Search Results (149)

Despite remarkable progress in cancer immunotherapy, many agents that show efficacy in murine or in vitro models fail to translate clinically. Zebrafish (Danio rerio) have emerged as a powerful complementary model that addresses several limitations of traditional systems. Their optical transparency, genetic tractability, and conserved immune and oncogenic signaling pathways enable high-resolution, real-time imaging of tumor–immune interactions in vivo. Importantly, zebrafish offer a unique opportunity to study the core mechanisms of health and sickness, complementing other models and expanding our understanding of fundamental processes in vivo. This review provides an overview of zebrafish immune system development, highlighting tools for tracking innate and adaptive responses. We discuss their application in modeling immune evasion, checkpoint molecule expression, and tumor microenvironment dynamics using transgenic and xenograft approaches. Platforms for high-throughput drug screening and personalized therapy assessment using patient-derived xenografts (“zAvatars”) are evaluated, alongside limitations, such as temperature sensitivity, immature adaptive immunity in larvae, and interspecies differences in immune responses, tumor complexity, and pharmacokinetics. Emerging frontiers include humanized zebrafish, testing of next-generation immunotherapies, such as CAR T/CAR NK and novel checkpoint inhibitors (LAG-3, TIM-3, and TIGIT). We conclude by outlining the key challenges and future opportunities for integrating zebrafish into the immuno-oncology pipeline to accelerate clinical translation. Full article

This retrospective cohort study evaluated characteristics, treatment patterns, and clinical outcomes in adults with locally advanced/metastatic urothelial carcinoma (la/mUC) receiving first-line (1L) systemic treatment with or without avelumab 1L maintenance (1LM) between January 2020 and July 2023. The index date was the first date with a claim for 1L systemic therapy after a la/mUC diagnosis. Patients with continuous health plan enrollment for ≥6 months before and ≥1 month after the index date were identified from Carelon Research’s Healthcare Integrated Research Database. Of 2820 patients receiving 1L treatment, 37.0% received platinum-based chemotherapy (PBC); 39.0%, immuno-oncology (IO) monotherapy; and 24.0%, other therapies. Renal disease and other comorbidities influenced 1L regimen choice. Healthcare resource utilization (HCRU) and costs were reported for patients receiving second-line (2L) treatment. HCRU was high in 32.8% of patients (926 of 2820) who received 2L treatment. Median all-cause direct medical costs per patient per month were USD 15,859, USD 19,781, USD 11,346, and USD 9516 for 1L PBC, 1L PBC + avelumab 1LM, 1L IO monotherapy, and 1L other therapies, respectively. Most direct healthcare costs were attributed to all-cause outpatient visits. Full article

Immuno-oncology has rapidly evolved into a cornerstone of modern cancer therapy, offering promising avenues for durable responses and personalized treatment strategies. This narrative review provides a thorough overview of the mechanisms underlying tumor–immune system interactions and the therapeutic innovations emerging from this knowledge. Central to this discussion is the tumor microenvironment (TME), a complex ecosystem of immune and stromal cells that supports tumor growth and shapes therapeutic outcomes. Key cellular and molecular factors within the TME are examined, along with diverse immune escape strategies. We further analyze the landscape of immunotherapeutic approaches, including immune checkpoint inhibitors, cancer vaccines, adoptive cell therapies such as CAR-T cells, and cytokine-based interventions. This review also addresses the increasing importance of predictive biomarkers in immuno-oncology, particularly in patient stratification, monitoring resistance, and managing immunotherapy-related toxicity. Finally, we explore the emerging role of the microbiome as a modulator of immunotherapy efficacy, shedding light on host–microbe–immune interactions that may influence clinical outcomes. By integrating current biological insights with therapeutic innovation, this review outlines the challenges and opportunities ahead in immuno-oncology and emphasizes the need for translational research and cross-disciplinary collaboration to optimize cancer immunotherapy in the era of precision medicine. Full article

