Clinical Cancer Research[JOURNAL]
Sun
200 papers
Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC).
Slovin S, Gao X, Wei XX … +19 more , Oh DY, McKay RR, Falchook G, Hussain A, McKean M, Wibmer A, Ho A, Eskew JD, Belani R, Coronella J, Haag S, Martin CE, McCaigue J, Mendoza J, Murphy A, Namini H, Spear MA, Shedlock DJ, Dorff TB
Clin Cancer Res · 2026 Mar · PMID 41779004 · Publisher ↗
PURPOSE: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong...
PURPOSE: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). PATIENTS AND METHODS: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. RESULTS: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. CONCLUSIONS: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.
Allogeneic B7-H3-Targeted CAR Vδ1T-cell Therapy in Advanced Solid Tumors: A Phase I Study.
Liu C, Li J, Liu D … +25 more , Zhang P, Zhang M, Xue R, Gong J, Liu L, Tao M, Cheng S, Xu T, Yuan J, Cao Y, Wang Z, Wang Y, Zhou J, Lu M, Peng Z, Lu Z, Li J, Zhang X, Wang T, Wang M, Jiang L, Meng H, Yang L, Qi C, Shen L
Clin Cancer Res · 2026 May · PMID 41779003 · Publisher ↗
PURPOSE: The aim of the study was to evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an "off-the-shelf" allogeneic B7-H3-targeted chimeric antigen receptor (CAR) Vδ1T-cell therapy, in...
PURPOSE: The aim of the study was to evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an "off-the-shelf" allogeneic B7-H3-targeted chimeric antigen receptor (CAR) Vδ1T-cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. PATIENTS AND METHODS: In this first-in-human, phase I, dose-escalation study (NCT06372236), 10 patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5 × 108, 8 × 108, or 1 × 109 cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and antitumor efficacy. RESULTS: UTAA06 demonstrated a manageable safety profile; no GVHD was observed, and cytokine release syndrome was limited to two transient grade 1 events. A single dose-limiting toxicity (grade 3 pneumonitis) was reported in one patient at the 5 × 108 cell dose level. Although UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by RECIST v1.1 criteria was observed. Further analysis identified that the limited CAR T-cell persistence was likely driven by subclinical host-versus-graft rejection. CONCLUSIONS: This study provides clinical proof of concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GVHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.
Improving Preclinical Cancer Drug Development Models to Avoid Clinical Failure.
Gewirtz DA, Teicher BA, Greenberg E
Clin Cancer Res · 2026 Jun · PMID 41779001 · Publisher ↗
It is well established that the majority of anticancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into la...
It is well established that the majority of anticancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later-stage clinical trials. The simple explanation is that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. Although this is certainly hyperbole, it is true that drug efficacy often seems significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models commonly used for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.
131I-LNTH-1095 Radioligand Therapy plus Enzalutamide versus Enzalutamide Alone in Men with PSMA-Avid Metastatic Castration-Resistant Prostate Cancer: A Phase II Study.
Yu EY, Narayan V, Esposito G … +15 more , Szmulewitz R, Lu Y, Lilly MB, Calais J, Bratslavsky G, Menda Y, Vasanawala M, Pouliot F, Laidley D, Fleshner N, Saad F, Provost JC, Teslenko I, Rawat NK, Ulaner G
Clin Cancer Res · 2026 May · PMID 41779000 · Full text
PURPOSE: The phase II ARROW study was designed to evaluate radioligand therapy (RLT) with 131I-LNTH-1095, an iodine-131-labeled small molecule targeting prostate-specific membrane antigen (PSMA), in combination with enza...
PURPOSE: The phase II ARROW study was designed to evaluate radioligand therapy (RLT) with 131I-LNTH-1095, an iodine-131-labeled small molecule targeting prostate-specific membrane antigen (PSMA), in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer after progression on prior abiraterone therapy. PATIENTS AND METHODS: Men ≥18 years with PSMA-positive prostate cancer (PSMA PET tracer uptake >1× liver SUVmean in all CT-measurable lesions) were randomly assigned 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks) + enzalutamide (160 mg orally once daily) versus enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included radiographic progression-free survival (rPFS), objective response rate, overall survival (OS), and safety. RESULTS: Of 177 screened subjects, 120 were randomly assigned (80: 131I-LNTH-1095 + enzalutamide; 40: enzalutamide monotherapy). PSA50 response was 62.9% [95% confidence interval (CI), 50.5-74.1] for 131I-LNTH-1095 + enzalutamide versus 31.3% (16.1-50) for enzalutamide alone (P = 0.003). The median rPFS was 14.0 months (95% CI, 8.64-18.20) for 131I-LNTH-1095 + enzalutamide versus 11.5 months (2.79-18.43) for enzalutamide alone (P = 0.10). The incidence of grade ≥3 treatment-emergent adverse events (TEAE) was 65.8% for 131I-LNTH-1095 + enzalutamide versus 41% for enzalutamide monotherapy; the most frequent TEAEs were fatigue (75% vs. 53.8%), nausea (59.2% vs. 33.3%), thrombocytopenia (51.3% vs. 0%), and decreased appetite (48.7% vs. 17.9%), respectively. Two deaths in the 131I-LNTH-1095 + enzalutamide group were considered treatment-related. The study was not powered to detect rPFS and OS differences. CONCLUSIONS: 131I-LNTH-1095 + enzalutamide was associated with a statistically significant improvement in PSA50 response compared with enzalutamide alone despite a lower dosing schedule (4 cycles of 3.7 GBq/dose every 8 weeks) than the other approved PSMA RLT agents. Grade ≥3 adverse events were more frequent with combination therapy, particularly hematologic toxicity.
