Cancer research communications最新文献

Neuronal autoantibodies have been identified in immune-mediated encephalitis, and most of which are related to paraneoplastic neurological syndromes (PNS). We detected neuronal autoantibodies in gastric cancer patients without PNS, and illustrated their correlation with clinical prognosis. All serum samples were tested by the mouse brain tissue-based assay (TBA) using immunofluorescence for screening neuronal autoantibodies. Known PNS related neuronal autoantibodies were detected by cell-based assay (CBA). A single-center cohort has been started in Nanfang hospital. T cells status of the tumor microenvironment was assessed. Singel cell sequencing was performed with limited tumor samples. Patients were grouped into TBA positive (n=144) and TBA negative (n=179) groups by the TBA status. Further screening of TBA+ specimens using the CBA method revealed known PNS-related autoantibodies in 13.2% (19/144) of cases. Additionally, TBA positive gastric cancer patients exhibited lower CD8+ T cell infiltration in the tumor tissue. The Survival analysis show that neuronal autoantibodies in patients (TBA positive) were associated with shorter OS (P=0.014). In the multivariate survival analysis, TBA positive was still associated with shortened OS after adjusting the major covariates (HR = 2.28, 95% CI: 1.31-3.97, P = 0.004). Meanwhile, Single-cell sequencing indicates that cell junction assembly and synapse organization may play important roles in biological process. In this cohort study, neuronal autoantibodies were highly prevalent among gastric cancer patients and were associated with shortened OS and features of immunosuppression within the tumor microenvironment, suggesting a candidate for exploring therapeutic relevance, with further mechanistic studies needed to validation.

Endometrioid and mucinous ovarian carcinomas represent nearly a fifth of ovarian cancers, but their molecular characteristics and pathologic origins are poorly understood. To identify the genomic and epigenomic alterations characteristic of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed a combination of sequence, copy number, mutation signature, and rearrangement analyses from tumor samples and matched normal tissues of 133 patients, as well as methylation analyses of these tumors and tissues of 150 patients from The Cancer Genome Atlas. Genomic analyses included samples from patients with ovarian endometrioid (n = 44), ovarian mucinous (n = 43), uterine endometrioid (n = 15), and gastrointestinal mucinous carcinomas (n = 31), including mucinous carcinomas of the stomach, colon, and pancreas. In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4, and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous carcinomas. Whole-genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid carcinomas and NF1 and MED1 in ovarian mucinous carcinomas. The number of alterations, affected genes, and genome-wide methylation profiles were not distinguishable between ovarian and uterine endometrioid carcinomas, supporting the hypothesis that these tumors share a tissue of origin. In contrast, mutation and methylation patterns in ovarian mucinous carcinomas were different from gastrointestinal mucinous carcinomas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers.

Significance: Integrative multi-omic analyses support a common tissue of origin between ovarian endometrioid and uterine endometrioid carcinomas but not between ovarian mucinous and gastric or pancreatic mucinous carcinomas.

The incidence of colorectal cancer in young adults (age of diagnosis <50 years) has been rapidly increasing. Although ∼20% of early-onset colorectal cancer (EOCRC) cases are due to germline mutations, the etiology of the majority of EOCRC cases remains poorly understood. Nongenetic factors such as environmental exposure and lifestyle changes are likely to have a direct link to the increased incidence of sporadic EOCRC. We hypothesize that such factors may be observable as alterations in the epigenome, microbiome, and immunome. We characterized the DNA methylation (DNAm) signature and measured DNAm age in EOCRC by using The Cancer Genome Atlas (TCGA). Furthermore, we carefully identified intratumoral microbes from TCGA and the Oncology Research Information Exchange Network datasets and then related the microbes to deconvolved immune cell abundances in EOCRC. We observed that the DNAm age in the EOCRC cohort was 12 years older when compared with the average-onset colorectal cancer (AOCRC) cohort, using three different epigenetic clocks. Differentially methylated sites associated with gene expression include cAMP-responsive element binding protein signaling in neurons, G protein-coupled receptor signaling, phagosome formation, and S100 family signaling. These differences were validated in the gene expression data from TCGA and the Oncology Research Information Exchange Network. When comparing the intratumoral microbes between EOCRC and AOCRC, no consistent differences were observed. Interestingly, the most abundant microbes interacted with the immune systems differently between the EOCRC and AOCRC tumors, characterized by more and larger positive correlations in EOCRC. These data suggest that epigenetic modulation and accelerated aging may play a key role in the development of EOCRC.

Significance: We investigated whether environmentally driven factors contribute to EOCRC. We observed accelerated epigenetic aging in EOCRC and epigenetic changes associated with chronic inflammation. Tumor immune cell abundances correlated more strongly with microbes in EOCRC than in AOCRC. These data suggest a dysregulation of the immune response in EOCRC, driving chronic inflammation and tissue aging.