Background: Advanced adrenocortical carcinoma (ACC) remains a challenging malignancy with limited therapeutic options. Multi-kinase inhibitors (MKIs), either alone or in combination with immuno-oncology (IO) agents, have been investigated in recent single-arm clinical trials and retrospective series. Methods: We conducted a systematic review and single-arm meta-analysis of studies evaluating MKIs in advanced ACC. Objective response rate (ORR) and disease control rate (DCR) were pooled using random-effects models for single-arm proportions. Overall survival (OS) and progression-free survival (PFS) were summarized descriptively due to limited variance data. Subgroup analyses compared MKI monotherapy versus MKI + IO combinations, and meta-regression was performed to assess the impact of prior mitotane exposure. Results: Eleven studies (n = 208 patients) were included. The pooled ORR was 21% (95%CI, 11–36%), and the DCR was approximately 57%. Subgroup analysis revealed a higher ORR with MKI + IO regimens (26%; 95%CI, 12–48%) compared to MKI monotherapy (15%; 95%CI, 3–47%). Median OS ranged from 5.4 to 30.6 months, and PFS from 2.8 to 13.3 months, both favouring MKI + IO combinations. Meta-regression identified prior mitotane exposure as a significant predictor of ORR (p = 0.0279), particularly within the MKI + IO subgroup. Conclusions: MKI-based regimens, especially when combined with IO, demonstrate promising efficacy in advanced ACC, a disease with few established second-line options. While limited by the non-comparative design of available studies, these findings support further investigation in prospective, randomized clinical trials. Full article

Background: Pseudomonas aeruginosa (PSA) infections are associated with a high recurrence rate and high mortality in immuno-compromised patients. There are limited studies regarding pediatric hematopoietic cell transplantation recipients. Aim: The nationwide multicenter study was conducted to analyze the epidemiology of PSA infections in children treated with chemotherapy (PHO, pediatric hematology and oncology) or undergoing hematopoietic allogeneic or autologous cell transplantation (HCT) in the period 2014–2023. Methods: We retrospectively analyzed the clinical and microbiological data of children who underwent anticancer therapy or hematopoietic cell transplantation in 17 Polish PHO centers and six pediatric HCT centers. The data were collected in two-year intervals. Results: During the 10-year study period, a total of 1629 HCTs (both autologous and allogeneic) and 9614 children newly diagnosed with neoplasms were analyzed. The cumulative incidence of PSA infection was similar in both groups (6.71% in PHO vs. 6.32% in HCT, p = 0.624). The total number of PSA bloodstream infections was comparable in the PHO and HCT groups (31.9% vs. 26.2%; p = 0.223). In both analyzed groups, the antipseudomonal drugs of choice were as follows: meropenem, ceftazidime, and tazobactam/piperaciline in combination with other antibiotics. In the HCT group, high rates of meropenem (20.4%) and tazobactam/piperaciline (18.4%) non-susceptibility were observed. This led to colistin therapy in 5.3% of patients. There was no difference in the median antibiotic therapy time in both groups; however, the survival rates from PSA infection were significantly lower in the HCT group (89.3% vs. 96.0%, p = 0.004). Conclusions: Although the risk of infection and the occurrence of resistant bacterial strains in HCT patients were comparable with those in PHO patients, the outcome of PSA infections was better in the PHO setting. Full article

Background: In recent years, there has been an exponential growth in global anti-cancer drug research, prompting the necessity for comprehensive analyses of publication output and thematic shifts. Methods: This study utilized a comprehensive set of PubMed records from 1962 to 2024 and examined growth patterns, content classification, and co-occurrence of key pharmacological and molecular terms. Results: Our results highlight an exponential rise in publications, with an annual compound growth rate of over 14%, influenced by advancements in digital knowledge sharing and novel therapeutic breakthroughs. A pronounced surge occurred during the COVID-19 pandemic, suggesting a sustained shift in research dynamics. The content analyses revealed a strong emphasis on classical chemotherapeutic agents—often studied in combination with targeted therapies or immunotherapies—and a growing focus on immune checkpoint inhibitors and vaccine platforms. Furthermore, co-occurrence networks indicated robust links between chemotherapy and supportive care, as well as emerging synergies between immuno-oncology, precision medicine approaches. Conclusions: Our study suggests that while novel modalities are reshaping treatment paradigms, chemotherapy remains central, underscoring the value of integrative regimens. This trend toward personalized, combination-based strategies indicates a transformative era in oncology research, where multidimensional data assessment is instrumental in guiding future therapeutic innovations. Full article

