Background: Cancer-related cognitive impairment (CRCI) affects quality of life, daily functioning and return-to-work. However, CRCI remains under-addressed in cancer care. Since cognitive complaints often co-occur with fatigue and psychological distress, a multimodal approach is warranted. We developed Integrative Neuro-Cognitive Remediation Therapy (INCRT), a multidisciplinary survivorship program combining personalized cognitive function and strategy training with group-based psychoeducation, cognitive-behavioral therapy and Acceptance and Commitment Therapy, and onco-yoga. Methods: Cancer survivors suffering from CRCI were eligible. Assessments included neuropsychological testing, patient-reported outcomes, and daily functioning at baseline (T0), post-intervention (T1), and 6-month follow-up (T2). Primary outcomes were objective and subjective neurocognitive functioning (NCF); secondary outcomes were psychological distress, fatigue, metacognition, and daily functioning. Changes were analyzed using linear mixed models. Results: Between November 2022 and January 2025, 44 of 56 eligible survivors enrolled; 38 completed the program (71.1% female; median age 53.5). Objective and subjective NCF improved significantly at T1 and T2 (ps < 0.001). Psychological distress, fatigue, and unhelpful metacognitions decreased over time (ps < 0.05). Participants reported greater emotional and cognitive insight and improved daily functioning. Conclusions: INCRT improves cognitive functioning, reduces psychological distress and fatigue, and enhances daily functioning, with benefits maintained at follow-up. The integrative design supports sustained effects by promoting internalization and daily application of learned strategies.

Significant heterogeneity in the immune microenvironment of Glioblastoma, IDH-wildtype (GBM), has been reported, necessitating a standardized approach to evaluate immune infiltration in the context of emerging immunotherapies. To address this, we developed and validated a standardized immunohistochemistry-based scoring system for quantifying immune cell infiltration in formalin-fixed, paraffin-embedded (FFPE) tissue. Paired primary and recurrent GBM specimens from 20 adult patients were labeled for CD3, CD8, CD45, CD68, and PD-1, and scored across six anatomical regions, including intra- and peritumoral, meningeal, and normal brain areas. The scoring system demonstrated excellent interrater (ICC = 0.932) and intrarater (ICC = 0.953) reliability. CD68+ and CD45+ cells were most numerous across all regions. CD3+ and CD8+ cells concentrated more in the perivascular area rather than within the parenchyma. No significant differences in immune infiltration were observed between primary and recurrent GBM. Cox proportional-hazards analysis showed worse survival with higher CD8+ and CD45+ infiltration in primary GBM, and higher CD45+ and CD68+ infiltration in recurrent GBM. In conclusion, we propose a feasible, cost-efficient, and robust method to assess immune infiltration on FFPE material, enabling standardized comparison of inflammation, with applications for ongoing clinical trials.

BRAFV600-mutant metastatic colorectal cancer comprises a biologically distinct and clinically aggressive subset of metastatic colorectal cancer. Early attempts to apply single-agent BRAFV600 inhibition failed because of rapid acquired resistance and reactivation of mitogen-activated protein kinase signaling. Over the last decade, rational combinations (BRAF inhibitors and epidermal growth factor receptor inhibitors with or without mitogen-activated protein kinase kinase inhibitors) have become the standard of care in the refractory setting and are now being evaluated upfront, whereas a wave of next-generation approaches (extracellular signal-regulated kinase and SHP2 inhibitors, receptor tyrosine kinase-targeted agents, and immunotherapy combinations) aims to prevent or overcome resistance. The objective of this comprehensive review was to summarize historic therapeutic approaches, current standards, and the mechanistic rationale and clinical development of next-generation strategies to combat resistance in BRAFV600-mutant metastatic colorectal cancer.