Pembrolizumab Monotherapy in Sorafenib-Treated and Treatment-Naïve Advanced Hepatocellular Carcinoma: Long-Term Follow-up of the Open-Label, Phase II KEYNOTE-224 Study.
Finn RS, Kudo M, Borbath I … +16 more , Edeline J, Cattan S, van Vlierberghe H, Verslype C, Palmer D, Stål P, Ogasawara S, Vogel A, Chan SL, Knox JJ, Daniele B, Odeleye-Ajakaye A, Hatogai K, Siegel AB, Cheng AL, Van Laethem JL
Clin Cancer Res · 2026 May · PMID 41770235 · Publisher ↗
PURPOSE: In the phase II KEYNOTE-224 study, pembrolizumab showed durable antitumor activity and manageable safety in participants with sorafenib-treated (cohort 1) or treatment-naïve (cohort 2) advanced hepatocellular ca...
PURPOSE: In the phase II KEYNOTE-224 study, pembrolizumab showed durable antitumor activity and manageable safety in participants with sorafenib-treated (cohort 1) or treatment-naïve (cohort 2) advanced hepatocellular carcinoma (HCC). We present data after a median follow-up of ∼7 years for cohort 1 and ∼5 years for cohort 2. PATIENTS AND METHODS: Adults with advanced HCC received pembrolizumab 200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity for ≤35 cycles. The primary endpoint was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Overall, 155 participants received ≥1 dose of pembrolizumab (cohort 1, n = 104; cohort 2, n = 51). The median follow-up was 83 months (range, 79.3-87.3) for cohort 1 and 58.8 months (range, 55.3-60.8) for cohort 2. The median OS was 13.2 months [95% confidence interval (CI), 9.7-15.3] and 16.9 months (95% CI, 8.3-23.1), respectively; 24- and 48-month OS rates were 31%/17% and 34%/20%, respectively. The median PFS was 4.9 months (95% CI, 3.5-7) and 4.3 months (95% CI, 2.1-7.8), respectively. Treatment-related adverse events occurred in 76 participants [73.1%; grade 3-5, 27 (26%)] in cohort 1 and 28 participants [54.9%; grade 3-5, 8 (15.7%)] in cohort 2. CONCLUSIONS: Pembrolizumab continued to show durable response and manageable safety in participants with advanced HCC with or without prior systemic therapy, with long-term effects on OS lasting beyond 48 months in some participants despite receiving study treatment for ≤2 years.
PET/CT-Guided Neoadjuvant Tislelizumab plus Chemotherapy/Chemoradiotherapy for Resectable Esophageal Squamous Cell Carcinoma: RATIONALE-213 Final Analysis.
Yang Y, Yan X, Jiang H … +10 more , Kang M, Mei X, Tan L, Liu J, Du W, Shi Y, Zhang Z, Liang L, Liao Y, Chen L
Clin Cancer Res · 2026 May · PMID 41770095 · Full text
PURPOSE: The aim of this study is to assess positron emission tomography/computed tomography (PET/CT)-guided neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in patients with resectable esophag...
PURPOSE: The aim of this study is to assess positron emission tomography/computed tomography (PET/CT)-guided neoadjuvant treatment with tislelizumab plus chemotherapy/chemoradiotherapy in patients with resectable esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: RATIONALE-213, a multicenter, open-label, two-cohort phase II study, enrolled 70 patients with resectable ESCC. After one induction chemotherapy cycle, patients were categorized as PET responders (PET maximum standardized uptake value decrease ≥35%) or PET nonresponders (<35%). Subsequently, all patients received three cycles of tislelizumab 200 mg intravenously. In addition, PET responders received chemotherapy and PET nonresponders received chemoradiotherapy as neoadjuvant treatment followed by surgery. The primary endpoint was the pathologic complete response (pCR) rate. RESULTS: As of October 25, 2024 (median follow-up 25.5 months), pCR rates were 30% [95% confidence interval (CI), 11.9-54.3] in PET responders and 34.4% (95% CI, 18.6-53.2) in PET nonresponders. Higher pCR rates were associated with higher baseline programmed cell death ligand 1 tumor area positivity scores in both cohorts. One-year disease-free survival rates were 79% and 74.2%, and event-free survival rates were 87.1% and 67.8%, respectively. Any-grade and grade ≥3 treatment-related adverse events (TRAE) occurred in 93.3% and 50% of PET responders and 97.5% and 82.5% of PET nonresponders, with no new safety signals. The most common grade ≥3 TRAE was decreased neutrophil count (36.7% and 70%, respectively). CONCLUSIONS: Tislelizumab with chemotherapy/chemoradiotherapy as neoadjuvant treatment for resectable ESCC yielded promising pCR rates and favorable survival outcomes with a tolerable safety profile in both PET/CT-guided responders and PET nonresponders.
Efficacy and Safety of Belantamab Mafodotin with Bortezomib plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: The DREAMM-6 Arm B Trial.