Background/Objectives: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, life-threatening toxicity and the lack of precise representative immunocompetent research models. Considering its typically dense and immunosuppressive tumour microenvironment (TME) and early metastasis, pancreatic ductal adenocarcinoma (PDAC) was employed as a model to address the challenges that hinder CAR T cell therapies against solid tumours and to expand immunotherapeutic options for advanced disease. Methods: A novel murine A20FMDV2 (A20) CAR T cell targeting integrin αvβ6 (mA20CART) was developed, demonstrating efficient and specific on-target cytotoxicity. The mA20CART cell as a monotherapy for orthotopic pancreatic cancer in an immunocompetent model demonstrated modest efficacy. Therefore, a novel triple therapy regimen, combining mA20CART cells with oncolytic vaccinia virus encoding IL-21 and a TGF-β-blocking antibody was evaluated in vivo. Results: The triple therapy improved overall survival, improved the safety profile of the CAR T cell therapy, attenuated metastasis and enhanced T cell infiltration. Notably, the potency of mA20CART was dependent on IL-2 supplementation. Conclusions: This study presents an αvβ6-targeting murine CAR T cell, offering a novel approach to developing CAR T cell technologies for solid tumours and a potential adjuvant therapy for pancreatic cancer. Full article

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite the established benefits of hormone therapy, chemotherapy, and bone-targeting agents, mPCa commonly becomes treatment-resistant. Recent breakthroughs have highlighted the importance of identifying actionable genetic alterations, such as BRCA2 or ATM defects, that render tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Parallel efforts have refined imaging—particularly prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography—to detect and localize metastatic lesions with high sensitivity, thereby guiding patient selection for PSMA-targeted radioligand therapies. Multi-omics innovations, including liquid biopsy technologies, enable the real-time tracking of emergent AR splice variants or reversion mutations, supporting adaptive therapy paradigms. Nonetheless, the complexity of mPCa necessitates combination strategies, such as pairing AR inhibition with PI3K/AKT blockade or PARP inhibitors, to inhibit tumor plasticity. Immuno-oncological approaches remain challenging for unselected patients; however, subsets with mismatch repair deficiency or neuroendocrine phenotypes may benefit from immune checkpoint blockade or targeted epigenetic interventions. We present these pivotal advances, and discuss how biomarker-guided integrative treatments can improve mPCa management. Full article

The landscape of adult acute lymphoblastic leukemia (ALL) is dramatically changing. With very promising results seen with novel immunotherapeutics in the setting of relapsed and refractory disease, the prospect of using these agents in first-line therapy has prompted the development of multiple clinical trials addressing this question. This review seeks to outline and expand the current standard of care, as well as new advances, in the treatment of adult patients with ALL and address future areas of research. We expect the frontline integration of immuno-oncology agents such as bispecific T-cell engagers, antibody–drug conjugates, and chimeric antigen receptor (CAR) T cells may maintain or improve outcomes in adults while also minimizing toxicity. Treatment of ALL will continue to evolve as we focus on personalized, patient-centered approaches. Full article

