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Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms. Synopsis: Circadian rhythms of macrophages are altered by conditions associated with the tumor microenvironment, including acidic pH. This may be responsible for the heterogeneity in circadian clock gene expression within the tumor-associated macrophage population. Circadian rhythms of macrophages are altered by polarizing stimuli, acidic pH, and lactate. There is circadian disorder in the tumor-associated macrophage population. Heterogeneity of circadian rhythms and circadian gene expression within a population may underlie circadian disorder. The circadian clock in tumor-associated macrophages plays a tumor-suppressive role in pancreatic cancer. Circadian rhythms of macrophages are altered by conditions associated with the tumor microenvironment, including acidic pH. This may be responsible for the heterogeneity in circadian clock gene expression within the tumor-associated macrophage population. [ABSTRACT FROM AUTHOR]

Cancer cells effectively evade immune surveillance, not only through the well-known PD-1/PD-L1 pathway but also via alternative mechanisms that impair patient response to immune checkpoint inhibitors. We present a novel co-culture model that pairs a reporter T-cell line with different melanoma cell lines that have varying immune evasion characteristics. We developed a scalable high-throughput lentiviral arrayed CRISPR interference (CRISPRi) screening protocol to conduct gene perturbations in both T-cells and melanoma cells, enabling the identification of genes that modulate tumor immune evasion. Our study functionally validates the co-culture model system and demonstrates the performance of the CRISPRi-screening protocol by modulating the expression of known regulators of tumor immunity. Together, our work provides a robust framework for future research aimed at systematically exploring mechanisms of tumor immune evasion. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model‐based clinical pharmacology profiling and benefit–risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. Methods: Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure‐response (E‐R) analyses included data from 756 patients from CheckMate 577. E‐R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease‐free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune‐mediated adverse events (Gr2 + IMAEs) for safety. Results: Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E‐R relationships within the exposure range produced by the studied regimen. Model‐predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks followed by 480 mg Q4W up to 1 year. Conclusions: The analyses demonstrated a flat E‐R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC. [ABSTRACT FROM AUTHOR]

Originally devised for cancer control, mRNA vaccines have risen to the forefront of medicine as effective instruments for control of infectious disease, notably their pivotal role in combating the COVID-19 pandemic. This review focuses on fundamental aspects of the development of mRNA vaccines, e.g., tumor antigens, vector design, and precise delivery methodologies, - highlighting key technological advances. The recent, promising success of personalized mRNA vaccines against pancreatic cancer and melanoma illustrates the potential value for other intractable, immunologically resistant, solid tumors, such as glioblastoma, as well as the potential for synergies with a combinatorial, immunotherapeutic approach. The impact and progress in human cancer, including pancreatic cancer, head and neck cancer, bladder cancer are reviewed, as are lessons learned from first-in-human CAR-T cell, DNA and dendritic cell vaccines targeting glioblastoma. Going forward, a roadmap is provided for the transformative potential of mRNA vaccines to advance cancer immunotherapy, with a particular focus on the opportunities and challenges of glioblastoma. The current landscape of glioblastoma immunotherapy and gene therapy is reviewed with an eye to combinatorial approaches harnessing RNA science. Preliminary preclinical and clinical data supports the concept that mRNA vaccines could be a viable, novel approach to prolong survival in patients with glioblastoma. [ABSTRACT FROM AUTHOR]

Transforming growth factor β (TGFβ) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFβ/VEGF is more effective than targeting TGFβ alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFβ and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy. [ABSTRACT FROM AUTHOR]

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.