Popat R, Augustson B, Cannell P … +14 more , Stockerl-Goldstein K, Spencer A, Khot A, Nooka A, Patel N, Kasinathan RS, McKeown A, Curry A, Rogers R, Shaikh M, Carreno F, Roy-Ghanta S, Opalinska J, Quach H
Clin Cancer Res · 2026 May · PMID 41770089 · Full text
PURPOSE: The phase I/II DREAMM-6 arm B study (NCT03544281) explored belantamab mafodotin combined with bortezomib/dexamethasone (BVd) in relapsed/refractory multiple myeloma (RRMM). PATIENTS AND METHODS: Adults with RRMM...
PURPOSE: The phase I/II DREAMM-6 arm B study (NCT03544281) explored belantamab mafodotin combined with bortezomib/dexamethasone (BVd) in relapsed/refractory multiple myeloma (RRMM). PATIENTS AND METHODS: Adults with RRMM were enrolled sequentially in two belantamab mafodotin (intravenous) dose-escalation (DE) cohorts (2.5 then 3.4 mg/kg every 3 weeks). Additional patients enrolled sequentially to eight dose-expansion cohorts: 1.9, 2.5, or 3.4 mg/kg every 3 weeks; 2.5 or 3.4 mg/kg every 3 weeks split dose (days 1 and 8); 1.9 or 2.5 mg/kg every 6 weeks; or 2.5 mg/kg in cycle 1 stepped down to 1.9 mg/kg every 6 weeks thereafter. Patients received bortezomib twice weekly and dexamethasone four times weekly. Endpoints were dose-limiting toxicities (DLT; DE), adverse events (AE), serious AEs (SAE; DE and expansion), overall response rate (ORR; expansion), and pharmacokinetics. RESULTS: One hundred seven patients (median 4 prior lines of therapy) received BVd (n = 12-18/cohort). The median follow-up was 15.2 to 25.4 months. No DLTs occurred during DE. The most common grade 3/4 AE was keratopathy (53%). Protocol-defined ocular events (change in best corrected visual acuity and/or corneal examination findings) were reported in 93% of patients (grade 3/4: 77%). Twenty-eight (26%) patients experienced any study treatment-related SAEs; 3 of 7 fatal SAEs had a treatment-related primary cause. The ORR was 70% (95% confidence interval, 60.5-78.6). Higher initial exposures had higher probabilities of response and ocular events; lower exposures resulted in fewer deep responses, with small differences in ocular events. CONCLUSIONS: BVd demonstrated manageable safety and clinical activity across all dosing cohorts in heavily pretreated RRMM, supporting the 2.5 mg/kg every 3 weeks dose.
Association of Intratumoral Microbiota with Prognosis in Head and Neck Squamous Cell Carcinoma.
Yin S, Cheng L, Hu E … +16 more , Li J, Wu G, An J, Nunez L, Kawachi N, Zhu J, Rosenblatt G, Segall JE, Ostrer H, Augustine S, Song EZ, Ow TJ, Smith RV, Prystowsky MB, Verma A, Deng W
Clin Cancer Res · 2026 May · PMID 41758690 · Publisher ↗
PURPOSE: To evaluate whether intratumoral bacterial load and diversity are associated with survival outcomes in head and neck squamous cell carcinoma (HNSCC) and to examine their relationship with human papillomavirus (H...
PURPOSE: To evaluate whether intratumoral bacterial load and diversity are associated with survival outcomes in head and neck squamous cell carcinoma (HNSCC) and to examine their relationship with human papillomavirus (HPV) status. EXPERIMENTAL DESIGN: This retrospective cohort study included 312 adults with surgically treated, primary HNSCC at Montefiore Einstein Cancer Center (2000-2023). Intratumoral bacterial load was quantified via quantitative PCR (qPCR), and microbial diversity was assessed via 16S ribosomal RNA (rRNA) sequencing in 312 tumor and 34 paired normal tissues. HPV status was determined via p16 immunohistochemistry (IHC) and qPCR. Overall survival (OS)was the primary outcome. RESULTS: HNSCC tumors showed higher bacterial load and lower bacterial diversity compared with adjacent normal tissues. High bacterial load [hazard ratio (HR), 1.85; 95% confidence interval (CI), 1.31-2.61; P < 0.001] and low bacterial diversity (HR, 1.65; 95% CI, 1.19-2.28; P = 0.003) were independently associated with reduced OS, with the greatest risk in patients carrying both features (HR, 3; 95% CI, 1.76-5.09; P < 0.001). The high-risk bacterial features were less frequent in HPV-positive than in HPV-negative tumors (high load: OR, 0.46; 95% CI, 0.29-0.73; P = 0.001; low diversity: OR, 0.51; 95% CI, 0.32-0.81; P = 0.004), and their prognostic significance was more pronounced in HPV-negative cases. Taxonomic profiling revealed marked depletion of predominant bacterial taxa in HNSCC, especially in HPV-negative tumors. Notably, loss of the class TM7-3 and the orders Actinomycetales and Burkholderiales was specifically associated with poor HNSCC survival, including early mortality. CONCLUSIONS: High intratumoral bacterial load and low diversity are prognostic factors associated with survival in HNSCC, particularly in HPV-negative patients. Incorporating microbiome assessment into risk stratification may enhance prognostic precision and inform microbiota-directed therapeutic approaches.
