Abstract Background: Advances in multiplexed imaging now profile cell phenotypes from 2D to 3D, creating new opportunities to analyze spatial organization in complex tissue. A 3D view of tissue architecture enables a re-examination of tumor-immune interactions in the tumor microenvironment, revealing spatially organized niches with direct biological and clinical relevance that may be obscured in 2D. Methods: We developed SpatialTopic1, a fast, scalable, unsupervised niche-detection method that identifies recurrent spatial patterns (“topics”) across multiplexed tissue images. SpatialTopic analyzes datasets with millions of cells within minutes using modest memory. With cell-type annotations as input, it applies to both spatial transcriptomics and proteomics (e.g., Xenium, CosMx, IMC and CODEX). Here, we extend SpatialTopic to 3D multiplexed images and demonstrate its applicability on a 3D CyCIF dataset from the melanoma invasive margin2. We also introduce a supervised framework of SpatialTopic that predicts spatial topic distributions using fixed, predefined topic compositions (“known topics”), enabling more scalable inference across multiple samples and facilitating links between spatial niches and clinical outcomes. Results: SpatialTopic delineates four main topics along the vasculature-to-tumor-core axis at the melanoma invasive margin: (1) Vascular topic: endothelial cells with CD4 T cells and macrophages; (2) Immune topic: mainly including CD4 T cells, dendritic cells, as well as Regulatory T cells (Tregs), and B cells; (3) Tumor-immune boundary topic: tumor cells mixed with dendritic cells and CD4 T cells; and (4) Tumor core topic. In this dataset, relative to the prior publication2, SpatialTopic more cleanly resolves vascular structures and reveals a graded shift in immune composition from vasculature toward the tumor boundary: decreasing macrophages and increasing CD4 T cells and dendritic cells at the invasive front of melanoma. 1.Peng, X. et al. Scalable topic modelling decodes spatial tissue architecture for large-scale multiplexed imaging analysis. Nat. Commun. 16, 6619 (2025). 2.Yapp, C. et al. Highly multiplexed 3D profiling of cell states and immune niches in human tumors. Nat. Methods 22, 2180-2193 (2025). Citation Format: Xiyu Peng, James Smithy, Mohammad Yosofvand, Caroline Kostrzewa, Fiona Ehrich, MaryLena Bleile, Jasme Lee, Michael A. Postow, Margaret K. Callahan, Katherine Panageas, Ronglai Shen. SpatialTopic exploring tumor ecosystem in 3D multiplexed imaging of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5499.

BACKGROUND:CD8 T cells mediate the effects of cancer immunotherapies. CD8 positron emission tomography (PET) imaging with [89Zr]Zr-berdoxam-crefmirlimab enables whole body CD8 cell assessment and has been shown to be safe in Phase I evaluation. The correlation between CD8 PET imaging parameters and the quantity of CD8 cells assessed by the gold standard of immunohistochemistry (IHC) is unknown. METHODS:The Phase II, prospective multicenter study (iCorrelate) tested the correlation between CD8 PET and CD8 cells by IHC of core needle biopsies from patients with solid tumors receiving immune checkpoint blockade. The safety of repeat CD8 PET was additionally analyzed. RESULTS:49 patients had 70 biopsies (37 baseline and 33 on-treatment) for correlating CD8 PET with IHC. Standard uptake value mean of the biopsied tumor normalized to aorta showed a correlation with IHC of 0.49 (95% CI 0.26 to 0.59). The correlation was 0.71 (95% CI 0.48 to 0.85) in patients with renal cell carcinoma. Repeat CD8 PET imaging on-treatment was safe. CONCLUSIONS:We found a modest correlation between CD8 PET with [89Zr]Zr-berdoxam-crefmirlimab and intratumoral CD8 cell counts, likely because core needle biopsies do not fully represent the intratumoral heterogeneity of the CD8 cell distribution. Continued research is essential to evaluate in vivo CD8 PET signals, autoradiography, and CD8 T-cell presence by IHC in fully resected tumors. Further studies investigating the correlation between CD8 PET and immunotherapy outcomes are necessary to determine whether CD8 PET imaging could become a valuable tool for guiding immunotherapy development and informing clinical decision-making.

