI: 40-64%), invasive mucinous (46%, 95% CI: 32-66%), colloid (36%, 95% CI: 30-43%) and adenocarcinoma NOS (24%, 95% CI: 24-25%). Male 5-year survival for lepidic (46%, 95% CI: 40-53%) and colloid subtypes (22%, 95% CI: 16-29%) was significantly lower than female survival. Survival slopes for T1, T2, N0, M0 cases of lepidic, papillary and adenocarcinoma NOS were almost linear, suggesting homogeneous diagnostics. Survival kinetics were in agreement with Weibull modelling k-values of 1.00 or slightly higher, implying that mortality increased slowly with time, only moderately faster than for the background population of similar age. Conclusions:The present study is among the largest ones so far published on unselected stages of adenocarcinoma subtypes. Our findings demonstrate a significant female survival advantage across most adenocarcinoma subtypes. Survival in T1 and T2 classes with N0 and M0 for lepidic, papillary and adenocarcinoma NOS was close to linear, suggesting that patients are homogeneously diagnosed and treated. Survival benefits of lepidic and papillary subtypes over adenocarcinoma NOS give justification for adenocarcinoma subclassification, and independently validate the prognostic advantage of lepidic and papillary subtypes proposed in the World Health Organization (WHO) 2021 adenocarcinoma grading classification.

Swedish family and cancer data constitute the largest source on familial cancer in the world. We analyze here familial risks in prostate cancer (PC) with focus on multiple affected brothers and comparation of full-brothers to maternal and paternal half-brothers. Age-specific incidence and standardized incidence ratios (SIRs) were calculated for PC in brothers. Curves for relative risk (RR) by diagnostic age were plotted for risk distributions. A total of 115,066 PCs were diagnosed in 1.2 million men. Familial SIR for full brothers was 2.23, for maternal half-brothers it was 1.92 and paternal half-brothers was 1.34. Considering SIRs with least possible detection bias (7+ years after first brother's diagnosis) the above SIRs were 2.06, 1.66 and 1.41. SIRs in full brothers increased stepwise by the number of affected brothers reaching 21.33 when 6 brothers were affected. Age-RR curves for two affected brothers declined evenly from RR 2.8 at age 45 to below 2.0 at age 80. When four or more brothers were affected, a discrete high-risk peak (RR 4-7) was detected between ages 60 and 69. Data on full-brothers and half-brothers indicate that familial risk in PC is largely genetic which is also supported by discrete RR peaks in high-risk families at ages matching preferential penetrance age for known predisposition genes of PC. Familial risk increased already when two brothers were affected calling for clinical vigilance concerning family history. Family history should deserve a place as an inclusion criterium in schemes for PC screening.

TILT-123 (Ad5/3-E2F-d24-hTNFα-IRES-hIL2, igrelimogene litadenorepvec) is a chimeric oncolytic adenovirus engineered to selectively replicate in tumor cells and express tumor necrosis factor (TNF) and interleukin-2 (IL-2). While oncolytic viruses are commonly administered intratumorally, this approach often restricts practical applicability. Intravenous delivery is less invasive and offers a more practical alternative; however, systemic immune barriers challenge effective tumor targeting. In a cohort of a phase 1 clinical trial, six patients with advanced solid tumors who had exhausted standard treatments received two intravenous doses of TILT-123 (split-dose), per treatment day across seven cycles. Safety was the primary objective, while efficacy outcomes were exploratory and assessed using positron emission tomography/-computed tomography (PET/CT) imaging, along with overall survival. Split-dosing was safe, with chills, fever, fatigue, and lymphocyte reduction being the most common treatment-related events. In imaging, the disease control rate was 83.3% according to PET criteria and 33.3% by RECIST 1.1. The median overall survival was 198 days. Split-dosing increased the area under the curve of TILT-123 and amplified systemic cytokine responses. Proteomic analysis of serum and neutralizing antibody profiling indicated that enhanced humoral immune activity was associated with shorter overall survival. Post-treatment biopsies confirmed virus presence and alterations in immune cell composition. These findings support further evaluation of intravenous TILT-123 administration in clinical trials.