Identification of additional DPYD polymorphisms that increase the risk of severe fluoropyrimidine toxicity and improved predictive accuracy when combined with previously validated variants.
Nguyen-Hoang N, Nugent K, Jaso S … +5 more , Shakeel F, Kwon JW, Koo K, Pasternak AL, Hertz DL
Clin Cancer Res · 2026 Feb · PMID 41758686 · Publisher ↗
PURPOSE: Fluoropyrimidine (FP) chemotherapy can cause life-threatening toxicity. Four DPYD polymorphisms (DPYD*2A, *13, p.Asp949Val, HapB3) are well-established to increase FP toxicity risk. This study aimed to identify...
PURPOSE: Fluoropyrimidine (FP) chemotherapy can cause life-threatening toxicity. Four DPYD polymorphisms (DPYD*2A, *13, p.Asp949Val, HapB3) are well-established to increase FP toxicity risk. This study aimed to identify additional DPYD polymorphisms that increase FP toxicity. EXPERIMENTAL DESIGN: Adult patients treated with standard doses of systemic FP (5-fluorouracil/capecitabine) for any cancer with available DPYD genetic data were included. The primary endpoint was a composite of CTCAE grade ≥3 toxicity or treatment modification due to toxicity in the first two FP cycles. A literature-curated list of suspected deleterious unvalidated DPYD variants was classified as uncommon (minor allele frequency <0.01) or common. The genetic association with toxicity was analyzed via multivariable logistic regression. RESULTS: Among 849 eligible patients, the composite toxicity endpoint occurred in 25%. Genetic data were available for five uncommon and six common suspected deleterious DPYD variants. In the primary analysis of 799 patients who did not carry a validated variant, carriers of uncommon deleterious variants (1.1% of patients) had significantly higher toxicity risk than non-carriers (67% vs. 24%; adjusted OR 7.36; 95% CI 1.75-38.20; p = 0.009). None of the common deleterious variants were associated with toxicity. Toxicity prediction in the entire cohort (n = 849) was slightly improved by testing the uncommon and validated variants vs. testing only the validated variants (positive predictive value: 44.1% vs. 40.0%). CONCLUSIONS: Five uncommon DPYD variants, in combination, increase FP toxicity risk and improve risk prediction. Testing these variants could identify more high-risk patients who should receive adjusted FP doses to prevent severe toxicity.
Characterizing Longitudinal Molecular Changes in ctDNA in Patients with Metastatic Castration-Resistant Prostate Cancer.
Jani CT, Tran E, Zhang N … +7 more , Tsai J, Dong J, Bucheit L, Pan E, Panian J, Chen YW, McKay RR
Clin Cancer Res · 2026 May · PMID 41746190 · Publisher ↗
PURPOSE: Circulating tumor DNA (ctDNA) next-generation sequencing complements tissue-based testing and offers insights into prognosis, treatment selection, and tumor evolution. Despite advances in metastatic castration-r...
PURPOSE: Circulating tumor DNA (ctDNA) next-generation sequencing complements tissue-based testing and offers insights into prognosis, treatment selection, and tumor evolution. Despite advances in metastatic castration-resistant prostate cancer (mCRPC) therapies, resistance remains a challenge. This real-world study evaluates longitudinal ctDNA changes following systemic treatments. EXPERIMENTAL DESIGN: We analyzed data from Guardant INFORM, a clinical genomic database linking ctDNA profiles with claims data. Patients with prostate cancer who received androgen receptor (AR) pathway inhibitors (ARPi), poly (ADP-ribose) polymerase inhibitors (PARPi), or taxanes and had ctDNA testing within 3 months before and after treatment discontinuation were included. We evaluated pre- and posttreatment mutational differences and survival outcomes (overall survival, time to treatment discontinuation, and time to next treatment), stratifying by treatment type and AR alterations. RESULTS: From 36,774 patients with prostate cancer, we identified 678 with paired pre-/post-ARPi, 188 with paired pre-/post-PARPi, and 844 with paired pre-/post-taxane ctDNA samples. After ARPi, the most frequent AR alterations included AR amplification (pre%/post%; 10.8%/25.6%), AR L702H (1.3%/7.9%), and AR T878A (2.9%/7.1%). Following PARPi, the most common homologous recombination repair gene alterations were ATM (25%/23.4%), BRCA2 (22.9%/17%), BRCA1 (4%/2.1%), and CDK12 (5.9%/5.9%). After taxane, frequent alterations included TP53 (47.2%→54%), AR (33.2%/49.9%), PIK3CA (9.4%/15.9%), and EGFR (9.6%/14.6%). All treatment cohorts showed a significant increase in mutation burden after therapy (mean increase 2.0-4.2 alterations; P < 0.001). Across all three treatment groups, the presence of AR alterations was consistently associated with inferior clinical outcomes. CONCLUSIONS: Our study revealed dynamic shifts in genetic mutations in patients with mCRPC following ARPi, PARPi, and taxanes. Furthermore, our findings highlight associations between AR alterations and clinical outcomes, emphasizing the potential for personalized treatment strategies.
Lactate-Driven IL8+ Tumor-Associated Macrophages Mediate Immunosuppression and Resistance to Immunotherapy in Clear-Cell Renal Cell Carcinoma.