Understanding the relationship between the Objective Response Rate (ORR) and survival outcomes, notably Progression-Free Survival (PFS) and Overall Survival (OS), is relevant for assessing the efficacy of regimens in oncology. We evaluate the relationship between ORR, PFS and OS in immuno-oncology (IO) trials. Data from 68 clinical trials submitted to the FDA were evaluated, examining immunotherapy regimens, notably immune checkpoint inhibitors such as anti-programmed death (ligand)-1 [anti-PD-(L)1], cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and combination therapies [e.g., IO + IO, anti-PD-L1 + chemotherapy, anti-PD-L1 + CTLA-4, anti-PD-L1 + TKI (tyrosine kinase inhibitors)]. Studies were included based on their reporting of ORR, PFS, and OS. Of the 68 clinical trials reviewed, 55 were included in the analysis. The correlation between ORR and PFS was moderate across most immunotherapy regimens, indicating that ORR can serve as a useful predictor of short-term disease control. However, the correlation between ORR and OS was weaker, especially in trials including combination therapies, indicating that ORR alone may not reliably predict long-term survival outcomes. ORR predicts PFS better in first-line treatment but declines in later lines and remains a weak OS predictor overall. Differing degrees of correlation between ORR and survival metrics, particularly across treatment lines and combinations, are observed. While ORR can serve as a surrogate marker for PFS in IO trials, its utility in predicting OS is restricted and the interpretation of the relationship between ORR and PFS or OS is a key limitation. Rather, a decline in PFS with increasing ORR may reflect trial differences rather than a direct relationship. Future analyses should adopt better methodologies to capture these dynamics and focus on improving surrogate endpoints for immunotherapy to improve clinical trial design and patient outcomes. Full article

Background: Immuno-oncology has transformed cancer treatment, with immune checkpoint inhibitors (ICIs) like pembrolizumab playing a key role. While highly effective, these therapies can also cause immune-related adverse events. This study examines the incidence and characteristics of hepatobiliary adverse events (AEs) linked to pembrolizumab, using data from the FDA Adverse Event Reporting System (FAERS). Objective: To investigate the rates of hepatobiliary AEs linked to pembrolizumab, providing insights into the risks of liver and biliary system damage in patients prescribed pembrolizumab. Methods: This study utilized the FAERS database via OpenVigil 2.1. Adverse events (AEs) related to pembrolizumab were identified and compared to those associated with other drugs. Reporting odds ratios (RORs) were calculated to assess the likelihood of hepatobiliary AEs in pembrolizumab-treated patients. Results: In total, 594 hepatic AEs and 181 biliary AEs were identified. Significant hepatic AEs included elevated ALT (ROR 3.00, 95% CI: 2.685–3.351), hepatotoxicity (ROR 6.436, 95% CI: 5.72–7.242), and hepatic cytolysis (ROR 15.721, 95% CI: 13.854–17.84). Immune-mediated hepatitis exhibited the highest ROR of 346.716 (95% CI: 303.568–395.997). For biliary AEs, cholangitis (ROR 19.597, 95% CI: 16.852–22.791) and sclerosing cholangitis (ROR 24.735, 95% CI: 19.888–30.763) were the most prominent. Conclusions: Pembrolizumab is associated with a significant risk of hepatobiliary adverse events, particularly immune-mediated hepatitis and cholangitis. The elevated RORs for these conditions highlight the importance of close monitoring and managing liver and biliary functions in patients undergoing pembrolizumab checkpoint blockade. These findings emphasize the need for personalized treatment strategies to mitigate risks and optimize outcomes in cancer immunotherapy, especially for those with preexisting hepatobiliary conditions. Full article

In 2024, the United States was projected to experience 2 million new cancer diagnoses and approximately 611,720 cancer-related deaths, reflecting a broader global trend in which cancer cases are anticipated to exceed 35 million by 2050. This increasing burden highlights ongoing challenges in cancer treatment despite significant advances that have reduced cancer mortality by 31% since 1991. Key obstacles include the disease’s inherent heterogeneity and complexity, such as treatment resistance, cancer stem cells, and the multifaceted tumor microenvironment (TME). The TME—comprising various tumor and immune cells, blood vessels, and biochemical factors—plays a crucial role in tumor growth and resistance to therapies. Recent innovations in cancer treatment, particularly in the field of immuno-oncology, have leveraged insights into TME interactions. An emerging example is the FDA-approved therapy using tumor-infiltrating lymphocytes (TILs), demonstrating the potential of cell-based approaches in solid tumors. However, TIL therapy is just one of many strategies being explored. This review provides a comprehensive overview of the emerging field of immuno-oncology, focusing on how novel therapies targeting or harnessing components of the TME could enhance treatment efficacy and address persistent challenges in cancer care. Full article

Olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC), and sinonasal neuroendocrine carcinoma (SNEC) are rare malignancies arising from the sinonasal tract with limited therapeutic options. The expression of the somatostatin receptor 2 gene (SSTR2), which is expressed in other neuroendocrine neoplasms and is therapeutically actionable, has been reported in these tumors. Here, we analyzed SSTR2 gene expression and its associations with genomic features, established biomarkers predicting of immune response, and the tumor immune microenvironment in a cohort of ONB, SNUC, and SNEC tumor samples (26, 13, and 8 samples, respectively) from a real-world database. SSTR2 gene expression was high in neural-type ONB and low in basal-type ONB and in most of the SNUC and SNEC cases; there was no difference in expression between primary and metastatic tumors. The T cell-inflamed (TCI) score analysis classified 38.5% of SNUC cases as T cell-inflamed compared to only 3.9% of ONB and 0% of SNEC cases; 26.9% of ONB cases were classified as intermediate TCI; and SNEC had the lowest relative immune cell infiltration by deconvolution. In high SSTR2-expressing ONB, there was a higher proportion of infiltrating of Natural Killer cells and dendritic cells by deconvolution. Additionally, high SSTR2-expressing ONB was enriched for proliferation pathways, including E2F and Myc targets and G2M checkpoints. In conclusion, our findings delineate significant differences between these three types of sinonasal malignancies that were examined. In ONB, relative to SNUC and SNEC, the SSTR2 expression profile, combined with its immune profiles, indicates potential novel therapeutic strategies and combinations for this unmet clinical need. Conversely, the inflammatory microenvironment of SNUC may be targetable using immuno-oncologic therapies. Full article

The addition of durvalumab consolidation to concurrent chemoradiation therapy (cCRT) has fundamentally changed the standard of care for patients with unresectable stage III non-small-cell lung cancer (NSCLC). Nevertheless, concerns related to esophagitis and pneumonitis potentially impact the broad application of all regimen components. A Canadian expert working group (EWG) was convened to provide guidance to healthcare professionals (HCPs) managing these adverse events (AEs) and to help optimize the patient experience. Integrating literature review findings and real-world clinical experience, the EWG used a modified Delphi process to develop 12 clinical questions, 30 recommendations, and a risk-stratification guide. The recommendations address risk factors associated with developing esophagitis and pneumonitis, approaches to risk mitigation and optimal management, and considerations related to initiation and re-initiation of durvalumab consolidation therapy. For both AEs, the EWG emphasized the importance of upfront risk assessment to inform the treatment approach, integration of preventative measures, and prompt initiation of suitable therapy in alignment with AE grade. The EWG also underscored the need for timely, effective communication between multidisciplinary team members and clarity on responsibilities. These recommendations will help support HCP decision-making related to esophagitis and pneumonitis arising from cCRT ± durvalumab and improve outcomes for patients with unresectable stage III NSCLC. Full article

Background/Objectives: Immuno-oncology plus tyrosine kinase inhibitor (IO+TKI) combination therapy is an essential first-line therapy for advanced renal cell carcinoma (RCC). However, reports of its efficacy and safety as late-line therapy are lacking. This study aimed to examine the efficacy and safety of IO+TKI combination therapy as a late-line therapy for patients with RCC. Methods: We retrospectively examined 17 patients with RCC who received IO+TKI combination therapy as a second-line therapy or beyond (pembrolizumab plus axitinib, n = 10; avelumab plus axitinib, n = 5; nivolumab plus cabozantinib, n = 2). Results: The overall response and disease control rates of IO+TKI combination therapy were 29.4% and 64.7%, respectively. The median overall survival was not attained. Progression-free survival was 552 days, and 94.1% of patients (n = 16) experienced adverse effects (AEs) of any grade; moreover, 41.2% of patients (n = 7) experienced grade ≥ 3 immuno-related AEs. Conclusions: IO+TKI combination therapy may be a late-line therapy option for RCC. Full article