Purpose: Subasumstat (TAK-981) is a first-in-class inhibitor of SUMOylation that can engage innate and adaptive immune responses in tumors by enhancing type I IFN (IFNI) production. We conducted a phase I/II dose-escalation/-expansion study (NCT03648372) to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of subasumstat as a single agent in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies.

Patients and methods: Eligible patients received subasumstat intravenously at escalating doses twice weekly (days 1, 4, 8, and 11) or once weekly (days 1 and 8) in 21-day cycles until disease progression or unacceptable toxicity.

Results: A total of 109 patients were enrolled (solid tumors: n = 100; lymphomas, n = 9). In phase I, four patients reported dose-limiting toxicities of grade 3 alanine transaminase/aspartate transaminase elevation, pneumonitis, stomatitis, and cognitive disorder; 120 mg twice weekly was determined as the MTD. The most common adverse events were fatigue (47%), nausea (41%), diarrhea (36%), and pyrexia (36%). Pharmacodynamic analyses demonstrated target engagement and SUMOylation pathway inhibition, induction of an IFNI-regulated gene signature and cytokine production, and activation of innate and adaptive immune cells. Based on safety, pharmacokinetic, and pharmacodynamic findings, 90 mg twice weekly was proposed as the recommended phase II dosage. Overall, three and 26 patients achieved a partial response and stable disease, respectively.

Conclusions: Subasumstat had a manageable safety profile, with evidence of innate and adaptive immune response engagement in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Further studies are needed to determine the role of subasumstat in cancer treatment.

Significance: Identification of novel and effective therapies for patients who become refractory to standard anticancer treatments remains paramount. In this phase I/II study, subasumstat, a first-in-class SUMOylation inhibitor, had preliminary clinical activity and demonstrated target engagement, upregulation of IFN and plasma cytokines, and activation of innate and adaptive immune cells.

We examined the role of SLFN12, a member of the Schlafen (SLFN) family of interferon-regulated genes and proteins in leukemogenesis, and its potential as a therapeutic target in acute myeloid leukemia (AML). We explored the effects of velcrins, a class of small molecules able to modulate SLFN12 biological activity, on AML cells. Velcrin treatment of AML cells stabilized SLFN12 and promoted SLFN12 complex formation with phosphodiesterase 3A or phosphodiesterase 3B. Such effects were associated with growth-inhibitory and proapoptotic responses, as well as potent suppressive effects on leukemic cell growth. In addition, velcrin treatment suppressed clonogenic capacity of primitive leukemic progenitors and significantly extended survival in a mouse AML xenograft model. Taken together, these findings establish an important role of SLFN12 in leukemogenesis and raise the potential for the use of velcrins as a therapeutic strategy for AML.

Significance: Our studies identify SLFN12 as a potential target in AML with important clinical-translational implications.

Purpose: AXL, a receptor tyrosine kinase related to oncogenic processes, is aberrantly expressed in various cancers and associated with treatment resistance. Enapotamab vedotin (EnaV), a novel anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, demonstrated antitumor activity in preclinical models, including non-small cell lung cancer (NSCLC). This phase 1/2 study assessed the safety and preliminary efficacy of EnaV in solid tumors.

Patients and methods: This study comprised dose-escalation and dose-expansion phases; both phases investigated EnaV once every 3 weeks (Q3W) and EnaV on days 1, 8, and 15 of a 28-day cycle (3Q4W). Primary objectives determined the maximum tolerated dose (dose escalation) and safety (dose expansion). Pharmacokinetic profile, antitumor activity, and AXL expression were also assessed.

Results: During dose escalation, 32 patients received EnaV Q3W; 15 received EnaV 3Q4W. The maximum tolerated dose and recommended phase 2 dose were 2.2 mg/kg in Q3W and 1.0 mg/kg in 3Q4W schedules. In dose expansion, 189 patients received EnaV Q3W; 70 received EnaV 3Q4W. Common adverse events in dose expansion included fatigue, constipation, nausea, decreased appetite, and diarrhea. Overall response rates ranged from 4.5% to 12.5% with Q3W dose schedule and from 9.1% to 11.5% with 3Q4W dose schedule. Disease control rates for NSCLC cohorts were 40.9% to 50.0%. NSCLC subset analysis demonstrated correlation between radiomics signature and disease control. The relationship between clinical activity and AXL expression was not apparent.

Conclusions: EnaV had an acceptable safety profile; however, because the evaluation of antitumor activity did not show clinically meaningful responses, clinical development of EnaV was discontinued.

Significance: EnaV, an anti-AXL human IgG1 and monomethyl auristatin E antibody-drug conjugate, showed single-agent antitumor activity in preclinical models. This phase 1/2 study of EnaV demonstrated a manageable safety profile and antitumor activity in selected tumor types. Further studies exploring alternative targeting modalities, patient selection, and/or combinations are needed.