Dong Y, Jiang W, Qiu Y … +9 more , Xu Z, Cheng J, Ke P, Dai S, Qu Y, Xia Y, Guo J, Liu L, Xu J
Clin Cancer Res · 2026 May · PMID 41733625 · Full text
PURPOSE: Immune checkpoint blockade (ICB) has revolutionized clear-cell renal cell carcinoma (ccRCC) therapy, yet resistance remains common. Tumor-associated macrophages (TAM) shape the tumor-immune interface and contrib...
PURPOSE: Immune checkpoint blockade (ICB) has revolutionized clear-cell renal cell carcinoma (ccRCC) therapy, yet resistance remains common. Tumor-associated macrophages (TAM) shape the tumor-immune interface and contribute to ICB resistance. Although IL8 (CXCL8) was known as a chemokine involved in tumor progression, the role of IL8+ TAMs in ccRCC remains poorly defined. In this study, we aimed to define the clinical and functional relevance of IL8+ TAMs in ccRCC. EXPERIMENTAL DESIGN: Two in-house and four external RCC cohorts, encompassing more than 1,400 patients, were analyzed to determine the clinical relevance of IL8+ TAMs. Immunofluorescence and IHC were applied to quantify IL8+ TAM infiltration. Mass/flow cytometry and multiomics were used to define their phenotype, metabolic profile, and immune interactions. Ex vivo tumor cultures were performed to test IL8 blockade and combination with anti-PD-1 therapy. RESULTS: High IL8+ TAM infiltration was consistently associated with ICB resistance. Transcriptomic analyses revealed that IL8+ TAMs adopt a glycolysis-associated metabolic program and are responsive to lactate, which directly promotes IL8 expression. Phenotypically, IL8+ TAMs exhibited an immunosuppressive and chemotactic profile that correlated with CD8+ T-cell dysfunction and regulatory T-cell accumulation. Importantly, ex vivo IL8 blockade alleviated CD8+ T-cell exhaustion and synergized with PD-1 inhibition to enhance antitumor immune responses. CONCLUSIONS: IL8+ TAMs represent a metabolically reprogrammed and immunosuppressive subset driving ICB resistance in ccRCC. Targeting IL8 may overcome resistance and enhance immunotherapy efficacy.
A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.
Román-Trufero M, Whitlock G, Seydoux C … +7 more , Blighe K, Perfler B, Zebisch A, Butt R, Fuchter MJ, Auner HW, Clemo N
Clin Cancer Res · 2026 May · PMID 41729725 · Full text
PURPOSE: GCN2, one of the four kinases that activate the integrated stress response to maintain proteostasis, has been shown to support cancer cell growth and survival in multiple preclinical cancer models. Acute myeloid...
PURPOSE: GCN2, one of the four kinases that activate the integrated stress response to maintain proteostasis, has been shown to support cancer cell growth and survival in multiple preclinical cancer models. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor prognosis and high relapse rates that is marked by a dependency on finely tuned proteostasis. In this study, we investigate the antileukemic potential of a new small-molecule GCN2 inhibitor, APL-4098. EXPERIMENTAL DESIGN: Selectivity and potency of APL-4098 were assessed using biochemical and cell-based assays. Antileukemic effects were evaluated ex vivo in primary patient-derived AML and in vivo using cell line-derived (CDX) and patient-derived xenograft (PDX) models. Synergy of APL-4098 and venetoclax was examined in the PDX model. RNA sequencing and metabolic assays were used to explore APL-4098 mechanism of action. RESULTS: APL-4098 exhibited nanomolar-range potency against and high selectivity for GCN2. APL-4098 showed strong antiproliferative activity ex vivo across two independent cohorts of cells from patients with primary AML, including cytotoxic effects on the leukemia stem cells (LSC) and in vivo, achieving 98% tumor growth inhibition in an AML CDX. In a PDX, APL-4098 preferentially depleted the LSC-enriched compartment and, in combination with venetoclax, reduced leukemia burden by more than 98%. Transcriptomic and metabolic analyses revealed that APL-4098 compromises mitochondrial function and elicits the mitochondrial unfolded protein response. CONCLUSIONS: APL-4098 is a novel, potent, and selective GCN2 inhibitor with strong preclinical efficacy against AML cells, including LSC. Our findings support APL-4098 as a promising candidate for AML treatment.
Repurposing Tumor Cells: A Paradigm Shift in Cell-Based Therapies for Cancer.
Chen KS, Lin LY, Chen YC … +1 more , Shah K
Clin Cancer Res · 2026 May · PMID 41718605 · Full text
Conventional cancer therapies emphasize eradication, often at the expense of harming healthy tissue and causing immune compromise. This article explores a paradigm-shifting concept: repurposing tumor cells not merely as...