Background and aimsHeart failure with preserved ejection fraction (HFpEF) prevalence increases, but in cancer patients undergoing potentially cardiotoxic treatments, HFpEF is not included in baseline risk stratification, nor in cancer therapy-related cardiac dysfunction (CTRCD) definitions. Data on HFpEF in this population are scarce. We described baseline HFpEF prevalence in cancer patients and compared incidence of cancer therapy-related cardiovascular toxicity (CTR-CVT), CTRCD and HFpEF events (new HFpEF diagnosis or decompensation of pre-existing HFpEF) and mortality in this subgroup compared to patients without pre-existing HF and to patients with pre-existing HF(m)rEF. Secondly, we investigated the incidence of HFpEF events and CTR-CVT after cancer therapy initiation, identifying predictors for developing HFpEF events.Methods and resultsThis retrospective analysis included 665 patients (54.1% female, mean age 62.1 years), of whom 36 (5.4%) had known HFpEF prior to cancer therapy initiation. Compared to patients without HF, pre-existing HFpEF implied higher mortality (27.8% vs. 12.8%, p = 0.011), numerically comparable to mortality in pre-existing HF(m)rEF (26.8%), with death occurring significantly earlier in pre-existing HFrEF, driving the mortality signal. Though no difference in CTR-CVT incidence was observed, pre-existing HFpEF predisposed to more HFpEF events (41.6%, p < 0.001) and less CTRCD (2.8%). Independent of baseline characteristics, 96/665 patients (14.4%) developed HFpEF events, of whom 47.9% had pre-existing CVD yet only 15/96 (15.6%) had a HFpEF diagnosis. Cancer therapy required adaptation in 12/96 patients (12.5%) but no mortality difference was observed in this subpopulation. Older age, female sex, arterial hypertension and previous arrhythmias predicted HFpEF events in multivariate analysis.ConclusionPre-existing HFpEF carries a significant morbidity and mortality risk, where pre-existing HFpEF identifies a high-risk phenotype with elevated crude mortality, but the independent mortality signal is driven by HFrEF. HFpEF events are common and may have important cancer treatment (and therefore prognostic) implications, despite not being formally included in the definition of “CTRCD” in current guidelines. In patients developing HFpEF events, HFA-ICOS baseline risk stratification proformas suggested a low to intermediate CTR-CVT risk in most patients, possibly reflecting an underestimation of this risk and encouraging further optimization of current risk stratification tools.

e21514 Background: Many advanced melanoma patients (pts) will not obtain a durable response on immune checkpoint- (ICI) and BRAF/MEK-inhibitors (in case of a BRAFV600 mutation). Dendritic cells are crucial for ICI effectiveness and are often excluded from the tumor microenvironment in refractory melanoma. In a previous phase I clinical trial (NCT03707808), low-dose IV NIVO (10 mg) combined with intratumoral (IT) injections of autologous CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC, IPI and synthetic adjuvant AS01B was proven feasible with a promising efficacy signal (DCR 50%) (Tijtgat et al, JITC 2024). We aimed to evaluate the added value of the myDC in a randomized trial. Methods: In this single-center, prospective, two-stage phase II clinical trial, advanced melanoma pts with injectable metastases progressive on standard-of-care life prolonging treatments were randomized 1:1 to receive weekly IT IPI and AS01B with (arm A) or without (arm B) a single IT injection of autologous myDC, and bi-weekly low-dose NIVO IV. At progression (PD), pts in arm B could cross-over to receive the single IT autologous myDC injection with continued study treatment. A sample size of 9 pts in each arm was determined according to a Simon’s two-stage study design. The 1-year PFS rate (1y PFS) served as primary endpoint. Key secondary endpoints were safety, ORR (per RECIST v1.1), PFS and OS. Results: At this interim analysis, 16 pts (8 in each arm) were enrolled (10 male, median (med) age 69, AJCC stage IIIB: 1, IIIC: 5; M1a: 6, M1c: 3, M1d: 1) between Jan ‘24 and DBL (20 Jan '26). There were no significant differences in treatment disposition between both study arms (med 6.5x IT (range 1-22) and 4x IV NIVO (range 1-12)). 13 pts were evaluable for response. The ORR was 28% in arm A (2 CR: 30 wks and 73+ wks), and 17% in arm B (1 CR: 48+ wks). 4 out of 5 pts crossed over at PD to receive myDC. After cross-over, there was one stable disease. After a median follow-up of 38 wks (range 2-101), 11 pts progressed (6 in arm A, 5 in arm B), and 6 had died (4 in arm A, 2 in arm B). Estimation of the 1y PFS is immature, requiring additional follow-up. Med PFS was 14 wks (95% CI 11-16) in arm A and 17 wks (95% CI 11-22) in arm B. All pts experienced at least one treatment-related adverse event (TRAE); most commonly low-grade fatigue (44%) and injection site reaction (56%) with equal frequency in both arms. 5 pts interrupted treatment temporary (4) or definitive (1) due to TRAE. No grade ≥4 TRAE occurred. Conclusions: Weekly IT IPI+AS01B and bi-weekly low-dose NIVO IV, with or without a single IT injection of myDC, is safe and results in durable tumor responses in a meaningful subset of advanced pretreated melanoma pts. Additional follow-up is needed to estimate the added value of IT myDC in this investigational IT immunotherapy regimen. Clinical trial information: EUDRACT 2017-003280-35.