Tumor burden may have opposing influences on immunotherapy outcomes by enhancing neoantigen load or imposing barriers to immune responses. Whether tumor burden is a specific determinant of immunotherapy benefit or a general prognostic factor irrespective of drug mechanism remains ambiguous. We performed a post hoc individual patient-level data analysis of eight prospective trials, including patients with non-small cell lung cancer, hepatocellular carcinoma (HCC), bladder cancer, and renal cell carcinoma to determine the association between tumor burden and immunotherapy and conventional therapy efficacy. Objective response rates were higher among patients with low tumor burden treated with either atezolizumab or conventional therapies. Low tumor burden was also associated with improved progression-free survival in most cancer types and overall survival in all cancer types irrespective of treatment class. Tumor burden effects were dose-dependent across cancer types. An exception to this was in HCC, in which sorafenib treatment was uniquely associated with improved antitumor effects in high tumor burden cancers. Comparisons of outcomes within tumor burden strata showed that atezolizumab is superior to conventional therapy in improving overall survival but not progression-free survival in both high and low tumor burden patients compared with conventional therapies in non-small cell lung cancer, HCC, and bladder cancer. These findings demonstrate that tumor burden is a histology-agnostic and dose-related prognostic factor rather than an immunotherapy-specific predictive biomarker. Cross-treatment analyses suggest that surrogate endpoints may inadequately account for the detrimental impact of tumor burden, with implications for nonrandomized studies and early-phase trials, particularly in which variations in tumor burden exist in the underlying population.

Significance: Tumor burden is not a specific predictive marker of immunotherapy benefit but has substantial prognostic effects across cancer types and treatment classes. These results highlight the importance and broad applicability of tumor burden as stratification or selection markers in trial design, especially because surrogate endpoints do not wholly capture the detrimental effects of tumor burden on overall survival.

Purpose: In this preclinical human immune system patient-derived xenograft (HIS-PDX) model and phase II clinical trial, we assessed evorpacept (anti-CD47 engineered fusion protein with inactive Fc), cetuximab, and pembrolizumab (triple therapy) in microsatellite-stable (MSS) colorectal cancer.

Patients and methods: HIS BALB/c-Rag2nullIl2rγnullSirpαNOD mice with PDXs were treated with triple therapy or its components. Patients with refractory MSS colorectal cancer were treated with triple therapy in a safety run-in (stage 1) followed by expansion (stage 2, planned N = 42). The co-primary objectives were to determine the recommended dose of evorpacept and objective response rate (vs. historic control).

Results: In HIS-PDX mice, triple therapy decreased the growth of MSS colorectal cancer tumors and increased tumor-infiltrating CD8+ T cells. Sixteen patients were treated on the clinical trial across two evorpacept dose levels: N = 12 in stage 1 and N = 4 in stage 2. Trial enrollment was terminated early because of safety concerns (one treatment-related grade 5 event each of hemophagocytic lymphohistiocytosis and cytokine release syndrome). Otherwise, the adverse event profile was as expected. Among all patients, the objective response rate was 6.3%; formal hypothesis testing was not performed. The disease control rate was 12.5%, the median progression-free survival was 2.3 months, and the median overall survival was 10.9 months. Blood- and tumor-based clinical trial correlative analyses identified innate and adaptive immune system activation.

Conclusions: Whereas triple therapy demonstrated evidence of efficacy in refractory MSS colorectal cancer, safety concerns halted enrollment. Further investigation is necessary to determine the optimal use of CD47-targeted therapies in MSS colorectal cancer.

Significance: Evorpacept, cetuximab, and pembrolizumab demonstrated antitumor activity in a preclinical HIS-PDX model and clinical trial in refractory MSS colorectal cancer; however, immune-related adverse events prompted early termination of study enrollment. Evidence of innate and adaptive antitumor immune activation was identified. The role of SIRPα/CD47 blockade in the treatment of MSS colorectal cancer needs to be further elucidated in future trials.

Xevinapant is an orally bioavailable antagonist of select members of the inhibitor of apoptosis protein family. Despite promising phase II data, combining xevinapant with chemoradiotherapy (CRT) failed to improve outcomes in the phase III TrilynX trial when combined with CRT for locally advanced head and neck squamous cell cancer (SCCHN). In immunocompetent mouse models of SCCHN, xevinapant plus CRT maintained or improved locoregional control but in a CD8+ T cell-independent manner. On addition of xevinapant to CRT, the numbers of tumor-infiltrating cytotoxic CD8+ T cells and NK cells were reduced, with remaining CD8+ T cells characterized by PD-1hi CD38hi expression and Nr4a3 dynamics consistent with nonresponsiveness to antigenic restimulation. Furthermore, combination treatment significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute-phase proteins, and decreased levels of necroptosis mediator receptor-interacting protein kinase 3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumor-immune microenvironment, which may explain its lack of clinical benefit.

Significance: Despite hugely promising randomized phase II study data, combined CRT plus xevinapant failed in the TrilynX phase III clinical trial in locally advanced SCCHN. We show that adding xevinapant to chemoradiotherapy in vivo dysregulates antitumor lymphocyte function, acute-phase proteins, and cell death pathways, with net immunosuppressive effects on the tumor-immune microenvironment.