1515 Background: Single agent pembrolizumab is standardly administered every 3 weeks (q3wk). Although extended interval dosing every 6 weeks (q6wk) was approved during the pandemic, most oncologists (65%) prefer q3-week dosing to monitor and mitigate immune-related adverse events (irAEs). We hypothesized that telehealth (TH)-enabled safety monitoring may facilitate broader adoption of q6 week dosing with reduced in-person health care visits while maintaining safety and patient experience. Methods: MAking Telehealth Delivery of Cancer Care at Home Effective and Safe for Immunotherapy (MATCHES-IO) is a single-arm pragmatic trial among patients with solid tumors receiving single-agent pembrolizumab. The intervention consisted of q6-week in-person pembrolizumab infusions with interim (eg. weeks 3,9,15) telehealth toxicity assessments during the first 6 months of therapy. Intervention components included a TH clinician visit, home phlebotomy, and biometric monitoring. The primary outcome was the number of days with an in-person health care facility visit, ascertained from the electronic health record. Participants were compared to a contemporaneous matched cohort receiving standard q3-week pembrolizumab, matched 1:1 on cancer type, stage (I–III vs IV), and age (15-year bands). Safety was evaluated by comparing irAEs requiring steroid use. Patient experience was assessed using a survey that included likelihood to recommend the intervention. Results: Between May 2023 and February 2025, 60 patients were enrolled (median age 69.5 [range: 25-85], 38% female, 78% white). Cancer diagnoses included thoracic (52%), genitourinary (30%), and melanoma (18%) in cases and controls. In matched analyses, there was a 3.5-day difference in total healthcare facility contact days between cases and controls (median 8.5 vs. 12.0, p = 0.14) that did not achieve statistical significance. Rates of irAEs requiring steroids were similar between groups (25.0% vs. 27.1%, p = 0.84). Fifty-two patients (87%) in the intervention group completed a patient experience survey. The median likelihood to recommend score was 10 (Q1,Q3: 8.0, 10.0). Most respondents (96%) perceived a benefit from the telehealth platform, including saved time (85%), increased convenience for patients (75%) and caregivers (44%), and cost savings (52%). Conclusions: Extended interval pembrolizumab supported by TH-enabled toxicity monitoring with remote phlebotomy and biometric assessments was associated with reduced in-person health care facility days but did not achieve the significance threshold. The intervention was associated with high patient satisfaction and no increase in irAEs. These results may address clinicians’ concerns about the safety of q6 week immunotherapy dosing and inform future care-delivery strategies integrating telehealth with immunotherapy treatment.

PURPOSE:Mucosal melanoma (MM) is a rare subtype of melanoma with inferior response rates and outcomes to immunotherapy. Vascular endothelial growth factor (VEGF) signaling may contribute to immune resistance and represents a potential therapeutic target. We evaluated nivolumab plus axitinib in untreated, advanced MM in a Western population, and explored escalation to triplet strategies for PD-1-refractory disease. PATIENTS AND METHODS:In this single center, investigator-initiated phase II study, patients with previously untreated unresectable or metastatic MM received nivolumab every 4 weeks and axitinib twice daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1. A sequential phase Ib exploratory cohort evaluated treatment intensification with addition of ipilimumab or stereotactic body radiotherapy (SBRT) at progression, with safety as the primary endpoint. RESULTS:Among 20 evaluable patients, the ORR was 45% (95% CI, 23-68), including 4 complete responses (20%) and 5 partial responses (25%). Median duration of response was 21 months (95% CI 8.6-NR). Median progression-free survival was 6.4 months (95% CI 3.5-NR); median overall survival was not reached. Grade 3-5 treatment-related adverse events occurred in 67%, including two treatment-related deaths. Seven patients received triplet therapy (n=5 ipilimumab, n=2 SBRT), with no unexpected toxicities observed. CONCLUSIONS:Nivolumab plus axitinib demonstrated meaningful activity in advanced mucosal melanoma and warrants further evaluation in randomized studies. The addition of ipilimumab or SBRT after progression was feasible and may inform future studies, including biomarker‑directed intensification to triplet strategies.

Immune checkpoint inhibitors are used in a wide range of cancers, offering durable responses for a substantial subset of patients. However, immune-related adverse events, the most clinically consequential checkpoint inhibitor-associated adverse reactions, pose a key challenge in practice, affecting virtually any organ system, resulting in treatment interruption, morbidity, or mortality. Patient education, early recognition, and effective management are essential to limit complications and maintain continuity of immunotherapy. Achieving this requires well-informed multidisciplinary teams who can identify, evaluate, and manage immune-related adverse events promptly. This review summarizes the most clinically significant immune-related adverse events and highlights the key principles of multidisciplinary diagnosis and management most relevant to the practicing allergist-immunologist to optimize patient outcomes.