The determination of prognoses for patients with recurrent glioblastoma remains challenging. This study aimed to evaluate the prognostic value of static O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET parameters in patients with recurrent glioblastoma. Methods: We retrospectively evaluated patients treated in 3 institutional clinical trials examining vascular endothelial growth factor inhibition, immune checkpoint inhibition, or their combination in recurrent glioblastoma. Patients with a baseline 18F-FET PET were included in the analysis and stratified by treatment group. Prognostic value was evaluated using univariate Kaplan-Meier and multivariate Cox regression analyses, with receiver-operating-characteristic analysis to identify optimal thresholds. Results: Both univariate and multivariate analysis revealed that patients with a larger baseline metabolic tumor volume (MTV) and higher mean tumor-to-background ratio (TBRmean) had an increased risk of death independent of treatment (MTV per 10 mL: hazard ratio, 1.06; 95% CI, 1.01-1.12; P = 0.023; TBRmean: hazard ratio, 1.91; 95% CI, 1.14-3.21; P = 0.014). Receiver-operating-characteristic analysis showed that an MTV and TBRmean of more than 27.94 cm3 and 2.15, respectively, identified patients with worse overall survival in our patient population. Conclusion: Pretreatment MTV and TBRmean had a significant prognostic value in patients with recurrent glioblastoma, independent of treatment, and could be useful to stratify and select patients for future clinical trials.

Background Nivolumab plus ipilimumab (COMBO) is the standard treatment for asymptomatic melanoma brain metastases (MBM), but current guidelines do not provide specific recommendations for treatment discontinuation in responding patients. This study aimed to evaluate outcomes after COMBO discontinuation within 24 months and the role of continuing treatment beyond 24 months. Methods Patients with MBM treated with COMBO who discontinued treatment within 24 months for reasons other than disease progression or continued beyond this time point were retrieved. Overall survival (OS), objective response, progression-free survival (PFS) and toxicities were analyzed. Results 465 patients were included: 392 discontinued COMBO within 24 months, while 73 continued beyond 24 months. Treatment was discontinued due to complete response (CR, n=47), partial response (PR, n=45), stable disease (SD, n=12), toxicity after SD (n=59), toxicity after CR (n=99), or toxicity after PR (n=130). At multivariable analysis, the line of treatment (>first vs first: HR 2.65 (1.62-4.32)), the immune-related adverse events (irrespective of anti-tumor necrosis factor-alpha) (HR 0.18 (0.07-0.42)); COMBO discontinuation after CR (HR 0.15 (0.05-0.40)), or PR (HR 0.08 (0.03-0.26)), as well as stopping due to toxicity after CR (HR 0.14 (0.07-0.27)) or PR (HR 0.51 (0.32-0.82)), were associated with OS. Notably, at a median follow-up of 51 months (IQR 31-70), patients with CR/PR who discontinued COMBO within 24 months had PFS and OS comparable to those who continued treatment beyond this time point. 4-year OS exceeded 83% in patients discontinuing COMBO after CR, PR, or toxicity following CR, compared with 66.4% in those discontinuing due to toxicity after PR; median PFS was not reached in the former groups but was 18.6 months in the toxicity after PR group. Conclusion Discontinuation of COMBO within 24 months appears safe in patients with CR and in selected cases of PR, with no survival disadvantage versus prolonged therapy.

