Antonarakis ES, Cao Q, Catharine V
… +16 more, Carneiro BA, De Souza AL, VanderWeele DJ, Singh P, Bryce AH, Kelly WK, Jha GG, Lewis B, Barata PC, Sartor AO, Stadler WM, Proudfoot JA, Davicioni E, Dhawan M, Morgans AK, Ryan CJ
Clin Cancer Res
· 2026 Jun · PMID 41880596
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PURPOSE: This multicenter, single-arm, phase II trial evaluated the safety and efficacy of cabazitaxel and carboplatin followed by abiraterone, plus androgen deprivation therapy (ADT), in patients with high-volume metast...PURPOSE: This multicenter, single-arm, phase II trial evaluated the safety and efficacy of cabazitaxel and carboplatin followed by abiraterone, plus androgen deprivation therapy (ADT), in patients with high-volume metastatic castration-sensitive prostate cancer (mCSPC). PATIENTS AND METHODS: Eligible patients had high-volume mCSPC and ≤3 months of prior ADT. Patients received six 21-day cycles of cabazitaxel (20 mg/m2) and carboplatin (AUC 4) with continuous ADT, followed by maintenance abiraterone (1,000 mg daily) and prednisone (5 mg daily). The primary endpoint was the proportion of patients free of prostate-specific antigen (PSA) or radiographic progression at 12 months. Secondary endpoints included complete PSA response (≤0.2 ng/mL), objective response, progression-free survival (PFS), and safety. Overall survival (OS) was also reported. RESULTS: Sixty-one participants were enrolled at eight sites. The median age was 64 years, median baseline PSA was 6.6 ng/mL (0.07-745.7 ng/mL), 73.3% had Gleason grade group 5, 69.5% had 10 or more metastases, and 19.6% had a homologous recombination repair (HRR) mutation. PSA PFS at 12 months was 84.6% [95% confidence interval (CI), 72.5%-91.7%], and OS at 12 months was 94.8% (84.7%-98.3%). Complete PSA response was 66.7%, and complete objective response was 30.7%. Contrary to our hypothesis, relative to HRR wild-type patients, HRR-mutated patients (19.6%) had numerically fewer complete PSA responses (33.3% vs. 70.3%) and inferior PFS (HR, 2.43; 95% CI, 0.93-6.39). Common side effects of this quadruplet regimen included fatigue, nausea, and diarrhea. CONCLUSIONS: Cabazitaxel and carboplatin followed by abiraterone, together with ADT, were feasible, safe, and efficacious in patients with high-volume mCSPC and warrant further study in larger randomized trials.
Rubinstein MM, Ge JY, Zhou Q
… +22 more, Iasonos A, Weigelt B, Selenica P, Muldoon DM, Bandlamudi C, Kaczynski C, Paroder V, Higgins K, Shah P, Weissblum S, Lyn A, Liu YL, Bose S, Cohen SM, Green AK, Grisham RN, Kyi C, O'Cearbhaill RE, Tew WP, Berger MF, Aghajanian C, Makker V
Clin Cancer Res
· 2026 Jun · PMID 41880595
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PURPOSE: Copy number-high (CN-H)/p53-abnormal endometrial cancers are high-grade uterine malignancies characterized by TP53 mutations, copy-number alterations, mismatch repair proficiency (MMRp), and absence of POLE muta...PURPOSE: Copy number-high (CN-H)/p53-abnormal endometrial cancers are high-grade uterine malignancies characterized by TP53 mutations, copy-number alterations, mismatch repair proficiency (MMRp), and absence of POLE mutations. A subset may be homologous recombination deficient (HRD), potentially conferring sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. We aimed to test the combination of PARP and immune checkpoint inhibitors in this subgroup, leveraging possible synergy from immune priming. PATIENTS AND METHODS: We conducted a single-arm, open-label, phase II trial evaluating the efficacy and safety of olaparib (300 mg orally twice daily) plus pembrolizumab (200 mg intravenously every 3 weeks) in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer. Eligible patients had p53-abnormal, MMRp, and POLE-negative disease and up to 3 prior lines of therapy. The primary endpoint was the best overall response rate (ORR) at 24 weeks. RESULTS: Of the 25 patients evaluable for efficacy, 2 patients achieved a complete response, and 6 achieved a partial response, resulting in an ORR of 32% [90% one-sided confidence interval (CI), 19.6%-100%]. The median duration of response was 11.2 months (80% two-sided CI, 6.4-11.9). The median progression-free survival was 3.9 months (80% two-sided CI, 2.1-5.8), and the median overall survival was 16.5 months (80% two-sided CI, 9.6-23.6). No new safety signals were identified. Genomic analyses suggested that responders had a numerically higher frequency of HRD tumors than nonresponders (50% vs. 17%). CONCLUSIONS: The combination of olaparib plus pembrolizumab has promising activity with durable responses in patients with persistent or recurrent CN-H/p53-abnormal endometrial cancer. Molecular biomarkers may be helpful for patient selection in future studies of this combination.