Conventional cancer therapies emphasize eradication, often at the expense of harming healthy tissue and causing immune compromise. This article explores a paradigm-shifting concept: repurposing tumor cells not merely as targets but as active therapeutic agents. By harnessing their self-homing ability, antigen diversity, and adaptive survival mechanisms, these engineered tumor cells can be repurposed to deliver therapeutic payloads, remodel the tumor microenvironment, and even function as antigen-presenting cells (APC). We begin by critically analyzing the mechanistic failures of early whole-cell vaccine approaches, highlighting how their limited efficacy stemmed from underestimating both the tumor's potent adaptive resistance and the deeply immunosuppressive nature of its microenvironment. We then discuss next-generation strategies designed to overcome these hurdles, with approaches ranging from "killer vaccines" and APC-like reprogramming to Trojan horse delivery of oncolytic viruses. The translational challenges, ranging from multilayered safety engineering, GMP manufacturing, regulatory navigation, patient selection, to ethical considerations, are examined in depth, with key insights drawn from the clinical evolution of chimeric antigen receptor T-cell therapy. We conclude by outlining a clinical roadmap and rational combinatorial strategies, proposing that if these barriers are overcome, tumor cell-based therapies could emerge as complements to immune checkpoint inhibitors and adoptive cell therapies, thus transforming the tumor from an adversary into a catalyst of its own defeat.
Apalutamide + Abiraterone Acetate plus Prednisone + Leuprolide with Stereotactic, Ultra-Hypofractionated Radiation in Very High-Risk Prostate Cancer: A Single-Arm, Phase 2 Study.
McBride SM, Spratt DE, Kollmeier M … +11 more , Abida W, Xiao H, Slovin SF, Paller CJ, Deville C, Den RB, Hearn J, Catharine V, Scher H, Zelefsky M, Rathkopf D
Clin Cancer Res · 2026 May · PMID 41712259 · Publisher ↗
PURPOSE: This study investigates a short-course, intensified regimen combining apalutamide, abiraterone acetate, and prednisone (AAP) and stereotactic body radiotherapy (SBRT) to reduce treatment burden and improve disea...
PURPOSE: This study investigates a short-course, intensified regimen combining apalutamide, abiraterone acetate, and prednisone (AAP) and stereotactic body radiotherapy (SBRT) to reduce treatment burden and improve disease control in a very high-risk (VHR) population inadequately represented in prior trials. PATIENTS AND METHODS: This multi-institutional, single-arm, phase 2 trial enrolled patients with VHR localized prostate cancer, defined according to the National Comprehensive Cancer Network as histologically confirmed adenocarcinoma with ≥2 high-risk features: Gleason score 8 to 10, prostate-specific antigen (PSA) ≥20, clinical or radiographic ≥T3, or >4 cores containing Gleason score 8 disease. Patients received 6 months of apalutamide, abiraterone acetate, and leuprolide plus prostate/seminal vesicle-directed ultra-fractionated SBRT. The primary endpoint was 3-year biochemical recurrence (BCR) rate by Phoenix criteria, with a prespecified superiority threshold of <10%. Secondary endpoints included PSA ≥0.2 ng/mL, metastasis-free survival (MFS), and time to testosterone recovery >150 ng/dL. RESULTS: Between August 2016 and December 2022, 63 patients were treated. At 3 years, the Phoenix-defined BCR rate was 19%. BCR-free survival was 84.2% [95% confidence interval (CI), 75.6-93.7] with a median follow-up of 41 months (34-43). The 3-year MFS was 93.6% (95% CI, 87.8%-99.8%), with no deaths observed. The median time to testosterone recovery >150 ng/dL was 6 months (range, 3-24 months). No new safety signals emerged, and the only significant quality-of-life (QOL) decline was in the EPIC sexual subdomain at 12 months. CONCLUSIONS: Treatment intensification with apalutamide, AAP, androgen deprivation therapy, and SBRT was well-tolerated with limited impact on QOL. Although BCR rates exceed the superiority threshold, outcomes aligned with historic benchmarks, supporting further evaluation of the regimen in prospective trials.
Shaping the Future of HER2-Directed Therapy in Biliary Tract Cancer.
Fitzpatrick OM, Harding JJ
Clin Cancer Res · 2026 May · PMID 41711894 · Publisher ↗
This commentary on a retrospective study of patients with HER2-positive biliary tract cancer highlights the importance of reflex and validated HER2 testing criteria, the discordance of next-generation sequencing and HER2...
This commentary on a retrospective study of patients with HER2-positive biliary tract cancer highlights the importance of reflex and validated HER2 testing criteria, the discordance of next-generation sequencing and HER2 IHC, the potential prognostic and predictive role of HER2, and the necessity to define HER2 therapy resistance mechanisms. See related article by Lee et al., p. 1745.
Contemporary Management of Radiation Necrosis: Insights and Avenues.
Williams MM, Haskell-Mendoza AP, Massat EA … +11 more , Mott BT, Smith EC, Zachem TJ, Loebel F, Cramer CK, Chan MD, Laxton AW, White JJ, Goodwin CR, Codd PJ, Fecci PE
Clin Cancer Res · 2026 May · PMID 41706018 · Publisher ↗
Radiation necrosis (RN) remains a challenging complication of upfront radiotherapy for both brain metastases and primary tumors. Despite the development of an array of advanced imaging modalities to differentiate RN from...
Radiation necrosis (RN) remains a challenging complication of upfront radiotherapy for both brain metastases and primary tumors. Despite the development of an array of advanced imaging modalities to differentiate RN from true tumor progression, tissue diagnosis remains the gold standard. Synergizing artificial intelligence to assist with imaging and intraoperative pathologic diagnosis may represent a fruitful future direction. Similarly, laser interstitial thermal therapy is an attractive alternative for RN management when the costs and complications of chronic steroids or bevacizumab are considered. Current evidence suggests that an angio-inflammatory cascade is responsible for RN development; tissue-based studies and preclinical modeling are needed to reveal targetable causal mechanisms that may support clinical risk stratification and treatment.