9543 Background: Pts with advanced cMEL R/R to PD-(L)1–based therapy, including PD-(L)1+CTLA-4, have few treatment options. BOT (Fc-enhanced anti–CTLA-4) augments T-cell priming, depletes Tregs, and activates antigen-presenting cells to overcome immune checkpoint inhibitor (ICI) resistance. BOT ± BAL (anti–PD-1) has shown activity in ICI-R/R and cold tumors. Methods: The open-label, global phase 2 C-800-23 trial (NCT05529316) enrolled pts with cMEL (stage III unresectable or IV) R/R to prior anti–PD-(L)1 ± CTLA-4. Part 1: randomized 1:1 to BOT 50 mg or 150 mg every 3 weeks (Q3W; up to 4 doses). Part 2: BOT 75 mg Q3W (up to 4 doses) plus BAL 450 mg Q3W (up to 2 years). Endpoints included confirmed objective response rate (ORR; primary; RECIST 1.1), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Clinical benefit rate (CBR) was complete or partial response or stable disease for ≥24 weeks. Results: As of Dec 13, 2025, 138 pts received BOT monotherapy (median follow-up, 12.3 mo; range, 0.2–35+) and 36 pts received BOT+BAL (median follow-up, 13.8 mo; range, 2–26+). Overall, 51% had stage M1c or M1d disease, 29% had BRAF mutant disease, and 39% had LDH >ULN. In pts R/R to anti–PD-(L)1, 72% (60/83 with pre-trial data available) had primary resistance (best overall response of progressive disease [PD] or PD ≤6 mo from most recent course of respective ICI type). In pts R/R to anti–PD-(L)1+CTLA-4, 69% (61/88) had primary PD-(L)1 resistance and 69% (60/87) had primary CTLA-4 resistance. With BOT+BAL, ORR was 22% (95% CI, 10–39), CBR was 33% (95% CI, 19–51), median DOR was not reached (NR; 95% CI, 4.17–NR), 12-mo PFS was 29% (95% CI, 15–44), and median OS was 16.6 mo (95% CI, 9.1–NR; 24-mo OS, 46%; 95% CI, 29–61). ORR with BOT+BAL was numerically higher in PD-(L)1+CTLA-4 R/R pts (29%, 4/14; 95% CI, 8–58; 3/4 responders had primary ICI resistance) vs PD-(L)1–only R/R pts (18%, 4/22; 95% CI, 5–40; all responders had primary ICI resistance). With BOT alone, ORR was 6% (95% CI, 3–11), CBR was 14% (95% CI, 9–21), 12-mo PFS was 7% (95% CI, 3–13), and median OS was 12.9 mo (95% CI, 9.7–16.2; 24-mo OS, 28%; 95% CI, 20–36). Responses were irrespective of Fcγ receptor genotype. Treatment-related adverse events occurred in 81% (grade ≥3, 30%) with BOT alone and 94% (grade ≥3, 36%) with BOT+BAL; most common was diarrhea (BOT 33%; BOT+BAL 42%). One possibly treatment-related death was reported with BOT monotherapy (immune-mediated enterocolitis). No new safety signals occurred. Conclusions: In this ICI-R/R cMEL population enriched with primary ICI-resistant pts, BOT+BAL showed durable responses, encouraging survival, and a stronger signal in pts who had prior conventional anti–CTLA-4. BOT monotherapy also showed activity. This supports a differentiated mechanism for BOT and continued development of BOT+BAL, including for pts with dual ICI-R/R cMEL. Clinical trial information: NCT05529316 .