Lee KW, Elimova E, Oh DY
… +9 more, Beeram M, Doi T, Yeung KT, Samuel Nached T, Shah KV, Fuller DS, Shpektor D, Loro E, Meric-Bernstam F
Clin Cancer Res
· 2026 Jun · PMID 41870284
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PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression occurs in various subtypes of salivary gland cancers (SGC) and can be associated with treatment challenges and poor clinical outcomes. Zanidatamab i...PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression occurs in various subtypes of salivary gland cancers (SGC) and can be associated with treatment challenges and poor clinical outcomes. Zanidatamab is a dual HER2-targeted, bispecific antibody that has demonstrated antitumor activity across multiple HER2-positive tumor types. This combined analysis aimed to assess the efficacy and safety of zanidatamab in HER2-positive SGC. PATIENTS AND METHODS: Adult patients with previously treated, unresectable locally advanced or metastatic HER2-positive SGC were enrolled in three early-phase trials of zanidatamab: a first-in-human phase I study (NCT02892123), a phase I study of patients in Japan (JRCT2031210161), and a phase Ib/II study evaluating zanidatamab plus evorpacept, a high-affinity CD47 inhibitor (NCT05027139). Confirmed objective response rate (cORR) and progression-free survival (PFS) were measured in each study. Outcomes with zanidatamab monotherapy were pooled for summary analysis. RESULTS: Ten patients with HER2-positive SGC were enrolled across trials; six patients were previously treated with HER2-targeted therapy. Among patients who received zanidatamab monotherapy (n = 9), seven experienced zanidatamab-related adverse events (all grade 1/2), the most common being diarrhea and infusion-related reactions. The cORR [95% confidence interval (CI)] was 44% (14%-79%), the median (95% CI) PFS was 10.1 (3.8-not estimable) months, and the median (range) duration of response was not reached (9.4 to 42.3+ months). All patients experienced a reduction in tumor size. One patient who received zanidatamab plus evorpacept experienced a confirmed partial response and 18.4 months of PFS. CONCLUSIONS: Although the sample size is small, these findings support the clinical benefit of zanidatamab treatment for HER2-positive SGC.
Cecchini M, Han SW, Lee S
… +12 more, Lee KW, Kopetz S, Mizrahi J, Hong YS, Ghiringhelli F, Italiano A, Tougeron D, Beagle B, Boakye M, Zhao T, Khemka V, Wainberg ZA
Clin Cancer Res
· 2026 Jul · PMID 41870279
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PURPOSE: Targeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced metastatic colorectal cancer (mCRC), for whom treatment options are limited....PURPOSE: Targeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced metastatic colorectal cancer (mCRC), for whom treatment options are limited. PATIENTS AND METHODS: The phase II ARC-9 study, Cohort B (NCT04660812), evaluated the efficacy and safety of etrumadenant (A2a and A2b receptor antagonist), zimberelimab (anti-PD-1 mAb), FOLFOX, and bevacizumab (EZFB) versus regorafenib in patients with third-line mCRC who previously progressed on oxaliplatin- and irinotecan-containing regimens. RESULTS: From September 21, 2021, to September 12, 2022, 112 patients were randomized 2:1 to EZFB (n = 75) or regorafenib (n = 37). As of November 13, 2023, the median survival follow-up was 20.4 months. The primary endpoint of progression-free survival (PFS) was improved with EZFB (6.2 months) versus regorafenib [2.1 months; hazard ratio (HR), 0.27; 95% confidence interval (CI), 0.17-0.43; nominal P < 0.0001], as was the secondary endpoint of overall survival (OS; EZFB, 19.7 months; regorafenib, 9.5 months; HR, 0.37; 95% CI, 0.22-0.63; nominal P = 0.0003). The confirmed overall response rate was 17% (90% CI, 10.6%-26.1%) with EZFB and 3% (90% CI, 0.1%-12.2%) with regorafenib. Treatment-emergent adverse events (TEAE), grade ≥3 TEAEs, and TEAEs leading to discontinuation of all study treatments were reported in 99%, 82%, and 5% of the EZFB arm and in 87%, 49%, and 17% of the regorafenib arm, respectively. CONCLUSIONS: EZFB significantly improved survival outcomes compared with regorafenib in patients with mCRC as a third-line treatment, with a manageable safety profile. Further investigation is warranted, given the clinically meaningful improvements in PFS and OS.