2538 Background: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can be effective in metastatic melanoma, but its routine use is limited by the need for lymphodepleting chemotherapy and systemic high-dose IL-2. To reduce toxicity while preserving antitumor activity, a strategy pairing TIL therapy with the oncolytic adenovirus igrelimogene litadenorepvec (TILT-123) was assessed. This virus selectively replicates in malignant tissue and drives local expression of TNF and IL-2 within tumors, functionally replacing the need for pre-infusion chemotherapy and post-infusion IL-2 administration. Methods: Seventeen patients with advanced melanoma resistant to immune checkpoint inhibitors were treated and sampled (NCT04217473). Treatment with igrelimogene litadenorepvec started upon tumor biopsy collection for TIL manufacturing took place and eventually followed by autologous TIL infusion around 36 days after. Hypotheses generated during data analysis were validated using additional patient datasets (NCT04695327, NCT05271318). Results: The regimen was well tolerated, with no dose-limiting toxicities. Objective response rate was 11.7%, with disease control in 35% by RECIST 1.1 and 47% by PET; metabolic responses were seen in 27%. Among those patients, higher baseline expression of epidermal and hepatocyte growth factors (EGF and HGF respectively) was associated with poorer prognosis. Higher than median HGF was negatively correlated with survival (p=0.032). Additionally, patients that achieved disease stabilization or better had a lower presence of circulating MDSCs (p=0.017). The link between growth hormones, MDSCs and disease progression was extrapolated to a larger dataset including other patients treated with igrelimogene litadenorepvec to find out the same trend for survival (HGF; p = 0.003, EGF; p = 0.029). In parallel, baseline circulating young memory T cells (CD27+CD28+CD8+) and an early expansion of NK cells (CD45+CD56+CD3-) correlated with a lower chance of progressing (T cells p=0.005, NK cells p=0.003). Conclusions: Combining TILT-123 with TIL therapy was safe and produced meaningful clinical activity in checkpoint inhibitor-refractory melanoma, especially in patients with lower HGF and EGF at baseline and a higher presence of young memory T cells and NK cells. In this clinical set-up, adapting the inclusion exclusion criteria to select patients with those defined immune system features, could help improve efficacy beyond. This approach may substantially broaden the feasibility and accessibility of TIL-based immunotherapy, especially due to the omission of the toxic conditioning regimens. Clinical trial information: NCT04217473 .

Accumulating evidence implicates the microbiome as an important determinant of clinical outcomes in cancer therapies; however, the role of the microbiome in oncolytic virus therapy remains largely unexplored. We investigated the gut microbiome of cancer patients following treatment with the oncolytic adenovirus igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123). Baseline fecal samples from phase I clinical trials (NCT04695327 and NCT05271318) were analyzed using shotgun metagenomic sequencing and compared to treatment outcomes. A higher relative abundance of Alistipes was observed in patients with treatment benefit, while elevated Eggerthella was observed with reduced benefit. These associations were validated in a preclinical mouse model where administration of Alistipes shahii improved the efficacy of adenovirus therapy. In addition, enrichment analysis in patient samples showed a positive correlation between higher relative abundance of Alistipes and elevated short-chain fatty acids in both feces and serum, which in turn revealed higher circulating neutrophil counts. Finally, in a case study, we observed that adenovirus treatment resulted in increased Alistipes relative abundance and reduced Eggerthella relative abundance, indicating that adenovirus therapy may beneficially modulate the microbiome. Overall, our findings reveal a novel association between Alistipes, Eggerthella, and the therapeutic response to oncolytic adenovirus therapy, highlighting their potential as biomarkers or targets for microbiome-based interventions such as pre-, pro-, or postbiotics.