Dendritic cells (DCs) are central to cancer immunity, orchestrating both innate and adaptive immune responses. In melanoma and other solid tumors, however, their function is often impaired within the tumor microenvironment (TME), leading to weakened antitumor immunity and diminished responses to immune checkpoint inhibitors (ICIs) and adoptive tumor-infiltrating lymphocyte (TIL) therapy. Among the various cell-based immunotherapy approaches, DC therapy—particularly using blood-derived conventional DCs (cDCs)—holds considerable promise. Compared with traditional monocyte-derived DCs (moDCs), cDCs exhibit superior antigen processing and cross-presentation capacities. The therapeutic application of cDCs was initially pioneered in vaccine strategies involving ex vivo antigen loading and maturation, followed by administration to lymph nodes. More recently, intratumoral (IT) cDC immunotherapy has emerged as a strategy to reinvigorate the cancer-immunity cycle by engaging the full repertoire of tumor-associated antigens while limiting systemic toxicity. This review discusses the underlying biological mechanisms and summarizes the clinical outcomes of IT DC therapy in cancer. Notably, combination approaches incorporating IT cDCs with ICIs, oncolytic viruses, synthetic adjuvants, radiation, or cryotherapy are emerging as promising strategies to overcome both primary and acquired resistance to ICI monotherapy. Collectively, these findings highlight the potential of integrating IT cDC therapy with complementary immunotherapies in next-generation, cross-tumor treatment strategies.

2049 Background: Intravenous (IV) administration of ipilimumab (IPI) and nivolumab (NIVO) has shown limited activity in recurrent glioblastoma (rGBM). Intracerebral (iCer; within the brain tissue lining the resection cavity) and intracavitary (iCav; through an Ommaya reservoir) administration (admin) of IPI and NIVO was proven to be safe and resulted in promising survival outcomes (Duerinck et al. Neuro-Oncol 2024). Adding a neoadjuvant (NEOADJ) treatment phase to iCer/iCav IPI/NIVO may further improve outcome. Methods: In the Neo-Glitipni trial (NCT06097975), a single center, phase I clinical trial, patients (pts) with resectable rGBM (WHO grade 4, IDH wild type) who progressed after radiotherapy and temozolomide, with a baseline ECOG performance status of 0-2 and ≤8 mg methylprednisolone daily, received 2 NEOADJ cycles of IV IPI 1 mg/kg + NIVO 3 mg/kg followed by maximal safe resection (MSR) in week 5 with iCer admin of IPI 5 mg + NIVO 10 mg and iCav admin of IPI 1 mg + NIVO 10 mg. The adjuvant phase consists of biweekly postoperative iCav admin of IPI 1 mg + NIVO 10 mg and IV NIVO 240 mg for 12 cycles, followed by monthly NIVO 480 mg IV maintenance for up to two years. Results: 5 pts (4 male, median age 57 years (44-65); 1st recurrence in 3 pts) were enrolled. All pts received the 1 st and 4 pts also the 2 nd NEOADJ dose of IV IPI/NIVO. Out of the 5 pts, 3 were not amenable to MSR with iCer/iCav IPI/NIVO admin according to the protocol because of disease progression during the NEOADJ treatment phase and required corticosteroids (1 pt in week 2, 2 pts in week 4). Two pts successfully underwent MSR with iCer/iCav admin of IPI/NIVO per protocol. One pt initiated adjuvant treatment with iCav IPI/NIVO and IV NIVO. There were no unexpected adverse events (AE). Two pts experienced an immune-related AE that required corticosteroids and interruption of study treatment (grade 4 hepatitis in 1 pt, onset 8 days after MSR and grade 2 colitis in 1 pt, onset 28 days after MSR). One pt developed a thyroiditis during the NEOADJ treatment phase and 2 pts experienced a grade 3 treatment related AE that was not immune-related (seizure and Ommaya reservoir infection). None of the rGBM were characterized by a high tumor mutational burden on next generation sequencing. Gene expression profiling, and pharmacokinetic analysis of NIVO and IPI in the cerebrospinal fluid and blood are ongoing. After a median follow-up of 15 weeks (9-35w) all pts are alive, one pt remains free of progression (median progression free survival: 4.3 weeks). Conclusions: Four weeks of NEOADJ IV IPI/NIVO (comprising 2 admin) is safe, but symptomatic disease progression was observed in 3 out of 5 rGBM pts prior to the planned MSR with iCer/iCav IPI/NIVO admin in week 5. Therefore, the trial is being amended by shortening the NEOADJ treatment phase to 2 weeks (1 admin) and planned MSR with iCer/iCav IPI/NIVO admin in week 3. Clinical trial information: NCT06097975 .

Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH-wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).

BACKGROUND:Ipilimumab plus nivolumab (COMBO) is the standard treatment in patients with asymptomatic melanoma brain metastases (MBM). We report a retrospective study aiming to assess the outcome of patients with MBM treated with COMBO with or without sequential/concomitant stereotactic radiotherapy (SRT). METHODS:MBM patients treated with COMBO with or without SRT have been retrieved: demographics, steroid treatment, Central Nervous System [CNS]-related symptoms, BRAF status, radiotherapy (yes/no and timing) or surgery, number of MBM, maximum diameter of metastasis, overall response rate (ORR), progression-free (PFS) and overall survival (OS) have been analyzed. RESULTS:453 patients were included: 190 received COMBO alone, 107 received COMBO and concomitant SRT, 156 COMBO and sequential SRT, respectively. At multivariable analysis the line of treatment [> 1st vs 1st: HR 2.60 (1.93-3.50)], sequential SRT vs no radiotherapy [HR 0.45 (0.32-0.64)], concomitant SRT vs no radiotherapy [HR 0.48 (0.33-0.69)], steroids [HR 1.56 (1.17-2.08)], age [HR 1.01 (1.00-1.02)] and number of MBM [≥ 3 vs 1 HR 1.55 (1.11-2.17)), 2 vs 1 HR 1.53 (1.02-2.31)] at baseline were associated with OS. There was no significant difference between patients who received concomitant vs sequential SRT. At a median follow-up of 29 months, the median-OS in the overall population was 17.8 months while in those who received SRT was 27.3 (15.3-39.4) for patients receiving sequential radiotherapy and 22.2 (12.7-31.7) for those receiving radiotherapy concomitantly to COMBO. The incidence of radionecrosis was 10.3 %. Toxicities were consistent with previous studies. CONCLUSIONS:Our results suggest a better OS in patients who receive SRT plus COMBO, regardless of timing of SRT. Prospective studies are needed to validate our findings.