DNA Methylation-Based Risk Stratification and Classification of Pediatric Thyroid Carcinoma.
Li JZ, Ricarte-Filho JC, Isaza AR … +6 more , Hinkle K, Xu F, Li MM, Bauer AJ, Franco AT, Zhou W
Clin Cancer Res · 2026 May · PMID 41701943 · Full text
PURPOSE: Accurate assessment of invasiveness in pediatric thyroid carcinomas is essential to prevent unnecessary surgery and avoid surgery-associated complications. DNA methylation, a proven molecular biomarker for cance...
PURPOSE: Accurate assessment of invasiveness in pediatric thyroid carcinomas is essential to prevent unnecessary surgery and avoid surgery-associated complications. DNA methylation, a proven molecular biomarker for cancer classification, holds promise for stratifying thyroid cancer risk. The objectives were to determine the epigenetic hallmarks of pediatric thyroid carcinomas and investigate whether DNA methylome profiling is a feasible approach for preoperative risk stratification of this pediatric disease. EXPERIMENTAL DESIGN: We interrogated genome-wide DNA methylation profiles from two separately processed cohorts of pediatric thyroid carcinoma. The reference cohort included 100 samples, consisting of 87 well-differentiated primary tumors-77 papillary and 10 follicular thyroid carcinomas-and 13 matched lymph node metastases. To predict oncogenic drivers and tumor invasiveness, defined by the presence of nodal metastasis, we trained two classifiers on the reference cohort and then evaluated their performance on a second validation cohort of 84 samples, including 83 primary tumors and one lymph node metastasis. RESULTS: We identified distinct methylation patterns associated with tumor invasiveness and key driver mutations, including BRAF p.V600E, RAS-like mutations, kinase fusions, and DICER1 mutations. The differentially methylated regions reflect inflammatory stress and disrupted thyroid development and function, implicating androgen receptor, Hippo, and AP-1 signaling. Leveraging these epigenetic signatures, we developed and validated two methylation-based classifiers that accurately predict tumor invasiveness and oncogenic mutation subgroups. CONCLUSIONS: In patients with pediatric thyroid carcinoma, DNA methylation assays accurately predict tumor invasiveness and driver mutations. Our findings highlight the clinical value of DNA methylation profiling for risk stratification and classification of pediatric thyroid cancers.
Safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy from a first-in-human study of volrustomig, a novel PD-1/CTLA-4 bispecific antibody.
Tran B, Voskoboynik M, Kim SW … +26 more , Lemech C, Carcereny E, Rha SY, Ahn MJ, Felip E, Lee KH, Castañón Álvarez E, Yang JC, Ascierto PA, Provencio Pulla M, Kondo S, Kuboki Y, Freeman D, Song X, Blando J, Eck S, Song FJ, Tang Z, Kuziora M, Gainer SD, Mitchell P, Asare J, Ayyoub A, Achour I, Subramaniam DS, Im SA
Clin Cancer Res · 2026 Feb · PMID 41701940 · Publisher ↗
PURPOSE: Volrustomig is an IgG1 monovalent bispecific antibody engineered to preferentially target CTLA-4 on PD-1-positive T cells while providing adequate and durable PD-1 inhibition. The aim of this phase I, first-in-h...
PURPOSE: Volrustomig is an IgG1 monovalent bispecific antibody engineered to preferentially target CTLA-4 on PD-1-positive T cells while providing adequate and durable PD-1 inhibition. The aim of this phase I, first-in-human study (NCT03530397) is to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and antitumor activity of volrustomig. This manuscript reports findings for the dose-exploration and immunotherapy-naïve expansion cohorts. PATIENTS AND METHODS: Patients aged ≥18 years who had histologically or cytologically confirmed advanced cancer, measurable disease, performance status of 0-1, and adequate organ and marrow function received volrustomig 2.25-2500 mg intravenously every 3 weeks until confirmed disease progression, initiation of alternative cancer therapy, unacceptable toxicity, or consent withdrawal. The primary objective in the dose-exploration phase was to evaluate the safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose. Secondary objectives included assessment of preliminary antitumor activity and volrustomig pharmacokinetics. RESULTS: 86 patients received volrustomig treatment in the dose-exploration and immunotherapy-naïve expansion cohorts; 78 (90.7%) patients were immunotherapy-naïve. Common treatment-related adverse events (TRAEs) were pruritus (30.2%), hypothyroidism (26.7%), hyperthyroidism (24.4%), and rash (24.4%). TRAEs led to treatment discontinuation in 33.7% of patients and one death. At doses ≥500 mg, volrustomig demonstrated robust peripheral and intra-tumoral T cell activation and proliferation at levels greater than those seen with approved PD-1/CTLA-4 regimens. Seventeen (19.8%) patients had objective responses, including 2 (2.3%) complete responses; median response duration was 17.5 months. CONCLUSIONS: These results support further development of volrustomig as monotherapy and in combination regimens, with phase 3 trials ongoing.
Integrated Germline and Somatic Molecular Profiling to Detect Cancer Predisposition Has a High Clinical Impact in Poor-Prognosis Pediatric Cancer.