Background Oncolytic viruses (OVs) are promising immunotherapeutics to treat immunologically cold tumors. However, research on the mechanism of action of OVs in humans and clinically relevant biomarkers is still sparse. To induce strong T-cell responses against solid tumors, TILT-123 (Ad5/3-E2F-d24-hTNFa-IRES-hIL2, igrelimogene litadenorepvec) was developed. TILT-123 encodes two transgenes: tumor necrosis alpha (TNFa) and interleukin-2 (IL-2). TUNIMO (NCT04695327) was a phase I clinical trial using TILT-123 in patients with advanced solid tumors aiming to assess the safety, efficacy, and immunological effects of TILT-123. Research presented in this study evaluated the immunological effects of TILT-123 in the TUNIMO trial by using biological samples collected from the patients during the study, with an objective to leverage the findings to develop possible biomarkers of response and gain insights into possible synergistic combination treatments.Methods 20 patients with advanced solid tumors were treated with TILT-123. Response to therapy was assessed with contrast-enhanced CT and fluorodeoxyglucose positron emission tomography, along with overall survival (OS) calculation. Biological samples from patients were collected in the form of blood and tumor biopsies. Collected samples were analyzed with immunohistochemistry, transcriptomics, proteomics, and flow cytometry.Results TILT-123 induced cyclical decreases in blood lymphocyte count, and more substantial blood lymphocyte count correlated with better radiographical response and longer OS. Lymphocyte count findings were confirmed with external control dataset of 96 patients. More substantial lymphocyte count change was linked to stronger immune activation in plasma proteome after intravenous TILT-123 and the presence of TILT-123 mRNA in tumors. Regarding other assays. tumor biopsies profiled showed increased amounts of CD8+ T cells, CD4+ T cells and NK cells after intravenous TILT-123, but not after intratumoral TILT-123. Transcriptional differences were seen in tumors after intravenous therapy and intratumoral therapy, with patients benefitting therapy showing stronger downregulation of immune activation at all time points.Conclusions TILT-123 therapy induced accumulation of effector lymphocytes in tumors. Peripheral lymphocyte count decrease is a promising biomarker for assessing oncolytic adenovirus therapy response.

Abstract Immune checkpoint inhibitors have demonstrated modest efficacy as a monotherapy in ovarian cancer. Originally developed to improve efficacy of T-cell therapies such as immune checkpoint inhibitors and adoptive cell transfer, TILT-123 (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a serotype chimeric oncolytic adenovirus encoding tumor necrosis factor alpha and interleukin-2. Here we report results from phase 1a of PROTA, a single-arm, multicentre dose escalation trial with TILT-123 and pembrolizumab in female patients with platinum resistant or refractory ovarian cancer (NCT05271318). The primary endpoint was safety. Secondary endpoints included efficacy, tolerability, virus persistence and anti-viral immunity. Patients (n = 15) received intravenous and intraperitoneal and/or intratumoral injections of TILT-123 as well as intravenous pembrolizumab. Treatment was well tolerated, and no dose-limiting toxicities were observed. The most frequent adverse events were fever (40%), fatigue (40%) and nausea (40%). Disease control was achieved in 64% of evaluable patients (9/14). Median progression-free survival and overall survival were 98 and 190 days respectively. Clinical responses were associated with higher serum anti-adenovirus neutralizing antibody titer at baseline and post-treatment. The phase 1b investigating TILT-123, pembrolizumab and PEGylated liposomal doxorubicin in a similar patient population is underway.

Abstract Background The Swedish Family-Cancer Database (FCD) is the largest source of data on familial cancer in the world, including practically complete family structures and individual cancer diagnoses from the high-quality cancer registry. We present a novel application of FCD by analyzing age-specific familial risks and interpreting them through likely causes, such as germline pathogenic variants and/or environmental exposures. Main body The basic assumption for this approach is that a discrete familial clustering in a narrow age-interval is not random but may provide causal clues. For this analysis we selected reasonably common cancers to meaningfully scrutinize familial risk through adulthood in which cancers are diagnosed, that included colorectal (CRC) and endometrial cancers, prostate and kidney cancers and breast and lung cancers. The interpretation is based on the literature. The highest familial relative risks for CRC and endometrial cancers were found at ages 40–44 years, matching the peak impact of mismatch repair gene mutations. However endometrial cancer showed also a small early onset component which could not be explained. Age-related familial risks for breast, prostate and kidney cancers also matched data from large-scale sequencing; these included the early onset component in kidney cancer which was likely due to VHL mutations. Age distribution of familial lung cancer was unique in showing a wide peak extending from middle to old ages, which would be consistent with a combination of direct genetic effects and indirect influence on inheritance of smoking dependence. Conclusions The present review of age-specific familial risks and age-of-onset data from the literature may allow an interpretation that the familial and germline landscapes are reasonably harmonious for relatively early onset cancers but at higher ages no discrete peaks can be found which may implicate attenuated impact of high-risk genes and polygenic influence.

BACKGROUND:Familial clustering of initial primary lung cancer (IPLC) may be related to shared smoking habits, other environmental exposures and hereditary factors, but whether familial risk also influences the risk of second primary LC (SPLC) is not well known. We aimed to carry out a family study between first-degree relatives on SPLCs in Sweden. METHODS:Population data on Swedish family relationships and the diagnosed cancers were obtained from the national registers from 1961 to 2021. IPLC was diagnosed in 54,429 patients of whom 534 were diagnosed with SPLC. Familial risk was assessed through the standardized incidence ratio (SIR with 95% confidence interval) adjusted for several potential confounders, including sex, age, calendar period, educational level and geographic region. Familial risks were analyzed by type of proband, histology and sex. In addition, we estimated the effect of family history on the cumulative proportion of patients developing SPLC by sex and histology. RESULTS:The estimated SIR for SPLC was 3.98 in patients without family history and 5.24 among those with a history of lung cancer in first-degree relatives. The SIR values depended on the histology of IPLC and of SPLC, with the highest SIRs for concordant histologies. For the adenocarcinoma-adenocarcinoma sequence, SIR estimates were 5.60 and 7.51 for non-familial and familial patients, respectively. The familial risks were further modulated by sex and type of affected relative, with the highest SIR for females with affected mothers (9.14). CONCLUSIONS:The results showed a positive association of family history of LC with risk of SPLC on top of high risk for SPLC in non-familial patients. The risks differed by sex, histology and type of affected relative. The data on family history of LC should alert about surveillance for SPLC and may be used in future risk stratification when eligibility for population screening is considered.

Pancreatic ductal adenocarcinoma (PDAC) is a cancer with dismal prognosis due to resistance to most current therapies. Although immunotherapy has improved the treatment of many solid cancers, pancreatic cancer remains resistant to immunotherapy due to immunosuppressive tumor microenvironment, limited lymphocyte infiltration and lack of neoantigens. Oncolytic adenoviruses are a possible solution to treatment resistance in PDAC due to their ability to elicit lymphocyte trafficking and epitope spreading. Herein, we tested if an oncolytic adenovirus encoding a variant interleukin-2 molecule (Ad5/3-E2F-d24-vIL2), could enable immune checkpoint inhibitor (ICI) therapy in PDAC when combined with chemotherapy. Rationale for Ad5/3-E2F-d24-vIL2 was tested in vitro, where increase in programmed death ligand 1 (PD-L1) expression was seen after virotherapy and chemotherapy. Expression of other B7 family proteins was characterized in mono- and co-culture settings of cancer cells, fibroblasts, and macrophages. The combination therapy of virotherapy, chemotherapy and ICI was characterized in freshly resected ex vivo pancreatic tumor samples. Combination of ICI with virotherapy showed increased interferon and chemokine production in samples, with expansion of cytotoxic CD8 + T cells seen by flow cytometry. In vivo evaluation of the triple combination therapy in a Syrian hamster model showed improved tumor growth control and overall survival, with concurrent increase in intratumoral lymphocytes during therapy. Animals cured with the therapy showed resistance to re-challenge with the same cell line, supportive of successful generation of anti-tumor immunity in the animals. The combination treatment of Ad5/3-E2F-d24-vIL2, chemotherapy, and checkpoint inhibition is a promising treatment modality to tackle treatment resistance in PDAC.

Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 (TILT-123) is an oncolytic adenovirus armed with TNFa and IL-2. The cytokine pairing demonstrated superior tumor immunomodulation in preclinical studies. Subsequent studies supported evaluation of TILT-123 in PROTA, a phase 1 study of TILT-123 in combination with pembrolizumab in platinum resistant or refractory ovarian cancer patients. Biomarker analysis is ongoing. In this phase 1a dose escalation trial (NCT05271318), 15 patients received an initial single intravenous dose of TILT-123 ranging from 3x1011 to 4x1012 VPs, followed by intratumoural and/or intraperitoneal injections ranging from 1x1011 to 5x1011 VPs. Patients also received i.v. pembrolizumab (200mg) every three weeks starting on day 36. The primary endpoint was safety by day 92, while efficacy by RECIST1.1 and overall survival (OS) were secondary endpoints. Collection of tumour biopsies and blood, including PBMCs and serum, enabled evaluation of MoA and identification of preliminary biomarkers. ORR was 7.1% in evaluable patients (1/14). Disease control rate was 64% in evaluable patients (n = 14) and median OS was 190 days (n =15). Patients with disease control and no disease control by 92 achieved a median OS of 571 days and 138 days respectively. Correlations of complete blood count with differential to OS (n =15) and imaging response (n = 14) revealed a greater drop in lymphocyte count after treatment, as well as baseline lymphocyte count positively correlated with OS and disease control (PR/SD vs PD). Correlation of prothrombin INR to OS revealed patients with a slower blood-clotting rate at baseline and post-treatment positively correlated with OS. Analysis of anti-adenovirus neutralizing antibody (nAb) titer revealed 77% of all patients were positive for nAbs prior to treatment. All patients developed nAbs in blood and ascites (ascites n = 3). Patients presenting with nAbs at baseline achieved longer OS than those not positive. Additionally, a higher titer post-treatment positively correlated with OS and disease control. Percentage and fold change increase in IgM expression on plasma cells on day 36 positively correlated with OS. In addition, a higher expression of IgM on the surface of plasma cells at baseline was observed in patients achieving disease control. These preliminary results identify a key role of circulating lymphocyte re-distribution and humoral immune response as markers of treatment benefit. Initial phenotyping implicates IgM producing plasma cells as a potentially relevant immune cell population. Additionally we observed a correlation between the coagulation cascade and OS. James H. Clubb, Matthew Block, Johanna Mäenpää, Victor Arias, Mirte van der Heijden, Santeri Pakola, Dafne C. Quixabeira, Tatiana Kudling, Elise Jirovec, Lyna Haybout, Tuomo Alanko, Daniel Adamo, Susan Ramadan, Jorma Sormunen, Juha Kononen, Michael J. Chisamore, Julia W. Cohen, Nadena Singh, John Goldfinch, Suvi Sorsa, Riikka Havunen, Claudia Kistler, João M. Santos, Víctor Cervera-Carrascon, Akseli Hemminki. Clinical-immunological correlates in platinum resistant or refractory ovarian cancer patients treated with chimeric oncolytic adenovirus encoding TNFa and IL-2 (TILT-123) in combination with pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2035.

Elevated levels of immune infiltration found in renal cell carcinoma are often associated with poor patient prognosis, likely due to T cell exhaustion and an immunosuppressive tumor microenvironment, which limits the efficacy of current immunotherapies. In this study, we focused on the use of Ad5/3-E2F-d24-hIL7 (TILT-517), an oncolytic adenovirus expressing interleukin-7, as a strategy to selectively lyse tumors. This approach also seeks to activate infiltrating immune cells, thereby reprogramming the immune landscape characteristic of renal cell carcinoma tumors. Furthermore, we evaluated the combination of TILT-517 with immune checkpoint inhibitors, main immunotherapeutic component for this disease. Anti-tumor efficacy was significantly observed in ex vivo patient-derived tumors when treated with TILT-517 in monotherapy and in treatment combination. Cellular and proteomic changes were detected in the tumor microenvironment, including enhanced cytotoxicity of effector populations such as CD4+, CD8+ T cells, natural killer, and natural killer T cells. In vivo, we developed a novel syngeneic Syrian hamster model for renal cancer, and TILT-517+anti-PD-L1 group presented significant enhanced tumor growth control and led to an increased number of effector and antigen-presenting cells compared to anti-PD-L1 monotherapy. Hence, TILT-517 offers a promising approach for renal cell carcinoma treatment, boosting therapeutic efficacy and reshaping the tumor microenvironment.