Immunotherapy has proved to be a breakthrough in cancer treatment. So far, a bulk of the approved/late-stage cancer immunotherapy are antibody-based. Although these antibody-based drugs have demonstrated great promise, a majority of them are limited due to their access to extracellular targets, lack of oral bioavailability, tumor microenvironment penetration, induction of antibody dependent cytotoxicity etc. In recent times, there has been an increased research focus on the development of small molecule immunomodulators since they have the potential to overcome the aforementioned limitations posed by antibodies. Furthermore, while most biologics based therapeutics that are in clinical use are limited to modulating the adaptive immune system, very few clinically approved therapeutic modalities exist that modulate the innate immune system. The innate immune system, which is the body's first line of defense, has the ability to turn cold tumors hot and synergize strongly with existing adaptive immune modulators. In preclinical studies, small molecule innate immune modulators have demonstrated synergistic efficacy as combination modalities with current standard-of-care immune checkpoint antibodies. In this review, we highlight the recent advances made by small molecule innate immunomodulators in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA‐approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)‐based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature‐sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti‐CD47 monoclonal antibodies, when incorporated into subsurface‐injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high‐grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site‐specific modification with hydrolysable "azidoester" adapters, allowing for user‐defined release profiles from the hydrogel. Hydrogel‐generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8+ T‐cells and the attenuation of tumor growth in a "cold" syngeneic melanoma model. This study highlights a highly customizable, hydrogel‐based delivery system for local protein therapeutic administration to meet diverse clinical needs. [ABSTRACT FROM AUTHOR]

This study aimed to identify the 25 most prevalent adverse events (AEs) associated with FDA-approved immune checkpoint inhibitors (ICIs)—specifically, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors—using data from the FDA Adverse Events Reporting System (FAERS), a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events. For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab. PD-L1 inhibitors also frequently caused pyrexia, diarrhea, and fatigue, with interstitial lung disease and hypothyroidism showing a class effect, and drug-specific AEs such as hepatotoxicity and chills. CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia. Rare but significant AEs across all inhibitors included myocarditis and myasthenia gravis. This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer. [ABSTRACT FROM AUTHOR]

The advancement of immuno-oncology has brought about a significant shift in cancer treatment methods, with antibody-based immune checkpoint inhibitors like atezolizumab leading the way in this regard. However, the use of this checkpoint blockade can result in immune-related adverse events due to increased T-cell activity. The full spectrum of these events is not yet completely understood. In this study, the United States FDA Adverse Event Reporting System (FAERS) was utilized to investigate immune-related adverse events linked with the use of atezolizumab. The study identified forty-nine immune-related adverse events that affected multiple organ systems, including cardiovascular, respiratory, hematologic, hepatic, renal, gastrointestinal, neurologic, musculoskeletal, dermatologic, endocrine, and systemic disorders. The strongest signals for relative risk occurred for immune-mediated encephalitis (RR = 93.443), autoimmune myocarditis (RR = 56.641), immune-mediated hepatitis (RR = 49.062), immune-mediated nephritis (RR = 40.947), and autoimmune arthritis (RR = 39.382). Despite the morbidity associated with these adverse events, emerging evidence suggests potential associations with improved survival outcomes. Overall, this report sheds light on the widespread immune-related adverse events that cause significant morbidity and mortality in patients with cancer being treated with atezolizumab and brings attention to them for the clinicians treating these patients. [ABSTRACT FROM AUTHOR]

Advancements in imaging technologies have revolutionized our ability to deeply profile pathological tissue architectures, generating large volumes of imaging data with unparalleled spatial resolution. This type of data collection, namely, spatial proteomics, offers invaluable insights into various human diseases. Simultaneously, computational algorithms have evolved to manage the increasing dimensionality of spatial proteomics inherent in this progress. Numerous imaging-based computational frameworks, such as computational pathology, have been proposed for research and clinical applications. However, the development of these fields demands diverse domain expertise, creating barriers to their integration and further application. This review seeks to bridge this divide by presenting a comprehensive guideline. We consolidate prevailing computational methods and outline a roadmap from image processing to data-driven, statistics-informed biomarker discovery. Additionally, we explore future perspectives as the field moves toward interfacing with other quantitative domains, holding significant promise for precision care in immuno-oncology. [ABSTRACT FROM AUTHOR]