Fuentes-Bolanos NA, Courtney EK, Mayoh C … +45 more , Warby M, Lau LMS, Wong-Erasmus M, Khuong-Quang DA, Barahona P, Padhye B, Warren N, El-Kamand S, Nunag S, Ajuyah P, Sherstyuk A, Altekoester AK, Sullivan A, Poplawski N, Kiraly-Borri C, O'Sullivan S, Mar Fan H, Alli R, Curnow L, Bhatia K, Anazodo A, Trahair TN, Mateos MK, Hansford JR, Dholaria H, Josephi-Taylor S, Moore AS, Nicholls W, Gottardo NG, Downie P, Khaw SL, Tapp H, McCowage G, Dalla-Pozza L, Alvaro F, Wood PJ, Tyrrell V, Haber M, Cowley MJ, Ekert PG, Marshall GM, Kirk J, Tucker K, Pinese M, Ziegler DS
Clin Cancer Res · 2026 May · PMID 41686853 · Full text
PURPOSE: The role of germline predisposition in pediatric cancer is increasingly recognized. However, the optimal approach to identifying cancer predisposing germline pathogenic variants (GPV) in children, and even the p...
PURPOSE: The role of germline predisposition in pediatric cancer is increasingly recognized. However, the optimal approach to identifying cancer predisposing germline pathogenic variants (GPV) in children, and even the prevalence of GPVs among children with cancer, remain unclear. We examined GPV prevalence and diagnostic yield of different test approaches within a national pediatric precision oncology program. EXPERIMENTAL DESIGN: We performed prospective rapid-turnaround whole-genome and -transcriptome profiling of 496 consecutively recruited children with poor-prognosis cancer to identify genetic variants linked to cancer risk. RESULTS: Integration of tumor and germline molecular profiling identified GPVs in 15.5% of patients, an incremental GPV yield of 7.9% above that detected by standard care. Although the cancer type was outside the recognized phenotypic spectrum for 43.7% of reported GPVs, 63.2% of these were clinically actionable. Integrated germline-tumor analysis increased the GPV detection rate by 8.5%, informed germline interpretation in 14.3% of patients with GPVs, and provided biological insight into tumor etiology, together highlighting the value of integrated analyses. Cascade testing in first-degree relatives confirmed that the GPV was de novo in 21% of tested families. Within inherited GPVs (73.9%), 47.8% had direct implications for risk management recommendations in the relevant parent. CONCLUSIONS: Our findings establish the clinical benefit and feasibility of integrated tumor-germline whole-genome screening to detect GPVs in children with poor-prognosis cancers and their first-degree relatives.
Efficacy of the ATR Inhibitor Ceralasertib in Patients with ARID1A-Deficient Gynecologic and Other Solid Tumor Malignancies.
Zhu X, Alvarez EA, Umetsu SE … +18 more , Chapman JS, Chen LM, Ueda S, Henderson S, Nguyen P, Calabrese S, Russell J, Aguilar J, Smith SA, Shah N, Feeney L, Van Ziffle J, Turski ML, Ko AH, Munster PN, Ashworth A, Collisson EA, Aggarwal RR
Clin Cancer Res · 2026 May · PMID 41686845 · Publisher ↗
PURPOSE: ARID1A is frequently mutated in cancer. Motivated by the preclinical synthetic lethality between ARID1A loss and ataxia telangiectasia and Rad3-related (ATR) inhibition, we performed an investigator-initiated ph...
PURPOSE: ARID1A is frequently mutated in cancer. Motivated by the preclinical synthetic lethality between ARID1A loss and ataxia telangiectasia and Rad3-related (ATR) inhibition, we performed an investigator-initiated phase II study of the ATR inhibitor (ATRi) ceralasertib in ARID1A-deficient solid tumors (NCT03682289). PATIENTS AND METHODS: This was a phase II, Simon two-stage study with a planned sample size of 29 evaluable patients. Eligible patients had locally advanced or metastatic solid tumors with measurable disease by Response Evaluation Criteria in Solid Tumors 1.1 and radiographic progression at study entry. Patients were required to have ARID1A loss as determined by immunohistochemistry analysis of tumor tissue. Patients received ceralasertib 160 mg twice daily on days 1 to 14 every 28 days. RNA sequencing (RNA-seq) and cyclic immunofluorescence were performed on tumor tissue to identify potential biomarkers of treatment response. RESULTS: The confirmed objective response rate (ORR) was 14% among the 29 efficacy-evaluable patients. All four responses, including three complete responses, occurred in endometrioid endometrial carcinoma or ovarian clear-cell carcinoma, with an ORR of 33% and a median duration of response of 33.7 months in this subset. Including one patient with uterine carcinosarcoma who had stable disease, the ORR was 31% among the 13 patients with gynecologic malignancies. Exploratory RNA-seq analysis of pretreatment archival tumor tissue identified upregulated G2-M checkpoint and DNA double-strand break-sensing pathways in patients who responded. Immune profiling revealed tumor immune microenvironment changes associated with the response to ceralasertib. CONCLUSIONS: Ceralasertib monotherapy demonstrated promising antitumor activity in ARID1A-deficient gynecologic malignancies. Tumor molecular and immune correlates may inform the further development of ATRis in this patient population.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe