This review aims at exploring nanoparticle-based phototherapies of uveal melanoma (UM), the most common primary intraocular malignancy in adults with an estimated incidence of 5-7 cases per million individuals per year, a disproportionately high metastatic risk and poor prognosis in advanced stages. UM exhibits unique biological and anatomical features, including an immune-privileged ocular microenvironment, the blood-ocular barrier, and high melanin content, contributing to therapeutic complexity. Current treatments, including radiotherapy, surgery, and systemic therapies, achieve local tumor control but remain limited by adverse effects, recurrence, and insufficient efficacy against metastatic disease. Laser-based therapies, including transpupillary thermotherapy and photodynamic therapy, offer minimally invasive alternatives. However, their performance is constrained by limited light penetration, melanin-induced uneven absorption, and incomplete tumor eradication. Recent advances in nanotechnology offer opportunities to overcome these limitations. Nanoparticle-based phototherapies can improve tumor targeting, photosensitizer delivery, and localized activation while reducing off-target effects. Multifunctional nanoplatforms may combine imaging, drug delivery, and synergistic therapies such as immunotherapy or chemotherapy. Although promising preclinical results highlight improved tumor control and antitumor responses, challenges related to safety, biodistribution, and clinical translation remain. This review discusses these challenges and future directions for optimized nanoplatforms to improve disease management and metastasis prevention.

Abstract Background: Uveal melanoma (UM) is the most common intraocular tumor of the eye in adults. About 50% of cases become metastatic, indicating poorer prognosis and survivability. There is currently no well-established blood-based method to accurately predict the risk of metastasis and disease progression of UM using proteomic analysis. This study aimed to test the efficacy and utility of proteomics in the risk assessment of UM. Methods: Proteomic analysis from serum and extracellular vesicles (EV) of 49 samples from 27 unique patients was performed to classify metastatic and non-metastatic disease. Controls were taken from 5 patients with cutaneous melanoma. Initial serum depletion was completed using the ProteoSpin Abundant Serum Protein Depletion Kit. EVs were extracted via the qEV Concentration Kit IZON system. Proteins from depleted serum and EVs were analyzed via Mass Spectrometry (MS) using a standard trypsin-based workflow. A data-dependent MS2 method on Thermo Fisher Orbitrap Lumos generated MS data. Orbitrap MS1 spectra was followed by MS2 fragmentation via ion trap using collision-induced dissociation. Machine learning was used to develop a predictive proteomic signature for metastasis. Models were trained with 3052 EV and serum protein levels and 906 serum only levels. Model sensitivity and positive predictive value (PPV) were calculated using out-of-bag bootstrap sampling conducted 500 times. Candidate models for classification of disease vs controls were used to classify holdout surveillance samples from 9 unique patients. Additionally, differential abundance analysis of each sample classification used the log(2) ratio of protein abundances with a cut off >1 and <-1, indicating increased and decreased abundance, respectively. Statistical significance of abundance was set at p<0.05. Results: Machine learning models revealed EVs showed higher sensitivity and PPV than serum. EV proteins with the strongest signals for disease (primary, surveillance, metastatic) vs controls include immunoglobulin (Ig) lambda variable 3-10, Ig mu heavy chain, 14-3-3 protein zeta/delta, heat shock cognate 71 kDa protein, and fibrinogen beta chain. Serum proteins include trypsin-3, mitochondrial ATP synthase complex subunit C1, type 2 cytoskeletal keratin, and polymeric Ig receptor. Dopamine beta-hydroxylase was most prominent in metastatic vs non-metastatic (primary, surveillance) in serum. Differential expression analysis of EV and serum revealed significant abundance of proteins related to metabolism, cellular organization and biogenesis, and cell proliferation in disease groups vs controls. Conclusion: This preliminary analysis demonstrates that blood-based proteomic analysis of various UM stages can be useful in providing diagnosis or prognosis of disease course for such patients. Further work with a larger sample size and repeated sampling at different disease progression stages is warranted to advance this work. Citation Format: Abarajithan Chandrasekaran, Nikhil Nayee, Jerome Lacombe, Timothy Karr, Frederic Zenhausern, Justin Moser. Blood-based proteomics analysis for uveal melanoma prognosis [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 7695.

Lifileucel is a tumor-derived autologous T-cell therapy approved by the US Food and Drug Administration for patients with advanced melanoma previously treated with an immune checkpoint inhibitor and, for BRAF V600-mutated disease, a BRAF ± MEK inhibitor. The real-world effectiveness of commercially available lifileucel has not yet been characterized. We conducted a retrospective study across four US centers of adults with metastatic melanoma treated with standard-of-care lifileucel per the US prescribing information. The primary objective was to evaluate real-world effectiveness based on treating physician-assessed objective response rate (ORR). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Preconditioning lymphodepletion was administered per institutional practice, followed by lifileucel infusion and up to six doses of interleukin-2 (IL-2; 600,000 IU/kg). Forty-three patients were included (median age 59 yr [range, 28 to 79]; 54% male); 44% had BRAF V600 mutations. Melanoma subtypes included cutaneous nonacral (70%), acral (9%), mucosal (19%), and unknown primary (2%); liver and treated brain metastases were present in 30% (n = 13) and 28% (n = 12), respectively. Patients received a median of three prior systemic anticancer therapies (range, 1 to 7). Prior to lymphodepletion, 44% received bridging therapy, which predominantly reflected continuation of prior targeted therapy. Following lifileucel infusion, patients received a median of five IL-2 doses (range, 1 to 6). Among 41 response-evaluable patients, physician-assessed ORR was 44% (n = 18), including complete response in 5% (n = 2) and partial response in 39% (n = 16). ORR was 52% among patients who received ≤2 prior lines of therapy (n = 23) and 33% among those who received ≥3 prior lines (n = 18). ORR was 58% among patients receiving ≤3 IL-2 doses (n = 12) and 38% among those receiving ≥4 doses (n = 29). With a median follow-up of 5.7 mo (95% confidence interval [CI], 1 to 15), median PFS and OS were 4.4 (95% CI, 2.8 to 8.9) and 10.2 mo (95% CI, 6.1 to NR), respectively. In this multicenter real-world cohort, commercially available lifileucel demonstrated meaningful clinical activity in patients with advanced melanoma, with outcomes comparable to pivotal trial results. Fewer prior lines of therapy and normal lactate dehydrogenase were associated with improved outcomes, supporting earlier consideration of tumor-infiltrating lymphocyte therapy in appropriate patients.

Tumor-infiltrating lymphocyte (TIL) therapy, which involves extracting, expanding, and reinfusing immune cells to target cancer cells, has shown promise in melanoma treatment, but requires optimization for broader efficacy. The success of TIL therapy depends on the recognition of tumor-associated antigens, but neoantigen-reactive T-cells are often rare and exhausted in less immunogenic malignancies. Isolating T cells enriched in neoantigen reactivity prior to in vitro expansion and reinfusion may improve the response rates. To this end, our proprietary Specific Neo-Antigen Peptides (SNAP™) technology platform improves the accuracy of neoantigen prediction and validation by combining advanced computational modelling and PepSeq, a high-throughput screen for the physical credentialing of putative neoantigens based on their affinity to bind patient-specific HLA class II proteins. This approach allows for the education and enrichment of TILs (SNAP-TILs) with personalized, predefined, highly immunogenic neoantigens prior to expansion. Using the SNAP platform, we consistently achieved, on average, a SNAP-TIL product comprising 96% CD3+ cells, with a mixture of 75% effector and 23% central memory cells. SNAP-TILs exhibited greater efficacy and selectivity in immune infiltration than TIL, which was expanded by the rapid expansion protocol alone using ex vivo models. SNAP-TIL was also reactive in highly and poorly immunogenic tumors, with 70% and 50% tumor growth inhibition in melanoma and pancreatic patient-derived xenograft models, respectively. This study demonstrates the novel benefit of our Personalized Neoantigen Pipeline approach, potentially providing a durable antitumor immune response for a larger proportion of cancer patients.

Considering the rapid pace of developments in the field of cancer immunotherapy, continuous updates on the topic are critical for the medical community. With incidences of cutaneous malignancies on the rise, it is more imperative than ever to utilize and understand current and future treatment modalities. Currently, the United States (US) Food and Drug Administration (FDA) approval for various immune checkpoint inhibitors (ICIs), particularly programmed cell death protein 1 (PD-1) inhibitors, in an adjuvant setting for various cutaneous malignancies is the mainstay in treatment of a number of cutaneous malignancies. Given the transformative potential of PD-1 inhibitors within the realm of immunotherapy, an understanding of the current state of research in this area is essential for dermatologists. This is important because in the cutaneous oncological world, neoadjuvant therapy is quickly demonstrating to show significant importance skin cancer treatment. Traditional neoadjuvant therapy involves a combination of chemotherapy, radiation, and/or targeted therapy, depending on the type and stage of malignancy. The main objective in these therapies has been to reduce tumor size for improved operability, manage systemic disease, and treat operable tumors prior to surgical intervention to obtain a more favorable long-term survivability. This review aims to provide a succinct analysis of both recent and current research of PD-1 inhibitors in the neoadjuvant setting of melanoma, squamous cell carcinoma, and merkel cell carcinoma.

Leukocyte immunoglobulin-like receptor B2 (LILRB2) suppresses immune cell activation, particularly within myeloid cells in the tumor microenvironment (TME), while the PD-1/PD-L1 axis serves as a key immune checkpoint that inhibits T-cell function. SPX-303 is a novel bispecific antibody designed to simultaneously block LILRB2 and PD-L1, thereby revitalizing antitumor immune responses. Here, we present initial findings from the ongoing first-in-human Phase 1 trial of SPX-303 in patients with advanced solid tumors, including safety, pharmacokinetics (PK), and receptor occupancy (RO). This is an open-label, multicenter Phase 1 study for patients with advanced solid malignancies with 3+3 dose-escalation design, followed by an expansion cohort at the recommended Phase 2 dose (RP2D). SPX-303 is administered intravenously every three weeks and safety is assessed through CTCAE v5.0 criteria. Primary Objectives of this study are to determine the safety, tolerability, and RP2D of SPX-303. Secondary endpoints include antitumor activity as well as characterization of the PK and PD of SPX-303. This study is currently open and enrolling in escalation cohorts. Justin Moser, Hao Xie, Yujie Zhao, Yousef Zakharia, Dongdong Li, Brandon William, Dinh-Duc Nguyen, Jack Hovey, Tiffany Li, Robert Cai, Jichun Ma, Jingdong Qin, Martin Siekierzycki, Anthony Haight, Hua Jin, Weiwei Mao, Kevin Bin Li, Gui-Dong Zhu. A first-in-human phase 1 study on the safety, PK, receptor occupancy, and pharmacodynamic markers of SPX-303, a first-in-class LILRB2×PD-L1 bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT116.

Acral lentiginous melanoma (ALM) is a rare and insufficiently understood subtype of melanoma lacking in effective treatment options. Recent work has demonstrated that the response of ALM to immune checkpoint blockade is inferior to that of cutaneous melanoma (CM). Here we performed bulk genomic and transcriptomic sequencing of tumor tissue from 28 ALM and 5692 CM cases. Similar to prior studies, ALM was associated with a significantly lower incidence of point mutations, including in the TERT promoter and BRAF, but increased numbers of gene amplifications, notably of CCND1, HMGA2, and MDM2. Reactome pathway analysis revealed enhancement of keratinization and PI3K/AKT signaling pathways. Overall immunogenicity was decreased in ALM, which possessed lower IFNγ (p < 0.001) and T-cell inflammatory (p = 0.03) pathway scores than CM. Despite higher computationally inferred levels of myeloid dendritic cells (p = 0.006), neoantigen load independent of predicted HLA binding affinity was lower (p < 0.01) in ALM versus CM. Assessment of classical and nonclassical HLA mRNA levels revealed upregulation of HLA-G, suggesting alternative ALM immune evasion pathways in the setting of lower PD-L1 expression (p = 0.005). Additional research is needed to better understand and therapeutically target signaling networks in the ALM tumor microenvironment.

Colitis is a common side effect of all currently approved immune checkpoint inhibitors (ICIs). Vedolizumab is an α4β7 monoclonal antibody approved for treating inflammatory bowel disease (IBD) and is commonly used off-label to manage checkpoint inhibitor colitis (CIC). Previous studies have attempted dose escalation of vedolizumab for clinically unresponsive IBD patients and have been able to achieve clinical remission in 49.6% of these patients without an associated increase in adverse events. However, this has yet to be reported in patients with CIC. Here, we report on two patients who developed CIC after being treated with ICIs for metastatic cancer and received a double dose of vedolizumab. Both patients’ colitis was initially treated with infliximab, steroids, and standard 300-mg vedolizumab dosage with an incomplete response. When administered a double dose of 600-mg vedolizumab, colitis symptoms were resolved without further recurrence or the need for treatment in both patients. This case series outlines effective clinical experience in treating patients with CIC refractory to standard vedolizumab dosage and supports further study of vedolizumab dose escalation in this patient population.

While conventional assays such as affinity, cytokine secretion, and cytotoxicity provide valuable data at a molecular level, this information is insufficient to fully characterize and select the best cellular therapies. There is still a lack of understanding about cell-cell interactions that drive functional processes. Methods: Cell avidity, the collective strength of interactions between an effector and its target, can help elucidate the mechanism of action for therapeutic candidates. Our highly flexible Cell Avidity platform, the z-Movi Cell Avidity Analyzer, combines fluorescence microscopy with acoustic force to distinguish cell binding in a physiological context. This provides a comprehensive view of cell binding characteristics to interrogate potency, safety, sensitivity, and binding kinetics. Results: Here, we review recent publications highlighting how researchers have used Cell Avidity to: •Format-tune in vivo-launched bispecific T cell engagers to enhance efficacy against renal cell carcinoma. •Venetoclax-treated NK cells to improve cytoskeleton remodeling and lytic granule polarization, contributed to a more efficient IS, enhancing NK cell-mediated killing of AML cells. •Engineer CAR-T cells secreting a T-cell engaging molecule to overcome a challenging tumor microenvironment in pancreatic adenocarcinoma. •Phenotype the tumor-primed NK cells for cell binding and function •Fine-tune the affinity/cell avidity of CAR-T cells to mitigate on-target off-tumor toxicity in renal cell carcinoma. Conclusions: Cell Avidity is an emerging biomarker that directly quantifies the strength of the physical interactions between target and effector cells. We developed a Cell Avidity platform that enables the characterization and screening of molecular binders and cellular products, including antibodies, small molecules, and cell therapies. Cell Avidity provides comprehensive information on potency, safety, sensitivity, and kinetics, offering key insights into the mechanism of action for cell therapies. Citation Format: Russell W Mellen, Justin Moser. Cell Avidity – The Next-Gen cell binding to understand the mechanism of action through cell-cell and cell-protein interaction [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A036.

BACKGROUND:Combination immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) leads to high response rates and improved survival in patients with advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM). OBJECTIVES:To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a diverse, real-world population of patients with ALM. METHODS:This multi-institutional retrospective study analysed patients with histologically confirmed ALM treated with a combination of PD-1 and CTLA-4 inhibitors between 2010 and 2022. The primary objective of the study was the objective response rate (ORR) as per the RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS). RESULTS:In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n = 81; 74.3%). The ORR for the entire cohort was 18.3% [95% confidence interval (CI) 11.6-26.9], with 9 (8.3%) complete and 11 (10.1%) partial responses. A further 22 patients (20.2%) had stable disease, and the disease control rate was 38.5%. Median PFS was 4.2 months (95% CI 3.25-5.62), while median OS was 17 months (95% CI 12.4-23.1). Ninety-five patients (87.2%) had a treatment-related adverse event, with 40.4% (n = 44/109) experiencing at least one grade 3 or 4 toxicity. Elevated lactate dehydrogenase (P = 0.04), ≥ 2 lines of prior treatment (P = 0.03) and Asian ethnicity (P = 0.04) were associated with worse OS, while Hispanic/Latino ethnicity was associated with better OS (P = 0.02). CONCLUSIONS:Combination PD-1 and CTLA-4 blockade is less effective for ALM than for CM, despite similar toxicity. In particular, Asian patients appear to derive less benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype.

TPS2673 Background: Frequent recurrence and limited long-term survival in unresected or metastatic melanoma after relapse from 1L treatment with a checkpoint inhibitor (CPI) highlight the critical need for new therapies that deliver deeper, more durable responses (Knight Cancers 2023; Switzer JCO Oncol Pract 2022). ACTengine IMA203 is an autologous T cell receptor (TCR)-engineered T cell therapy (TCR-T) targeting PRAME, an intracellular protein displayed as peptide antigen at high density on the surface of multiple solid tumors, including melanoma. IMA203 TCR-T demonstrated a favorable tolerability profile and durable objective responses in heavily-pretreated patients with different tumor types. In melanoma, IMA203 showed 54% confirmed ORR (14/26), 12.1 months mDOR and 6 months mPFS. mOS was not reached at a mFU of 8.6 months (Wermke et al., SMR, Oct 10, 2024). Based on these observations, a registration-enabling randomized phase 3 trial, SUPRAME, was initiated to evaluate IMA203 in 2L patients with advanced cutaneous melanoma after treatment with a CPI. Methods: SUPRAME (NCT06743126) is a phase 3, multicenter, open-label, randomized, actively controlled, parallel-group trial that will evaluate the efficacy, safety and tolerability of IMA203 compared to investigator's choice of treatment in patients with previously treated, unresectable or metastatic cutaneous melanoma (incl. acral melanoma). Eligible patients are ≥18yo, HLA-A*02:01-positive, with measurable disease (RECIST v1.1), ECOG PS of 0-1 and disease progression on or after at least one PD-1 inhibitor. Patients with BRAF mutation should have been treated with one prior line of BRAF-directed therapy (± MEK inhibitor) prior to initial eligibility assessment. Patients with asymptomatic stable brain or leptomeningeal metastases will be assessed for eligibility. Patients with active brain metastases or with primary mucosal, uveal melanoma and melanoma of unknown primary are excluded. The study will randomize ~360 patients 1:1. Patients in the experimental arm will undergo leukapheresis to generate the PRAME-specific TCR-T product, IMA203. Following lymphodepletion with cyclophosphamide (500 mg/m 2 x 4 days) and fludarabine (30 mg/m 2 x 4 days), 1-10x10 9 IMA203 TCR-T cells will be administered, followed by low-dose IL-2 (1mio IU daily x5 days, twice daily x5 days). Patients in the control arm will receive approved investigator’s choice of standard treatment (nivolumab/relatlimab, nivolumab, ipilimumab, pembrolizumab, lifileucel (US), chemotherapy). The primary efficacy endpoint is BICR-assessed (RECIST v1.1) PFS. Secondary endpoints include OS, ORR, safety and patient-reported outcomes (EORTC QLQ-C30, EQ-5D-5L). The trial will enroll patients in the US and Europe. Clinical trial information: NCT06743126 .

Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes1-9. The mechanisms driving neuroendocrine-tuft tumour heterogeneity and the origins of tuft-like cancers are unknown. Using multiple genetically engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine-tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovered unexpected transcriptional states, including an Atoh1+ state, and lineage trajectories underlying neuroendocrine-tuft plasticity. Uniquely in basal cells, the introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss and ASCL1 suppression, cooperates to promote tuft-like tumours. Transcriptomics of 944 human SCLCs revealed a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate notable conservation between cancer states and normal basal cell injury response mechanisms10-13. Together, these data indicate that the basal cell is a probable origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine-tuft heterogeneity, offering new insights for targeting lineage plasticity.

Detecting high risk characteristics in intraocular retinoblastoma is important for determining metastatic risk. In this pilot study, preoperative Magnetic Resonance Imaging (MRI) radiomics data were compared to high-risk histopathology features after enucleation. A total of 2142 MRI features were extracted, and relevant features were selected to create predictive models for optic nerve and choroidal invasion. Among 31 eyes of 29 patients, 14 eyes had optic nerve invasion and 6 had choroidal invasion. The predictive model for optic nerve (ON) invasion achieved Area under the receiver operating characteristic curve (AUROC) of 0.85 (accuracy 0.84, sensitivity 0.93, specificity 0.76) using the radiomic features of maximum 2D diameter slice on the unaffected optic nerve (ON), correlation of grey level co-occurrence matrix (GLCM) on the affected ON, and kurtosis of affected ON. For choroidal invasion the model achieved AUROC of 0.86 (accuracy 0.94, sensitivity 0.83, specificity 0.96) using the radiomic features of sphericity of affected vitreous and surface volume ratio of affected ON. Radiomics could be useful to guide the decision of globe salvage versus enucleation in advanced retinoblastoma. Larger studies are required to validate and enhance this predictive model.

BACKGROUND:Patients with platinum-resistant/refractory ovarian cancer (PROC) experience suboptimal outcomes, highlighting an immediate need for novel therapies. This phase 1b study investigated the safety and efficacy of botensilimab (BOT), a fragment crystallizable (Fc)-enhanced anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody with differentiated mechanisms of action from first-generation CTLA-4 inhibitors, plus balstilimab (BAL; anti-programmed cell death protein 1 antibody), in an expanded cohort of patients with treatment-refractory ovarian cancer. METHODS:BOT was administered intravenously at 1 mg/kg or 2 mg/kg every 6 weeks in combination with BAL intravenously at 3 mg/kg every 2 weeks (up to 2 years). The primary objectives were to assess safety and tolerability. Efficacy end points included objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. Overall survival (OS) was an exploratory end point. RESULTS:Overall, 44 patients were evaluable for safety (with a median of 3 prior lines of therapy; median follow-up 9.6 months (range, 0.6-36.6)), and 35 for efficacy. The most common treatment-related adverse event was diarrhea/colitis (43%; 16% grade 3) with no treatment-related deaths. RECIST-confirmed ORR was 23% (8/35; 95% CI 10% to 40%; one complete (CR), seven partial responses (PRs)) and clinical benefit rate (CR, PR, or stable disease ≥24 weeks) was 31% (11/35; 95% CI 17% to 49%). Median DOR was 9.7 months (95% CI 2.8 to not reached (NR)), median PFS was 2.8 months (95% CI 1.4 to 5.5), median OS was 14.8 months (95% CI 12.1 to NR), and 12-month OS was 75% (95% CI 55% to 86%). Immune phenotypic analyses and biomarker data revealed significantly higher FcγRIIIA+CD11c+ cells and higher programmed death-ligand 1 expression in responding patients, a strong association between T-cell infiltrated tumors and clinical benefit, and differences in immune architecture across histologic subtypes. CONCLUSION:The BOT/BAL combination demonstrated deep, durable responses and complete remissions in patients with treatment-refractory ovarian cancer where no standard treatments are currently available. RECIST under-represented clinical benefit with 11 patients achieving prolonged/clinically meaningful stable disease (or better) for ≥24 weeks. Toxicities were manageable and reversible. The encouraging clinical activity of BOT/BAL in heavily pretreated patients, as well as biomarker associations, warrants further investigation of this combination.