BACKGROUND:Neoadjuvant therapy with immune checkpoint inhibitors (ICIs) is increasingly used in advanced or recurrent melanoma based on outcomes observed in clinical trials. The efficacy and toxicity of this in a real-world setting remain unclear. STUDY DESIGN:We conducted a retrospective review of adults with cutaneous melanoma who received neoadjuvant ICI as first line therapy at our institution between 2019 and 2024. Patients had advanced melanoma that was surgically resectable and treated with neoadjuvant intent. The primary outcome was pathological response, with a secondary outcome of immune-related toxicity. RESULTS:In total, 81 patients were identified. The median age was 64 (range: 21-86). There were 48 males. Most patients received 2 cycles (n = 53) prior to resection (range: 1-7 cycles). Dual ICI was the most common approach (n = 62). Disease stage ranged from IIC to IV, with 57% IIIC. Half were pathologic non-responders (n = 41). Pathologic complete response (pCR) was seen in 25% (n = 20), near-pCR in 2% (n = 2) and partial PR in 10% (n = 8). Ten (12%) patients had a discrepant PR between two or more resected sites. Immune related adverse events were observed in 34 (42%) patients; 21 (26%) grade 1-2, and 13 (16%) grade 3-4. Overall survival trended towards significance (p = 0.07) for those with mPR. CONCLUSIONS:Non-trial use of neoadjuvant ICI therapy is associated with a less favourable pathological response than reported in clinical trials and similar risks of toxicity.

9519 Background: IO102-IO103 is an investigational cancer vaccine that targets both tumor and immune-suppressive cells in the tumor microenvironment. IO102-IO103 has demonstrated clinical activity in combination with anti-PD-1 monotherapy in advanced melanoma, with concordant clonal T cell expansion observed in the tumor and peripheral blood in patients with radiographic response. IO102-IO103 has not yet been assessed in combination with nivolumab-relatlimab (nivo-rela). Methods: In this multicenter, phase 2 trial (NCT05912244) patients with unresectable, previously untreated non-uveal melanoma were treated with subcutaneous IO102-IO103 and intravenous nivo-rela for up to two years. IO102-IO103 was administered every two weeks for eight weeks, and every four weeks thereafter. PD-L1 protein expression was assessed using the 28-8 pharmDx assay on pre-treatment tissue. The primary endpoint was best overall response rate (BORR) by RECIST v1.1, with a plan to reject the null hypothesis based on the proportion of patients with ≥1% membranous PD-L1 staining in the tumor compartment. Secondary endpoints included progression-free survival (PFS), safety assessed by Common Terminology Criteria for Adverse Events v 5.0, and duration of response (DOR). PFS and DOR were summarized using Kaplan-Meier methods. Bulk T cell receptor (TCR) sequencing was performed on peripheral blood mononuclear cells using an RNA-based assay at baseline, week 4 and week 8. Results: Among 43 evaluable patients, the BORR was 60% (95% confidence interval [CI]: 44-75%), including 19 patients with partial response and 7 patients with complete response. At database lock (Dec 1 2025), median follow up was 10.1 months (interquartile range 6.1-19.3). The median duration of response was not reached (95% CI: 14, NR) and median PFS was 8.2 months (95% CI 6.8, not reached [NR]). Among patients with PD-L1 negative tumors (n = 25), the BORR was 52% (95% CI 31-72%) and median PFS was 8.2 months (4.2, NR). Grade 3-4 treatment-related adverse events occurred in 9 patients (21%), including adrenal insufficiency (2 patients), acute kidney injury (2), aseptic meningitis (1), arthritis (1), maculopapular rash (1), myositis (1), neutropenia (1), and colitis (1). There were no treatment related deaths. T cell clonal expansion was observed at on-treatment time points compared to baseline in patients with and without radiographic response. Conclusions: IO102-IO103 in combination with nivo-rela was associated with a higher objective response rate compared to historical data for nivo-rela alone, meeting the trial’s primary endpoint. No unexpected safety signals were observed. These findings support the further clinical investigation of IO102-IO103 with nivo-rela as an initial treatment for unresectable melanoma. Clinical trial information: NCT05912244 .

Introduction: Although cannabis has promise as a supportive care agent for patients with cancer undergoing chemotherapy or radiation, there is little evidence about its use among patients undergoing immune checkpoint inhibitor (ICI) therapy. We evaluated the extent of and reasons for cannabis use among patients currently receiving ICIs at a large cancer center. Materials and Methods: We conducted a survey among adults undergoing ICI treatment for melanoma or kidney cancer. Patients reported frequency of cannabis use since the start of ICI treatment, modes of ingestion, reasons for use, and experiences with cannabis. Results: Among 160 respondents, the median age was 65 years, 90% were White, 70% were male, and 68% had kidney cancer. Twenty-one percent of respondents used cannabis during ICI treatment (n = 34). Most users ingested cannabis through food (71%) or by smoking it (41%). The most common reasons for using cannabis during ICI treatment were for recreation (68%) or to address symptoms (65%), which included mood impairment (44%), difficulty sleeping (32%), and aching muscles or joints (30%). Of patients reporting cannabis use to address those symptoms, >80% reported symptom improvement. Eighteen percent of respondents spoke to their oncology team about using cannabis during ICI treatment. Discussion: Cannabis use during ICI treatment is relatively common. Patients report using cannabis for recreation and to successfully address symptoms. Additional research into the symptom management benefits of cannabis and its impact on ICI treatment effectiveness is needed to inform patients and their providers and to establish clinical care guidelines.

2614 Background: Noninvasive estimation of intratumoral CD8+ T-cell density using radiomics may enhance comprehensive immune profiling and support immuno-oncology development and treatment decisions. We evaluated the feasibility of using a multimodality radiomic approach incorporating SOC CT and CD8-PET/CT to characterize CD8+ T-cell density in solid tumor lesions. Methods: 71 soft-tissue lesions from 52 patients with solid tumors enrolled in a Phase II iCorrelate trial (NCT03802123) were retrospectively analyzed. Patients received a pre-treatment CD8-PET/CT scan (ImaginAb, Inc) before initiating SOC immunotherapy (IOT) and a second CD8-PET/CT scan on-treatment 4-8 weeks later, with selection of biopsied tumor lesions of known CD8+ T-cell density for radiomic analysis. Radiomic features were extracted from volumetric segmentations of these tumor lesions using 3D Slicer on Diagnostic contrast CT (DCT, n=27), CT attenuation correction (CTAC; n=71), and CD8 PET (n=71) images. Features were integrated with acquisition parameters, lesion location, and adenopathy status. Feature selection used maximum relevance–minimum redundancy and variance inflation factor methods. Elastic-Net classifiers were trained to predict binarized (median split at the 328 cells/mm 2 level) CD8+ T-cell density, with hyperparameter optimization via grid search and 5 fold Cross-Validation (CV). In each iteration of the CV, 1 fold (20%) was left out and models were trained on the remaining 4 folds (80%). Model performance was assessed using AUC and F1 score. Results: In the test set, Multimodality models (CTAC+DCT+PET) outperformed single-modality (AUC up to 0.94 vs. 0.80), with improved AUC and F1 scores and robust performance across endpoints. Single-modality models achieved AUCs of 0.76 (F1 0.55) for DCT, 0.80 (F1 0.72) for CTAC, and 0.80 (F1 0.70) for PET. The combined CTAC+DCT+PET model demonstrated superior performance with a test AUC of 0.85 (F1 0.79) and training AUC of 0.94 (F1 0.89). Application of previously reported DCT radiomic weights (Sun et al.) to this cohort yielded a lower AUC of 0.68, compared with the multimodality model. Conclusions: This study demonstrates robust radiomics-based characterization of intratumoral CD8+ T-cell density in patients with solid tumors is feasible using non-invasive multi-modality approach utilizing CD8-PET and SOC CT scans. These findings may lead to further clinical adoption and non-invasive monitoring of the tumor immune microenvironments with CD8-PET and SOC CT scans using radiomics, informing IOT decision-making, and enhancing patient stratification in both clinical development and routine oncology practice. Validation in larger, multicenter cohorts is still required to confirm generalizability and robustness of these radiomic signatures. Clinical trial information: NCT03802123 .

12156 Background: Biologic agents are increasingly used to treat immune-related cutaneous adverse events (ircAEs). However, limited data exist regarding immune checkpoint inhibitor (ICI) rechallenge and ICI efficacy following biologic therapy for ircAE management. Methods: We conducted a retrospective cohort study of patients enrolled under U01AR077511-01 (PIs Leung, Kern, Lacouture) treated with ICIs who developed dermatologist-confirmed grade ≥2 ircAEs. Demographics, ircAE treatments, and dermatologic and oncologic outcomes were collected via chart review and compared using t-tests and chi-square tests. Results: We identified 159 patients who developed grade ≥2 ircAEs, including 80 treated with biologic agents. Mean age was 66.8 years; 40% were female, 79% White, and 78% had stage IV disease. The most common tumor types were kidney (20%), lung (16%), and melanoma (12%). Common ICI regimens included ICI monotherapy (46%), ICI–ICI combination (21%), and ICI+chemotherapy (19%). Pruritus (23%), maculopapular rash (21%), and eczema (19%) were the most common ircAEs. Most patients received topical steroids (88%), while systemic steroids were used sparsely (13%). Biologics were used in ~50% of patients; the most common agents were dupilumab (43%), omalizumab (33%), and ustekinumab (11%). Median biologic duration was 16 weeks, with 25% receiving therapy for >40 weeks. ICI rechallenge occurred in 60% of biologic-treated versus 67% of non-biologic patients (p=0.35). Rechallenge rates were 67% vs 65% for grade 2 (p=0.85) and 44% vs 74% for grade 3 ircAEs (p=0.05) (biologic vs non-biologic, respectively). Antitumor outcomes were similar between biologics and non-biologic groups: 31% vs 28% achieved partial/complete response, 43% had stable disease, and 26% vs 29% had progressive disease, respectively. Conclusions: In this oncodermatology-managed cohort, ircAEs were primarily treated with topical corticosteroids and targeted biologics, with infrequent systemic steroid use. Biologic therapy enabled ICI rechallenge in most patients, and oncologic outcomes were comparable to those not receiving biologics. Overall, these findings support biologics as a steroid-sparing option for moderate-to-severe ircAEs that may allow continued immunotherapy without apparent loss of antitumor efficacy, warranting prospective validation. Clinical characteristics. Variable Overall n=159 No Biologics n=79 Biologics n=80 Age at ICI (mean) 66.8 64.3 69.4 Tumor Types Kidney/Lung/Melanoma (%) 20/16/12 22/17/9 18/15/15 Line of treatment 1L/2L/2+L (%) 52/25/23 49/27/24 54/24/22 ircAEs: Pruritus/MPR/Eczema/Others (%) 23/21/19/37 22/33/17/28 25/9/21/45 ircAE Grade 2/Grade 3 (%) 74/26 76/24 71/29 Dupilumab/Omalizumab/Ustekinumab/Others (%) 33/33/11/23 N/A 33/33/11/23 Systemic Steroids - Yes (%) 13 8 18 ICI Rechallenge - Yes (%) 64 67 60 Response CR-PR/SD/PD (%) 30/43/27 31/43/26 28/43/29

9557 Background: While inpatient toxicity associated with tumor infiltrating lymphocyte (TIL) therapy and IL-2 administration is well characterized, risks facing patients after hospital discharge are less understood. Better characterization of outpatient adverse effects (AEs) could guide the optimal frequency and duration of follow up for this growing patient population. Methods: We conducted a retrospective analysis of all patients with advanced melanoma discharged from Memorial Sloan Kettering Cancer Center after receiving investigational or commercial lifileucel from October 2020 to October 2024. We reviewed incidence and timing of new Grade 3+ treatment-related AEs (TRAEs), blood product administration, and readmission among all patients from the time of hospital discharge to the time of the start of a subsequent systemic therapy or death. Results: Fifty-three patients successfully discharged after lifileucel administration were identified; patient demographics are included in Table 1 . The median follow up time from discharge in survivors was 5 months (interquartile range (IQR): 3, 18). Two patients (4%) developed new Grade 3+ TRAEs following hospital discharge, including new Grade 3 neutropenia 73 days after discharge and new Grade 3 hypoxia 104 days from discharge. Hypoxia was secondary to pleural effusions that developed in the setting of renal thrombotic microangiopathy. Four patients (7.5%) were readmitted for TRAEs including cytopenias, dyspnea, and syncope while 7 patients (13%) were readmitted for melanoma progression. Readmissions occurred a median of 85 (IQR: 39, 128) days after lifileucel infusion and 69 days (IQR: 19, 98) after initial discharge. Twelve patients (23%) received at least one outpatient blood product transfusion, including packed red blood cells (PRBCs; 10 patients) and platelets (6 patients). Within 30 days of initial discharge, six patients (11%) received at least one PRBC transfusion and 3 patients (5.7%) received at least one platelet transfusion. The median number of transfused PRBC units was 2 (IQR: 1,4) and the median number of platelet transfusions was 4 (IQR: 2, 4). Conclusions: Rates of new severe toxicity and treatment-related readmissions were low among patients discharged post-lifileucel. About one in four patients required blood products after discharge. Identification of risk factors for the development of outpatient TRAEs may inform personalized care following lifileucel administration. Patient demographics. Characteristic N = 53 1 Age at TIL infusion 61 (42, 66) Sex Male 29 (55%) Female 24 (45%) Melanoma subtype Cutaneous 19 (36%) Uveal 9 (17%) Acral 8 (15%) Unknown primary 8 (15%) Mucosal 5 (9.4%) Other 4 (7.5%) BRAF status Mutated 13/51 (25%) Wild type 38/51 (75%) Treatment setting Investigational 45 (85%) Standard of care 8 (15%) 1. N (%); Median (interquartile range).

9555 Background: Mucosal melanoma (MM) is an aggressive subtype of melanoma with distinct biology, and outcomes in advanced disease are inferior compared with cutaneous melanoma. Frontline Chinese studies in MM have shown efficacy of combined VEGF/R and PD-1 blockade, but studies in more diverse populations and options in PD-1 resistance are lacking. Methods: We conducted a phase 2/1b single-center trial in patients (pts) with untreated, unresectable or advanced MM. Pts received standard nivolumab (nivo) plus axitinib (axi) 5mg PO twice daily. Primary endpoint of the phase 2 doublet arm was objective response rate (ORR) by RECIST 1.1 (H0=23%, Ha=48%). Clinical benefit rate (CBR) was defined as ORR or stable disease (SD) >6 months (mos). Upon progression with good tolerance, the phase 1b triplet arm pts received the addition of either stereotactic body radiotherapy (SBRT, 30Gy/5 fractions) or ipilimumab (ipi, 1mg/kg < 4 doses) to ongoing nivo + axi. The primary endpoint of the triplet was safety by CTCAE v5.0 and adverse events (AEs) of special interest (AESIs). Kaplan-Meier methods estimated time to event outcomes; ORR and AEs were reported as proportions with exact 95% confidence intervals. Results: N=21 pts were enrolled; N=20 were evaluable for efficacy. See Table for baseline population characteristics. Median follow up was 15 mos (IQR 6, 21), 45% of pts (95% CI: 23, 68) had an objective response; 3 complete and 6 partial responses. Median duration of response was 13 mos (8.6, not reached (NR)). SD persisted ≥ 6 mos in 2 of 7 pts; CBR was 55% (95% CI: 32,77). Median progression free survival (PFS) was 6.3 mos (3.5, NR), and 12-mos estimated PFS and overall survival was 37% (20,67) and 71% (52, 96), respectively. Rate of grade ≥3 treatment related AEs (TRAE) in the doublet arm (n=21) was 67% (95% CI: 43,85), most commonly hypertension & hepatitis, with two pt deaths; 1 nivo-related myasthenia gravis / myositis, and 1 nivo-related pancreatitis with steroid-related PJP pneumonia. 14 pts (70%) progressed on doublet therapy, of which 7 enrolled on the triplet arm. N=5 received ipi and N=2 SBRT (both to anorectal primaries and adjacent lymph nodes). There were 2 grade ≥3 TRAEs in the ipi triplet arm (hepatitis), 0 in the SBRT arm, no grade 5 events, and no AESIs. Zero of 4 evaluable pts in ipi triplet and 1 of 2 in the SBRT triplet responded (4+ mos, ongoing). Conclusions: The frontline combination of nivolumab and axitinib was effective in patients with unresectable or advanced outside of China, and a prospective global study randomized against immune checkpoint blockade is warranted. Adding either ipi or SBRT to nivo-axi appears safe in select pts with progressive disease and further studies are needed for pts with PD-1 resistant MM. Clinical trial information: NCT05384496 . Characteristic (n=21) N (%) Age (median) 73 years (IQR: 67, 82) Sex Female Male 13 (62%) 8 (38%) Race Caucasian Asian Black 16 (76%) 3 (14%) 2 (10%) Primary Site Anorectal Sinonasal Vulvovaginal 10 (48%) 8 (38%) 3 (14%) Stage Locoregionally advanced Metastatic 14 (67%) 7 (33%) LDH (median) 195 (IQR: 171,201)

This cohort study examines the response and survival rates associated with ipilimumab-nivolumab therapy in patients with progressive melanoma brain metastases after anti–programmed cell death 1 (anti–PD-1) therapy.

Study IPI-549-01 methodology and criteria for assessing MDSCs

Multiplex immunofluorescence (mIF) is a promising tool for immunotherapy biomarker discovery in melanoma and other solid tumors. mIF captures detailed phenotypic information of immune cells in the tumor microenvironment, as well as spatial data that can reveal biologically relevant interactions among cell types. Given the complexity of mIF data, the development of automated analysis pipelines is crucial for advancing biomarker discovery. In pre-treatment melanoma samples from 50 patients treated with immune checkpoint inhibitors (ICIs), a higher stromal B cell percentage is associated with the clinical benefit of ICI therapy. The automatic detection of B cell aggregates with DBSCAN, a novel application of a computer-aided machine learning algorithm, demonstrates the potential for enhanced accuracy compared to pathologist assessment of lymphoid aggregates. TCF1+ and LAG3- T cell subpopulations are enriched near stromal B cells, suggesting potential functional interactions. These analyses provide a roadmap for the further development of spatial immunotherapy biomarkers in melanoma and other diseases.

3098 Background: CD8-PET/CT imaging with 89 Zr crefmirlimab berdoxam (ImaginAb, Inc), which targets CD8-expressing T-lymphocytes, is being explored as an imaging tool to predict responses and monitor immune checkpoint inhibitors (ICI) in patients with advanced solid malignancies. Here we explore how quantitative imaging features from CD8 PET/CT may predict ICI responses. Methods: We studied quantitative imaging features (PET parameters and radiomics) in 45 patients from the ImaginAb IAB-CD8-201 phase II trial (NCT03802123). Tumoral lesions, peritumoral ring (ring shaped margin extending 0.5 cm inwards and outwards from the segmented tumor surface), healthy tissue, benign and pathological lymph nodes were segmented from baseline and first on-treatment (4-6 weeks after standard of care treatment including ICI blockade). Imaging features from CD8-PET/CT scans were extracted. Predictive models for best overall response (BOR) according to RECIST 1.1 were developed. Models’ performance was evaluated by the ability to distinguish responders (complete or partial response, n = 13) from non-responders (stable or progressive disease, n = 32). A survival random forest analysis was also conducted to estimate time to BOR. Results: Significantly greater delta values were identified in the tumor and peritumoral ring compared to healthy tissues, suggesting the tumor and peritumoral ring may reveal early treatment-induced changes important for predicting response. Eighteen predictive models were developed, with models using imaging features from the peritumoral ring showing comparable performance to those using features from lesions and pathological lymph nodes. The simplest BOR predictive model, which yielded the highest performance, used delta values extracted from the peritumoral ring (AUCs = 0.895, sensitivity = 0.900, specificity = 0.615). The inclusion of clinical variables (including age, sex, body mass index, cancer type, received treatments, number of lines of received treatment, white blood cell count) did not significantly enhance model accuracy, emphasizing the robustness of the imaging data alone. A final model integrating key imaging features from multiple regions successfully predicted time to BOR with a C-index, a generalizable AUC that considers censored data, of 0.86. Conclusions: This study highlights the potential of quantitative imaging analysis of CD8-PET/CT scans as a tool for predicting responses to cancer immunotherapy. Results suggest the effectiveness of delta imaging features from the peritumoral ring as a potential indicator of patient’s ability to respond to ICI treatment, simplifying the analysis without sacrificing accuracy. Further validation in trials with more homogeneous populations and treatment regimens (eg. NCT05013099) is warranted, with the potential to advance personalized cancer care.

Overall, much progress was made in 2024 in the realm of neoadjuvant immunotherapy including the firm establishment of neoadjuvant immunotherapy as superior to only adjuvant immunotherapy for patients with resectable stage III melanoma with the NADINA trial results. However, unanswered questions remain regarding the optimal neoadjuvant immunotherapy regimen, long‐term outcomes after modifying adjuvant approaches based on pathologic response, and if additional measurements of antitumor efficacy, in addition to pathologic response, can further help tailor adjuvant therapy decisions.