van der Elst A, Herrero-Saboya D, Michon L
… +23 more, Morfouace M, Liechti R, Devanand P, Schulz D, Persoons M, Rusakiewicz S, Eling N, Nicolas PA, Robert MS, Tissot S, Déglise S, Palau Fernandez B, Bodenmiller B, Hong HS, Galot R, Bossi P, Oliveira J, Pracht M, Even C, Saintigny P, Lefebvre C, Martignetti L, Machiels JP
Clin Cancer Res
· 2026 Jul · PMID 41870278
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PURPOSE: Recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a heterogeneous clinical entity with a poor prognosis. The molecular and immune landscape of R/M SCCHN is underexplored....PURPOSE: Recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is a heterogeneous clinical entity with a poor prognosis. The molecular and immune landscape of R/M SCCHN is underexplored. To offer a comprehensive view of the tumor microenvironment and molecular profile of R/M SCCHN, we performed an in-depth molecular and immune characterization, evaluating the impact of human papillomavirus (HPV) status, tobacco and alcohol history, primary tumor site, relapse pattern, and treatment history at the genomic, transcriptomic, and immune levels. EXPERIMENTAL DESIGN: We analyzed 253 R/M SCCHN fresh tumor biopsies from the IMMUcan project using RNA sequencing (RNA-seq), whole-exome sequencing, and multiplex immunofluorescence (mIF). RESULTS: The primary clinical factor affecting the immune microenvironment was the number of treatment lines, with significant declines in T cells and B cells observed via mIF and RNA-seq as the number of R/M treatment lines progressed. IL6, IL13, IL15, and NRF2 pathways were enriched in HPV-negative R/M SCCHN compared with HPV-positive tumors, whereas no immune differences were detected between these two clinical groups. Specific genomic alterations were observed in laryngeal cancer (DDR2, FOXP1, KLF5, and ROBO2), whereas nonsmokers/nondrinkers exhibited alterations in SPEN, PBRM1, and CYLD. 11q13.3 amplification was linked to HPV-negative metastatic tumors and hypopharyngeal cancer. HPV-negative SCCHN with locoregional recurrence showed elevated EGFR and CXCL12 pathway activity. Partial epithelial-mesenchymal transition transcriptomic signatures correlated with poor survival, whereas lymphocyte infiltration, especially in the context of tertiary lymphoid structures, was associated with improved survival. CONCLUSIONS: Our study highlights key molecular and immune differences across R/M SCCHN subgroups, identifies potential biomarkers, and suggests biological rationales for tailored therapeutic strategies.
Oberg AL, Bamlet WR, Izmirlian G
… +17 more, Balasenthil S, Batra SK, Hayashi M, Herman DS, Hollingsworth MA, Jain M, Killary AM, Krusen BM, Liu S, Majumder S, Natarajan G, Sen S, Smith LM, Srivastava S, Wolpin BM, Zaret KS, Goggins MG
Clin Cancer Res
· 2026 Jun · PMID 41870276
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PURPOSE: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network-defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel pe...PURPOSE: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network-defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, to compare the panels' performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. EXPERIMENTAL DESIGN: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum, and germline DNA from 140 stage I to IV pancreatic ductal adenocarcinoma (PDAC) cases and 140 controls from three tertiary care institutions, with controls frequency matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). RESULTS: The study population was 51% female, with median age 67.3 (minimum: 45, maximum: 90) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 [95% confidence interval (CI), 87.8-95.6]. Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC = 96.3, P = 0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC = 95, P = 0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC = 96.4 (94-98.9)]. CONCLUSIONS: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.
Lee JK, Quintanilha JCF, Chen KT
… +18 more, Fendler B, Tambaoan CFB, Graf R, Odzer N, Pusztai L, Lustberg M, Singh H, Strickland M, O'Meara TA, Tolaney SM, Yap TA, Ross J, Gasco Hernandez A, Decker B, Huang RSP, Klempner SJ, Sokol ES, Schrock AB
Clin Cancer Res
· 2026 Jul · PMID 41870274
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PURPOSE: Gene copy number (CN) amplifications and protein overexpression are common drug targets, and detection relies on various methodologies, including next-generation sequencing-based CN, immunohistochemistry (IHC),...PURPOSE: Gene copy number (CN) amplifications and protein overexpression are common drug targets, and detection relies on various methodologies, including next-generation sequencing-based CN, immunohistochemistry (IHC), and in situ hybridization (ISH). We investigated the pan-tumor landscape of amplifications and developed AmpRatio, a novel method of CN quantitation. EXPERIMENTAL DESIGN: Pan-tumor tissue (N = 486,340) and liquid (N = 85,635) samples underwent hybrid capture-based comprehensive genomic profiling. A genome-wide CN model for each sample was generated to estimate the purity, ploidy, and segment-level CN. AmpRatio was calculated by dividing gene CN/sample ploidy. A US-based deidentified clinicogenomic database was utilized to assess the relationship between ERBB2 AmpRatio and HER2 IHC/FISH and outcomes on anti-HER2 therapies. RESULTS: Amplifications with varying degrees of gain were reported in 38.6% of pan-tumor tissue samples, most frequently MYC (5.6%), 11q13 (5.2%), ERBB2 (5.2%), and CCNE1 (3.2%). ERBB2 AmpRatio was associated with HER2 positivity by IHC/FISH in gastroesophageal [overall percent agreement (OPA) 90%] and breast (OPA 95%) cancers. Among patients treated with anti-HER2 therapies, ERBB2 AmpRatio significantly stratified outcomes within the ERBB2-amplified and IHC-defined HER2+ and HER2-low/ultralow populations. High concordance (sensitivity 88%) of amplification detection in liquid biopsy versus tissue was associated with higher AmpRatio and ctDNA tumor fraction ≥20%. CONCLUSIONS: CN amplifications are prevalent and diverse biomarkers, and AmpRatio is variable across genes and tumor types. ERBB2 AmpRatio is associated with outcomes to HER2-directed therapies and may have utility alongside IHC for clinical decision-making. With the increasing number of therapies targeting amplifications/overexpression, it will be important to define harmonized methods for CN quantification for optimal patient selection.
Clin Cancer Res
· 2026 Jun · PMID 41855142
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In 390 patients with stage I to III hormone receptor-positive/HER2- breast tumors, a higher number of tumor-infiltrating lymphocytes (TIL) subtypes, regardless of whether they were immunostimulatory or immunosuppressive,...In 390 patients with stage I to III hormone receptor-positive/HER2- breast tumors, a higher number of tumor-infiltrating lymphocytes (TIL) subtypes, regardless of whether they were immunostimulatory or immunosuppressive, including regulatory T cells and CD8 and non-CD8 T cells, are associated with improved distant disease-free survival and overall survival at 8 years follow-up. See related article by Tesch et al., p. 2268.
Clin Cancer Res
· 2026 Jun · PMID 41855129
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Eribulin was evaluated in angiosarcoma and epithelioid hemangioendothelioma (EHE) through two prospective international trials. Although encouraging activity was observed in EHE, its role in angiosarcoma may depend on fu...Eribulin was evaluated in angiosarcoma and epithelioid hemangioendothelioma (EHE) through two prospective international trials. Although encouraging activity was observed in EHE, its role in angiosarcoma may depend on further refinement through subgroup selection. These findings underscore the importance of histology-specific interpretation, innovative endpoints, and coordinated strategies for ultrarare sarcoma drug development. See related article by Cote et al., p. 2206.
Carleton N, Chang AC, Chen F
… +23 more, Puhalla SL, Foldi J, Waltermire H, Tin A, Cowher MS, Lupinacci K, Diego EJ, Sabih Q, Johnson RR, Malhotra M, Laubenthal A, Gorantla V, Balic M, Bhargava R, Joy M, Freeman T, Bridges C, Kalashnikova E, Rodriguez A, Liu MC, Oesterreich S, Lee AV, McAuliffe PF
Clin Cancer Res
· 2026 Mar · PMID 41854411
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PURPOSE: For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) is a validated prognostic factor across solid tumors and may provide a st...PURPOSE: For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) is a validated prognostic factor across solid tumors and may provide a strategy to identify patients for whom safe de-escalation of certain therapies is possible. EXPERIMENTAL DESIGN: In this prospective, hybrid-decentralized trial (n = 43 patients; NCT05914792) that integrated clinical outcomes, patient- and caregiver-reported outcomes, and correlative tissue analysis, the primary objective was to determine if ctDNA levels were associated with tumor progression in older patients who opted to forgo breast cancer surgery in favor of primary endocrine therapy (pET). RESULTS: ctDNA levels were highly concordant with imaging findings, and a lack of ctDNA clearance at 6 months was associated with tumor progression. In a competing risk regression adjusted for patient age, tumor stage, tumor grade, and tumor Ki-67, pretreatment ctDNA positivity was associated with a significant risk of tumor progression (HR, 30; 95% confidence interval, 4.4-209; P = 0.0011). No patients with pretreatment ctDNA negativity experienced tumor progression. In correlative analyses examining ctDNA-positive tumors progressing on pET, we identified populations of CD11+ T cell-interacting macrophages that upregulate CD109 and CD89 and secrete immunosuppressive chemokines to create a favorable environment for cancer epithelial cell proliferation. CONCLUSIONS: These findings suggest that ctDNA may be a modality to identify older patients who can safely receive long-term pET, warranting future evaluation in a randomized setting.
Huang B, Zhao J, Zhu J
… +13 more, Wang X, Li M, Xu J, Wang K, Wang X, Wang W, Bo C, Yao J, Bai M, Cheng B, Yu J, Cai G, Meng X
Clin Cancer Res
· 2026 Mar · PMID 41849236
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PURPOSE: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the...PURPOSE: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear. EXPERIMENTAL DESIGN: This multicenter retrospective and prospective study included mNSCLC patients receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1-3 Gy, and >3 Gy groups and treatment outcomes were compared. The blood and fecal samples were subjected to multi-omics profiling. RESULTS: g>309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1-3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months) (P < 0.01), which was consistent across subgroups. Compared with 1-3 Gy, SIMRD >3 Gy (Hazard ratio [HR] = 4.87, P < 0.001) and <1 Gy (HR = 1.85, P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1-3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1-3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells. CONCLUSIONS: ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1-3 Gy range, likely through modulation of the gut microbiota-metabolite-immune axis.
Arbesfeld-Qiu JM, Cho JW, Nguyen PTT
… +23 more, Lester NA, Su J, Shiau C, Guo JA, Hoffman H, Caldwell NJ, Muratani S, Galvan M, Proctor JE, Ely ZA, Wang S, Ganci M, Dries R, Hong T, Wo J, Boland G, Fernandez-Del Castillo C, Ferrone CR, Heaphy CM, Zhang ML, Mino-Kenudson M, Hemberg M, Hwang WL
Clin Cancer Res
· 2026 Jun · PMID 41849229
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PURPOSE: Pancreatic neuroendocrine tumors (PNET) are rare malignancies of the endocrine pancreas with diverse clinical outcomes. Whereas some PNETs are indolent, others are aggressive and metastasize quickly. However, cl...PURPOSE: Pancreatic neuroendocrine tumors (PNET) are rare malignancies of the endocrine pancreas with diverse clinical outcomes. Whereas some PNETs are indolent, others are aggressive and metastasize quickly. However, clinically relevant molecular stratification for PNET to predict outcomes and guide therapeutic decision-making is limited. Thus, there is an urgent need to understand the molecular heterogeneity of PNETs to refine prognostication and discover novel therapeutic vulnerabilities. EXPERIMENTAL DESIGN: We performed single-nucleus RNA sequencing on untreated, resected primary, and metastatic PNETs (n = 18). We inferred gene expression programs (GEP) of malignant and nonmalignant cells and investigated associations with clinical outcomes. Next, we inferred interactions in the tumor microenvironment (TME) and performed transwell migration assays for functional validation. Finally, we explored genomic and transcriptomic evolution in a unique case study of an untreated primary PNET with two asynchronous hepatic metastases. RESULTS: A malignant GEP enriched for neural/synaptic signaling genes was associated with worse overall survival, broad chromosomal loss of heterozygosity, and alternative lengthening of telomeres. Another malignant GEP enriched for VEGF signaling increased throughout metastatic progression in our case study. We found that macrophage-derived glutamate drives polarization toward an immunosuppressive phenotype and activates the MAPK/ERK pathway in malignant cells to increase migratory capacity. CONCLUSIONS: This study provides a detailed single-nucleus transcriptomic classification of malignant, stromal, and immune cell types and states in PNETs, their interactions in the TME, and associations with clinical outcomes. The refined molecular taxonomy of PNET may guide the development of more efficacious biomarkers and therapeutic strategies.
Ninmer EK, Zhu H, Sarkar A
… +7 more, Chianese-Bullock KA, Ross MI, Haas NB, von Mehren M, Boisvert ME, Kirkwood JM, Slingluff CL
Clin Cancer Res
· 2026 Jun · PMID 41849224
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PURPOSE: We report the long-term clinical outcomes of a multicenter, randomized phase II trial (NCT00089193) that tested immunogenicity of a vaccine composed of 12 class I MHC-restricted melanoma peptides (12MP), with or...PURPOSE: We report the long-term clinical outcomes of a multicenter, randomized phase II trial (NCT00089193) that tested immunogenicity of a vaccine composed of 12 class I MHC-restricted melanoma peptides (12MP), with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant and administered at one or two sites in patients with resected high-risk melanoma. PATIENTS AND METHODS: Participants were randomized to one of four treatment arms: 12MP at one site (arm A), 12MP + GM-CSF at one site (arm B), 12MP at two sites (arm C), and 12MP + GM-CSF at two sites (arm D). The trial was powered to detect differences in immunogenicity by vaccine groups defined by GM-CSF status (arms B + D vs. A + C) and vaccine sites (arms A + B vs. C + D). For this analysis, overall survival (OS) and recurrence-free survival (RFS) were evaluated by these vaccine groups. RESULTS: All eligible participants (n = 121) were evaluated. The median follow-up was 5.6 years. No significant differences in RFS or OS were observed by GM-CSF status. Participants vaccinated at two sites compared with one had significantly improved RFS [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.38-0.93; P = 0.02] and a trend to improved OS (HR, 0.64; 95% CI, 0.39-1.06; P = 0.08). On landmark multivariable analysis, two-site vaccination was the only significant predictor of RFS (HR, 0.55; 95% CI, 0.34-0.88; P = 0.01) after adjusting for CD8+ T-cell response and other prognostic factors. CONCLUSIONS: These results challenge the use of GM-CSF as a local vaccine adjuvant and support two-site vaccination. Future work to characterize the locoregional immune response to cancer vaccination at the injection site and vaccine-draining lymph nodes is warranted.
Clin Cancer Res
· 2026 Mar · PMID 41842604
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Despite the recent approval of perioperative pembrolizumab for locally advanced, resectable head and neck squamous cell carcinoma, response rates to immunotherapy are low. A recent single-arm phase II trial of neoadjuvan...Despite the recent approval of perioperative pembrolizumab for locally advanced, resectable head and neck squamous cell carcinoma, response rates to immunotherapy are low. A recent single-arm phase II trial of neoadjuvant nivolumab in combination with carboplatin and paclitaxel demonstrated improved pathologic response rates compared to either chemotherapy or immunotherapy alone.