Immune checkpoint inhibitors (ICI) can achieve durable responses in patients with advanced melanoma, and results from clinical trials suggest cure may be possible for a subset of patients. Despite clinical trial data, little is known about the risk, character, and clinical outcome of late recurrences after ICI. This study aimed to explore the disease outcomes and survival in a cohort of patients with long-term responses to ICI.We retrospectively identified patients treated with ICI for advanced melanoma with long-term disease control, defined as not requiring a subsequent line of systemic therapy within 3 years of ICI commencement. We analysed disease characteristics, treatment, toxicity, recurrence patterns, management, and outcomes.A total of 567 patients were identified with a median follow-up of 7.1 years: 504 (89%) without disease progression within 3 years (cohort 1) and 63 (11.1%) with disease progression within 3 years managed without a change in systemic therapy (cohort 2). Subsequent progression after 3 years occurred for 39 (7.7%) patients in cohort 1, compared to 14 (22%) in cohort 2. Predictors for late progression after 3 years were a non-complete radiological response (CR) best response and prior progression within 3 years. Thirty-two patients (5.6%) died during follow-up, 8 (1.4%) from melanoma, 6 (1.2%) from cohort 1 and 2 (3.2%) from cohort 2.In this population of patients with advanced melanoma with long-term disease control from ICI, the risk of subsequent disease progression and death was low. This suggests that a significant proportion of long-term ICI responders are likely cured and may inform the frequency and duration of follow-up.

Background:Extent of resection (EOR) is a well-known prognostic factor in patients with newly diagnosed IDH-wildtype glioblastoma. However, reported survival times across resection categories vary between reports, and outcomes of submaximal or supramaximal resection remain less well defined. Methods:We conducted a systematic review and meta-analysis on the association between EOR and overall survival (OS) in patients with newly diagnosed IDH-wildtype glioblastoma treated with chemoradiotherapy. Studies were included if OS was reported by EOR category. Risk ratios (RRs) for 1- and 2-year survival were pooled using a random-effects model. Study quality was assessed using the Newcastle-Ottawa Scale. Results:Thirty-one studies involving 26,167 patients were included. Supramaximal resection (SupraMR) was associated with significantly improved 2-year survival compared to maximal CE resection (MR) (RR 0.70, 95 % CI 0.55-0.88). Compared to submaximal resection (subMR), MR was associated with higher 1-year survival (RR 0.59, 95 % CI 0.53-0.67) and 2-year survival (RR 0.82, 95 % CI 0.77-0.87). Biopsy alone was associated with the poorest outcome. Findings remained robust in sensitivity analyses excluding SEER and RTOG cohorts. Conclusions:Increasing EOR seems to be associated with improved survival in newly diagnosed IDH-wildtype glioblastoma. SupraMR offers the greatest benefit, while submaximal resection appears to be more favorable than biopsy. These findings support the prognostic relevance of EOR and underscore the need for prospective studies with standardized resection classifications. The balanced summary of survival data for each resection class provided in this review can serve as a basis for effect estimation and sample size calculations in future trials.

BACKGROUND:Therapeutic advances have reshaped the treatment landscape for patients with resectable melanoma, particularly for those with stage IIB/C and stage III disease. In this article, we discuss the current status and future outlook of adjuvant immunotherapy for melanoma in Europe. RESULTS:Adjuvant immunotherapy offers significant benefits in terms of recurrence-free survival and distant metastasis-free survival. Uncertainties regarding overall survival (OS) benefits, however, remain. Trials such as Keynote-054, which are expected to provide crucial OS information, have delayed their final analyses until 2027. Additionally, real-world studies have raised questions about the correlation between recurrence-free survival/distant metastasis-free survival improvements observed in clinical trials and OS outcomes in routine clinical practice. These uncertainties have led to ongoing debates about the cost-effectiveness of adjuvant therapies, with disparities in reimbursement policies across Europe reflecting these concerns. CONCLUSION:Looking ahead to 2028, adjuvant immunotherapy will remain a key option of comprehensive melanoma care, particularly for patients with stage IIB/C and stage III with micrometastatic disease, where neoadjuvant immunotherapy is not feasible.

Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

Oncolytic viruses (OVs) are promising anti-cancer agents designed to induce cancer cell death while simultaneously stimulating immune responses through encoded transgenes. FMS-like tyrosine kinase 3 ligand (FLT3L), a critical cytokine in dendritic cell (DC) biology, was incorporated into a genetically engineered OV derived from herpes simplex virus type 1. This virus was modified with deletions in the γ34.5 neurovirulence gene and the US12 gene. Treatment with the FLT3L-encoding OV resulted in a time- and dose-dependent increase in FLT3L secretion and inhibition of cell growth across all tested cell lines, although sensitivity varied among the lines. Susceptibility to oncolysis correlated with the expression levels of NECTIN1, NECTIN2, and ITGB6. OV-induced lysates from melanoma and ASPC1 cell lines showed minimal effects on the phenotype of conventional DCs (cDCs). However, oncolysates significantly increased the secretion of interferon (IFN)-λ1 and IFN-α-2a, particularly using BXPC3 oncolysates. Additionally, treatment of pancreatic cancer and 938-mel cell lines with the FLT3L-expressing OV elevated ATP levels but did not affect HMGB1 release. In conclusion, this study demonstrates the dual oncolytic and immunogenic potential of an FLT3L-encoding OV, particularly on cDCs. These findings support the further development of this approach as a novel cancer immunotherapy.

2071 Background: Innovative treatments are needed for recurrent high-grade glioma (rHGG) patients (pts) as current salvage therapies fail to improve overall survival (OS). Immune checkpoint inhibitors lack efficacy in rHGG when administered IV. This single center, multicohort phase I trial (Glitipni, NCT03233152) investigated intracerebral (iCer) administration of ipilimumab (IPI) +/- nivolumab (NIVO) +/- myDC after maximal safe resection (MSR), followed by adjuvant intracavitary (iCav) IPI/NIVO through an Ommaya reservoir. Methods: Eligible pts (ECOG ≤ 2, ≤ 8mg/day methylprednisolone) with rHGG (WHO 2021 grade 3/4, IDH-1/2 wild type (wt) or mutant) after standard postoperative radiotherapy (RT) and temozolomide (TMZ) were included. Pts underwent MSR or stereotactic biopsy (if unresectable) < 24h after receiving NIVO IV (10mg), followed by iCer injection of varying doses of IPI +/- NIVO +/- myDC and Ommaya catheter placement depending on the cohort (C). NIVO was administered IV (all cohorts) +/- iCav (C3-7) bi-weekly up to 12 cycles. Baseline tumor microenvironment characteristics were assessed by immunohistochemical (IHC) analysis and gene expression profiling (GEP). Results: Between 2016 and 2023, 110 pts (68% male, median age 57, 92% ECOG 0/1) were enrolled. At primary diagnosis, the majority (85%) were glioblastoma pts (WHO grade 4, IDH-wt), treated with the standard of care (MSR + RT + TMZ) (71%). All pts received 10mg NIVO IV preoperatively. Ninety percent of the pts who underwent the neurosurgical procedure started the postoperative treatment. Early discontinuation of study treatment occurred in 76% of pts, mainly due to tumor progression (86%). Treatment-related adverse events (TRAE) were mild (CTCAE grade 1/2), no grade 5 TRAE occurred. Most frequent TRAE were fatigue, headache and fever. At database lock (Jan 1st, ‘25), 9 pts remained progression-free. When including durable benefit from bevacizumab at first progression (13 pts), PFS and OS were significantly higher in C5/6 (+myDC) compared to other cohorts (-myDC) of our trial with resectable rHGG, and to a historical control group treated with VEGF(R)-inhibitors (descriptive p < 0.05 for each pairwise comparison). Absence of B7H3 on resected tumor tissues as demonstrated by IHC (C4, 5, 7) showed longer median OS, which was consistent with GEP. PD-L1 expression and density of CD8, Granzyme B or FOXP3 positive cells/mm 2 did not correlate with survival. A proliferative gene signature on GEP was significantly correlated with shorter PFS and OS. Conclusions: Intracranial administration of IPI/NIVO co-administered with myDC was feasible and safe, resulting in encouraging survival in pts with resectable rHGG. Baseline B7H3 levels and a proliferative gene signature correlated with survival. Clinical trial information: NCT03233152 .

Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB. In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS). Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10