Sanvito F, Raymond C, Telesca D
… +12 more, Yao J, Abrey LE, Garcia J, Simmons B, Chinot O, Saran F, Nishikawa R, Henriksson R, Mason WP, Wick W, Cloughesy TF, Ellingson BM
Clin Cancer Res
· 2026 Jun · PMID 41837753
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PURPOSE: Brain tumor location is known to affect survival, but there is a lack of methodologic tools for systematically studying the complex interplay between brain tumor location, prognostic variables, treatment schemes...PURPOSE: Brain tumor location is known to affect survival, but there is a lack of methodologic tools for systematically studying the complex interplay between brain tumor location, prognostic variables, treatment schemes, and survival. EXPERIMENTAL DESIGN: A total of 592 prospectively enrolled patients with newly diagnosed glioblastoma from the phase III AVAglio trial, randomized to postsurgical chemoradiation with or without bevacizumab, were retrospectively analyzed. Statistical parametric mapping was conducted with multivariate Cox proportional hazards models at the voxel-wise level, incorporating dedicated interaction variables to evaluate the impact of baseline tumor volume and treatment arm on survival for different tumor locations from magnetic resonance imaging (MRI) scans, with subsequent cluster-based correction for multiple testing and mathematical estimation of regional survival curves. RESULTS: Tumor location in the right prefrontal cortex was an independent favorable prognostic factor [median hazard ratio (HR) = 0.57] for survival, whereas tumor involvement in left hemisphere eloquent areas with language and visual functions was unfavorable (median HR = 1.69). Larger presurgical tumor volumes were associated with shorter survival independent of tumor location (HR = 1.005), but the effect was larger for tumor locations including eloquent structures (HR ranging 1.008-1.015), whereas nonsignificant for anterior frontal locations. Bevacizumab seemed to grant a survival benefit when specific brain regions were involved or spared by the tumor, but this result was not confirmed after correction for multiple testing. CONCLUSIONS: This workflow allows to map the survival effects of variables onto specific brain tumor locations, revealing location dependency of prognostic variables such as tumor volume, and potentially of treatment schemes, with relevant implications in risk stratification and clinical management.
Yang J, Chen W, Duan Z
… +10 more, Yang M, Tao L, Huo Y, Liu W, Zhang J, Yao L, Liu Y, Lin P, Li H, Sun Y
Clin Cancer Res
· 2026 Jun · PMID 41837750
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PURPOSE: Hepatic metastasis (HM) is the leading cause of death in pancreatic ductal adenocarcinoma (PDAC). However, the underlying cellular and molecular programs remain poorly understood, leading to limited therapeutics...PURPOSE: Hepatic metastasis (HM) is the leading cause of death in pancreatic ductal adenocarcinoma (PDAC). However, the underlying cellular and molecular programs remain poorly understood, leading to limited therapeutics for this disease. EXPERIMENTAL DESIGN: In this study, we integrated single-cell RNA sequencing data from paired primary tumors and HMs, along with bulk RNA sequencing and IHC data from hundreds of patients to elucidate metastasis-associated programs. RESULTS: Our analysis identified a metastasis-prone malignant subpopulation, which is associated with a higher risk of HM and a transitional plastic state. This malignant subpopulation represents a poorly differentiated and highly proliferative phenotype, with H2AFZ potentially contributing to this phenomenon. Moreover, the presence of tumor cells in the liver was accompanied by an increased abundance of M2 macrophages, regulatory T cells, and exhausted T cells (Tex) in HMs compared with adjacent tissues, indicative of a shift toward an immunosuppressive environment. Notably, within the tumor environment of HMs, Tex exhibited elevated expression of PDCD1 and LAG3. The combined therapy targeting these two genes effectively inhibited tumor growth in mouse models of metastatic PDAC. CONCLUSIONS: In conclusion, we reveal a metastasis-associated malignant subpopulation and provide a promising therapeutic strategy for metastatic PDAC.
Jhatakia A, Sun X, Vaccaro A
… +29 more, Wang M, Nasser M, Mukhopadhyay A, Gupta N, Kang K, Hu W, Newsome C, Leung CH, Le J, Yazdani M, Guo H, Chen L, Pradhan M, Lin HY, Mandawe R, Findeisen F, Lohre J, Leung L, Wei Y, Dobroff J, O'Brien S, Xu K, Hammell A, Price K, Engelhardt J, Selby M, Korman A, Wilson N, Cascone T
Clin Cancer Res
· 2026 Mar · PMID 41837748
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BACKGROUND: The anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, ipilimumab, has shown clinical benefit across multiple tumor types, both as monotherapy and in combination with nivolumab or chemotherap...BACKGROUND: The anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody, ipilimumab, has shown clinical benefit across multiple tumor types, both as monotherapy and in combination with nivolumab or chemotherapy. However, not all tumors respond, and peripheral effects can lead to immune-related adverse events. We characterized three novel anti-CTLA-4 antibodies: peptide-masked (PROBODY® conditionally activatable therapeutic [PB]), nonfucosylated (NF), and combined NF-PB (BMS-986288). METHODS: We evaluated the preclinical characteristics, including the pharmacodynamics, tolerability, antitumor activity and efficacy, and peripheral immune responses, of these novel anti-CTLA-4 antibodies using in vitro systems, animal models, and human data. This includes data in preclinical mouse models of colorectal cancer as well as non-small cell lung cancer. RESULTS: NF demonstrated greater T-cell priming and antitumor activity than both ipilimumab and the unmasked PB antibody in cell-based assays and mouse models. Whereas the intact PB antibody showed minimal CTLA-4 binding and peripheral immune activation, unmasking restored its functional activity to levels comparable with those of ipilimumab. Unmasked anti-CTLA-4 NF-PB retained the effectiveness of anti-CTLA-4 NF, and both molecules demonstrated more profound antitumor activity, increased effector memory T-cell response, and prolonged survival in mouse models compared with ipilimumab. Anti-CTLA-4 NF-PB demonstrated reduced peripheral immune responses than anti-CTLA-4 NF or ipilimumab in non-human primates and patients with solid tumors. CONCLUSION: Anti-CTLA-4 NF-PB has enhanced antitumor activity, efficacy, and reduced peripheral activity in preclinical models, and has the potential to provide therapeutic benefit in solid tumors.
Clin Cancer Res
· 2026 Jun · PMID 41837744
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PURPOSE: We conduct a systematic evaluation of cell-cell interactions between tumor-infiltrating immune cells in patients with head and neck squamous cell carcinoma (HNSCC) who have been treated with immune checkpoint bl...PURPOSE: We conduct a systematic evaluation of cell-cell interactions between tumor-infiltrating immune cells in patients with head and neck squamous cell carcinoma (HNSCC) who have been treated with immune checkpoint blockade (ICB) using spatial and single-cell omics data. EXPERIMENTAL DESIGN: We employed complementary techniques from both Visium spot-based spatial transcriptomics and CosMx Spatial Molecular Imager single-cell spatial omics, utilizing a 64-plex protein panel and a 1,000-gene RNA panel, which includes 435 ligands and receptors. We conducted integrated bioinformatics analyses to identify cellular neighborhoods of colocalizing cell types and ligand-receptor interactions across different single-cell and spatial data modalities. RESULTS: With 522,399 single cells profiled for both RNA and protein from 23 patients, along with spot-resolved spatial RNA sequencing (RNA-seq) data from eight patients treated with ICB, and through bioinformatics analysis of publicly available single-cell and bulk RNA-seq, we identified a spatial and cell type-specific context dependency in the differences in myeloid and T-cell interactions between responder and nonresponder samples. We further defined the cellular neighborhood and sources of chemokine CXCL9/10-CXCR3 interactions, emphasizing the specificity of this marker in responder samples, an emerging target in ICB, as well as other underappreciated markers and targets for ICB response in HNSCC, such as CXCL16-CXCR6 and CCL4/5-CCR5. CONCLUSIONS: We have provided a valuable resource for analyzing spatial and cell-cell ligand-receptor interactions, including the cellular and spatial contexts of ICB response markers. Our data suggest that future mechanistic studies should consider this context specificity when evaluating ICB response biomarkers and targets.