Simple Summary: Mammary carcinomas have been diagnosed with increasing frequency in pet rabbits. Prognostic biomarkers are limited, and the only available treatment is surgical excision. Additional treatment options are needed, e.g., for animals in which metastases to internal organs preclude complete tumor removal. Human breast cancer may express the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1), that represents a prognostic biomarker and a possible therapeutic target. Since previous studies revealed similarities between human breast cancer and pet rabbit mammary carcinomas, this study investigated IDO1 immunostaining in 96 mammary carcinomas of 96 pet rabbits with an average age of 5.5 years. All rabbits with reported sex were female. Variable percentages of IDO1-positive tumor cells were detected in 90 (94%) carcinomas. Furthermore, IDO1 immunostaining was observed in the secretory epithelial cells of the adjacent non-neoplastic mammary tissue. This study provides further information on the molecular features of mammary carcinomas in rabbits. It also shows similarities in IDO1 expression between rabbit mammary carcinomas and human breast cancer. These findings can have a mutual benefit. They could lead the development of novel treatment options for rabbits with mammary carcinomas. In addition, they further support the value of rabbits with mammary carcinomas for breast cancer research. For mammary carcinomas in pet rabbits, prognostic biomarkers are poorly defined, and treatment is limited to surgical excision. Additional treatment options are needed for rabbit patients for which surgery is not a suitable option. In human breast cancer, the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) represents a prognostic biomarker and possible therapeutic target. This retrospective immunohistochemical study examined IDO1 in 96 pet rabbit mammary carcinomas with known mitotic count, hormone receptor status, and percentage of stromal tumor infiltrating lymphocytes (TILs). Tumors were obtained from 96 pet rabbits with an average of 5.5 years. All rabbits with reported sex (n = 88) were female or female-spayed. Of the carcinomas, 94% expressed IDO1, and 86% had sparse TILs consistent with cold tumors. Statistically significant correlations existed between a higher percentage of IDO1-positive tumor cells, lower mitotic counts, and increased estrogen receptor expression. The threshold for significance was IDO1 staining in >10% of tumor cells. These results lead to the assumption that IDO1 expression contributes to tumorigenesis and may represent a prognostic biomarker and possible therapeutic target also in pet rabbit mammary carcinomas. They also support the value of rabbits for breast cancer research. [ABSTRACT FROM AUTHOR]

ABSTRACTDespite the large number of existing bispecific antibody (bsAb) formats, the generation of novel bsAbs is still associated with development and bioprocessing challenges. Here, we present RUBY, a novel bispecific antibody format that allows rapid generation of bsAbs that fulfill key development criteria. The RUBYTM format has a 2 + 2 geometry, where two Fab fragments are linked via their light chains to the C-termini of an IgG, and carries mutations for optimal chain pairing. The unique design enables generation of bsAbs with mAb-like attributes. Our data demonstrate that RUBY bsAbs are compatible with small-scale production systems for screening purposes and can be produced at high yields (>3 g/L) from stable cell lines. The bsAbs produced are shown to, in general, contain low amounts of aggregates and display favorable solubility and stress endurance profiles. Further, compatibility with various IgG isotypes is shown and tailored Fc gamma receptor binding confirmed. Also, retained interaction with FcRn is demonstrated to translate into a pharmacokinetic profile in mice and non-human primates that is comparable to mAb controls. Functionality of conditional active RUBY bsAbs is confirmed in vitro. Anti-tumor effects in vivo have previously been demonstrated, and shown to be superior to a comparable mAb, and here it is further shown that RUBY bsAbs penetrate and localize to tumor tissue in vivo. In all, the RUBY format has attractive mAb-like attributes and offers the possibility to mitigate many of the development challenges linked to other bsAb formats, facilitating both high functionality and developability.

ABSTRACTCombinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models. Investigation into the mechanism of action revealed that CTX-8371 co-engagement of PD-1 and PD-L1 induced the proteolytic cleavage and loss of cell surface PD-1, which is a novel and non-redundant mechanism that adds to the PD-1/PD-L1 signaling axis blockade. The combination of CTX-8371 and an agonistic anti-CD137 antibody further increased the anti-tumor efficacy with long-lasting curative therapeutic effect. In summary, CTX-8371 is a novel checkpoint inhibitor that might provide greater clinical benefit compared to current anti-PD-1 and PD-L1 antibodies, especially when combined with agents with orthogonal mechanisms of action, such as agonistic anti-CD137 antibodies.

Cancer cells effectively evade immune surveillance, not only through the well-known PD-1/PD-L1 pathway but also via alternative mechanisms that impair patient response to immune checkpoint inhibitors. We present a novel co-culture model that pairs a reporter T-cell line with different melanoma cell lines that have varying immune evasion characteristics. We developed a scalable high-throughput lentiviral arrayed CRISPR interference (CRISPRi) screening protocol to conduct gene perturbations in both T-cells and melanoma cells, enabling the identification of genes that modulate tumor immune evasion. Our study functionally validates the co-culture model system and demonstrates the performance of the CRISPRi-screening protocol by modulating the expression of known regulators of tumor immunity. Together, our work provides a robust framework for future research aimed at systematically exploring mechanisms of tumor immune evasion.

Background: Artificial intelligence in medicine is a field that is rapidly evolving. Machine learning and deep learning are used to improve disease identification and diagnosis, personalize disease treatment, analyze medical images, evaluate clinical trials, and speed drug development. Methods: First, relevant aspects of AI are revised in a comprehensive manner, including the classification of hematopoietic neoplasms, types of AI, applications in medicine and hematological neoplasia, generative pre-trained transformers (GPTs), and the architecture and interpretation of feedforward neural net-works (multilayer perceptron). Second, a series of 233 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-CHOP from the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) was analyzed. Results: Using conventional statistics, the high expression of MYC and BCL2 was associated with poor survival, but high BCL6 was associated with a favorable overall survival of the patients. Then, a neural network predicted MYC, BCL2, and BCL6 with high accuracy using a pan-cancer panel of 758 genes of immuno-oncology and translational research that includes clinically relevant actionable genes and pathways. A comparable analysis was performed using gene set enrichment analysis (GSEA). Conclusions: The mathematical way in which neural networks reach conclusions has been considered a black box, but a careful understanding and evaluation of the architectural design allows us to interpret the results logically. In diffuse large B-cell lymphoma, neural networks are a plausible data analysis approach.

This article provides an overview of recent advancements in veterinary cancer immunology, focusing on how the immune system interacts with animal cancer cells. It discusses novel immunotherapeutic approaches, such as cancer vaccines and monoclonal antibodies, that have shown promise in treating canine cancers. Comparative oncology, which examines cancer across different species, is highlighted as a valuable approach for identifying common mechanisms and potential treatments. The article also mentions the potential of chimeric antigen receptors (CARs) in veterinary immuno-oncology, although their use in veterinary medicine is still under development. The document is a collection of research articles covering various topics related to cancer treatment in animals, providing new insights and potential therapeutic strategies for veterinary oncology. Ongoing research in this field is crucial for improving cancer management and treatment options for dogs. [Extracted from the 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. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent lymphomas. DLBCL is phenotypically, genetically, and clinically heterogeneous. Aim: We aim to identify new prognostic markers. Methods: We performed anomaly detection analysis, other artificial intelligence techniques, and conventional statistics using gene expression data of 414 patients from the Lymphoma/Leukemia Molecular Profiling Project (GSE10846), and immunohistochemistry in 10 reactive tonsils and 30 DLBCL cases. Results: First, an unsupervised anomaly detection analysis pinpointed outliers (anomalies) in the series, and 12 genes were identified: DPM2, TRAPPC1, HYAL2, TRIM35, NUDT18, TMEM219, CHCHD10, IGFBP7, LAMTOR2, ZNF688, UBL7, and RELB, which belonged to the apoptosis, MAPK, MTOR, and NF-kB pathways. Second, these 12 genes were used to predict overall survival using machine learning, artificial neural networks, and conventional statistics. In a multivariate Cox regression analysis, high expressions of HYAL2 and UBL7 were correlated with poor overall survival, whereas TRAPPC1, IGFBP7, and RELB were correlated with good overall survival (p < 0.01). As a single marker and only in RCHOP-like treated cases, the prognostic value of RELB was confirmed using GSEA analysis and Kaplan–Meier with log-rank test and validated in the TCGA and GSE57611 datasets. Anomaly detection analysis was successfully tested in the GSE31312 and GSE117556 datasets. Using immunohistochemistry, RELB was positive in B-lymphocytes and macrophage/dendritic-like cells, and correlation with HLA DP-DR, SIRPA, CD85A (LILRB3), PD-L1, MARCO, and TOX was explored. Conclusions: Anomaly detection and other bioinformatic techniques successfully predicted the prognosis of DLBCL, and high RELB was associated with a favorable prognosis. [ABSTRACT FROM AUTHOR]

CAR-T cell therapy is at the forefront of next-generation multiple myeloma (MM) management, with two B-cell maturation antigen (BCMA)-targeted products recently approved. However, these products are incapable of breaking the infamous pattern of patient relapse. Two contributing factors are the use of BCMA as a target molecule and the artificial scFv format that is responsible for antigen recognition. Tackling both points of improvement in the present study, we used previously characterized VHHs that specifically target the idiotype of murine 5T33 MM cells. This idiotype represents one of the most promising yet challenging MM target antigens, as it is highly cancer- but also patient-specific. These VHHs were incorporated into VHH-based CAR modules, the format of which has advantages compared to scFv-based CARs. This allowed a side-by-side comparison of the influence of the targeting domain on T cell activation. Surprisingly, VHHs previously selected as lead compounds for targeted MM radiotherapy are not the best (CAR-) T cell activators. Moreover, the majority of the evaluated VHHs are incapable of inducing any T cell activation. As such, we highlight the importance of specific VHH selection, depending on its intended use, and thereby raise an important shortcoming of current common CAR development approaches. [ABSTRACT FROM AUTHOR]

Background The capability of large language models (LLMs) to understand and generate human-readable text has prompted the investigation of their potential as educational and management tools for patients with cancer and healthcare providers. Materials and Methods We conducted a cross-sectional study aimed at evaluating the ability of ChatGPT-4, ChatGPT-3.5, and Google Bard to answer questions related to 4 domains of immuno-oncology (Mechanisms, Indications, Toxicities, and Prognosis). We generated 60 open-ended questions (15 for each section). Questions were manually submitted to LLMs, and responses were collected on June 30, 2023. Two reviewers evaluated the answers independently. Results ChatGPT-4 and ChatGPT-3.5 answered all questions, whereas Google Bard answered only 53.3% (P  < .0001). The number of questions with reproducible answers was higher for ChatGPT-4 (95%) and ChatGPT3.5 (88.3%) than for Google Bard (50%) (P  < .0001). In terms of accuracy, the number of answers deemed fully correct were 75.4%, 58.5%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (P  = .03). Furthermore, the number of responses deemed highly relevant was 71.9%, 77.4%, and 43.8% for ChatGPT-4, ChatGPT-3.5, and Google Bard, respectively (P  = .04). Regarding readability, the number of highly readable was higher for ChatGPT-4 and ChatGPT-3.5 (98.1%) and (100%) compared to Google Bard (87.5%) (P  = .02). Conclusion ChatGPT-4 and ChatGPT-3.5 are potentially powerful tools in immuno-oncology, whereas Google Bard demonstrated relatively poorer performance. However, the risk of inaccuracy or incompleteness in the responses was evident in all 3 LLMs, highlighting the importance of expert-driven verification of the outputs returned by these technologies. [ABSTRACT FROM AUTHOR]

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumorspecific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient's clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-g following oncovirotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to oncovirotherapy at the early stage of the preclinical phases. [ABSTRACT FROM AUTHOR]

Flow cytometry is a mainstay technique in cell biology research, where it is used for phenotypic analysis of mixed cell populations. Quantitative approaches have unlocked a deeper value of flow cytometry in drug discovery research. As the number of drug modalities and druggable mechanisms increases, there is an increasing drive to identify meaningful biomarkers, evaluate the relationship between pharmacokinetics and pharmacodynamics (PK/PD), and translate these insights into the evaluation of patients enrolled in early clinical trials. In this review, we discuss emerging roles for flow cytometry in the translational setting that supports the transition and evaluation of novel compounds in the clinic. [ABSTRACT FROM AUTHOR]

Abstract Hydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA‐approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)‐based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature‐sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti‐CD47 monoclonal antibodies, when incorporated into subsurface‐injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high‐grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site‐specific modification with hydrolysable “azidoester” adapters, allowing for user‐defined release profiles from the hydrogel. Hydrogel‐generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8+ T‐cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel‐based delivery system for local protein therapeutic administration to meet diverse clinical needs.

Originally devised for cancer control, mRNA vaccines have risen to the forefront of medicine as effective instruments for control of infectious disease, notably their pivotal role in combating the COVID-19 pandemic. This review focuses on fundamental aspects of the development of mRNA vaccines, e.g., tumor antigens, vector design, and precise delivery methodologies, – highlighting key technological advances. The recent, promising success of personalized mRNA vaccines against pancreatic cancer and melanoma illustrates the potential value for other intractable, immunologically resistant, solid tumors, such as glioblastoma, as well as the potential for synergies with a combinatorial, immunotherapeutic approach. The impact and progress in human cancer, including pancreatic cancer, head and neck cancer, bladder cancer are reviewed, as are lessons learned from first-in-human CAR-T cell, DNA and dendritic cell vaccines targeting glioblastoma. Going forward, a roadmap is provided for the transformative potential of mRNA vaccines to advance cancer immunotherapy, with a particular focus on the opportunities and challenges of glioblastoma. The current landscape of glioblastoma immunotherapy and gene therapy is reviewed with an eye to combinatorial approaches harnessing RNA science. Preliminary preclinical and clinical data supports the concept that mRNA vaccines could be a viable, novel approach to prolong survival in patients with glioblastoma.

Background: Spatial biology is an emerging concept to interrogate tumor heterogeneity. The NanoString GeoMx® Digital Spatial Profiling (DSP) platform has become increasingly available. It combines high-plex analysis of protein or messenger RNA expression using barcoded antibodies or oligonucleotide probes with investigator-driven selection of regions of interest. Cell populations, e.g. immune cells, can be selectively analyzed via segmentation. A key advantage is the use of archived formalin-fixed, paraffin-embedded tissue, however, begging the question whether and to what extent tissue fixation and storage time affect the results. Materials and methods: Antibody binding density (ABD), i.e. the number of barcodes/μm2, is a key quality control measure for DSP spatial proteomics. To assess whether regional differences in tissue fixation have an influence on ABD, we compared 652 regions of interest selected from tumor center and periphery of 49 prostate cancer and 25 renal cell carcinoma (RCC) specimens. Moreover, the effect of tissue storage time on ABD was examined. Finally, we tested whether regional differences have an influence on ABD of segmented CD45+ or CD8+ cells. Results: No significant differences in ABD between tumor center and periphery were found in prostate cancer or RCC. However, ABD was significantly higher in recent specimens (≤5 years) when compared with those that were older (>5 years; P = 0.027). There was a trend towards higher ABD in the tumor periphery of RCC specimens after segmentation for immune cells, albeit without reaching statistical significance. Conclusions: The NanoString GeoMx® DSP platform delivers robust data to interrogate tumor heterogeneity, but tissue storage time should be considered when interpreting the results.

Immunotherapy has proved to be a breakthrough in cancer treatment. So far, a bulk of the approved/late-stage cancer immunotherapy are antibody-based. Although these antibody-based drugs have demonstrated great promise, a majority of them are limited due to their access to extracellular targets, lack of oral bioavailability, tumor microenvironment penetration, induction of antibody dependent cytotoxicity etc. In recent times, there has been an increased research focus on the development of small molecule immunomodulators since they have the potential to overcome the aforementioned limitations posed by antibodies. Furthermore, while most biologics based therapeutics that are in clinical use are limited to modulating the adaptive immune system, very few clinically approved therapeutic modalities exist that modulate the innate immune system. The innate immune system, which is the body’s first line of defense, has the ability to turn cold tumors hot and synergize strongly with existing adaptive immune modulators. In preclinical studies, small molecule innate immune modulators have demonstrated synergistic efficacy as combination modalities with current standard-of-care immune checkpoint antibodies. In this review, we highlight the recent advances made by small molecule innate immunomodulators in cancer immunotherapy.

Head and neck squamous cell cancers (HNSCCs) represent a diverse group of tumors emerging within different mucosal surfaces of the oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx. HNSCCs share common clinical risk factors and genomic features, including smoking, alcohol, age, male sex, aneuploidy, and TP53 mutations. Viral initiating and contributing events are increasingly recognized in HNSCCs. While both Epstein-Barr Virus (EBV) and human papilloma virus (HPV) are observed, EBV is more frequently associated with nasopharyngeal cancers whereas HPV is associated with oropharyngeal cancers. HNSCCs are associated with high tumor mutational burden and loss of tumor suppressor gene function, especially in TP53 and X-linked genes. Multiple lines of evidence suggest that HNSCCs are subject to immunologic surveillance and immune-induced evolutionary pressure that correlate with negative clinical outcomes. This review will discuss genomic mechanisms related to immune-mediated pressures and propose prognostic and therapeutic implications of detectable immune escape mechanisms that drive tumorigenesis and disease progression.

Cervical cancer is the most common malignant tumor of the female genital organs. In general, the prognosis in patients with advanced cervical cancer is unfavorable. The option of choice for stage IV of the disease and relapses is systemic platinum-containing chemotherapy. Its effectiveness is about 20-26%, life expectancy is 12 to 13 months. Undoubtedly, the search and development of new methods of treating this disease is an extremely urgent task. Immuno-oncology has emerged as a potential new strategy to improve the treatment outcomes of patients with malignant neoplasms. Much attention in research is focused on the opportunity of using interleukin-2, tumor necrosis factor (TNF) and interferon-gamma (IFNγ) for tumor immunotherapy, since these cytokines play a special role in antitumor protection. Due to the active search for new hybrid molecules based on TNFα, some domestically developed recombinant antitumor drugs are implicated into modern practice of clinical oncologists, in particular, “Refnot” (TNFα-thymosin-α1) and “Ingaron” (IFNγ preparation). We analyzed the result of combined treatment (standard polychemotherapy at the 1st line augmented with cytokinotherapy including Refnot + Ingaron therapy) in one patient with recurrent cervical cancer. According to the control examination, upon completion of the polychemotherapy course, a complete tumor response was registered according to the Recist 1.1 criteria. The patient continued to receive cytokines as supporting therapy. Currently, according to control quarterly examinations, a complete regression of recurrent tumor persists from the end of polychemotherapy to 28 months of observation. One should note that when monitoring the state of the immune system during therapy with Refnot and Ingaron, we noted an increase in absolute and relative numbers of T cells to normal levels along with higher cytotoxic and antitumor potential of NK cells without increasing their number. The patient well tolerates the therapy, improved quality of life is documented, and there are no clinically significant side effects. Hence, the therapy with “Refnot” (TNFα-thymosin-α1) and “Ingaron” (IFNγ) in this clinical case proved to be a safe method of maintenance therapy with a positive therapeutic effect thus allowing effective control of recurrent cervical cancer for more than 2 years, as well as significantly improve quality of life of the patient. This type of therapy may be recommended for usage in clinical oncology.

MICA and MICB are Class I MHC-related glycoproteins that are upregulated on the surface of cells in response to stress, for instance due to infection or malignant transformation. MICA/B are ligands for NKG2D, an activating receptor on NK cells, CD8+ T cells, and γδ T cells. Upon engagement of MICA/B with NKG2D, these cytotoxic cells eradicate MICA/B-positive targets. MICA is frequently overexpressed on the surface of cancer cells of epithelial and hematopoietic origin. Here, we created nanobodies that recognize MICA. Nanobodies, or VHHs, are the recombinantly expressed variable regions of camelid heavy chain-only immunoglobulins. They retain the capacity of antigen recognition but are characterized by their stability and ease of production. The nanobodies described here detect surface-disposed MICA on cancer cells in vitro by flow cytometry and can be used therapeutically as nanobody-drug conjugates when fused to the Maytansine derivative DM1. The nanobody-DM1 conjugate selectively kills MICA positive tumor cells in vitro. [ABSTRACT FROM AUTHOR]

Evaluating the ability of cytotoxic T lymphocytes (CTLs) to eliminate tumor cells is crucial, for instance, to predict the efficiency of cell therapy in personalized medicine. However, the destruction of a tumor by CTLs involves CTL migration in the extra-tumoral environment, accumulation on the tumor, antigen recognition, and cooperation in killing the cancer cells. Therefore, identifying the limiting steps in this complex process requires spatio-temporal measurements of different cellular events over long periods. Here, we use a cancer-on-a-chip platform to evaluate the impact of adenomatous polyposis coli (APC) mutation on CTL migration and cytotoxicity against 3D tumor spheroids. The APC mutated CTLs are found to have a reduced ability to destroy tumor spheroids compared with control cells, even though APC mutants migrate in the extra-tumoral space and accumulate on the spheroids as efficiently as control cells. Once in contact with the tumor however, mutated CTLs display reduced engagement with the cancer cells, as measured by a metric that distinguishes different modes of CTL migration. Realigning the CTL trajectories around localized killing cascades reveals that all CTLs transition to high engagement in the 2 h preceding the cascades, which confirms that the low engagement is the cause of reduced cytotoxicity. Beyond the study of APC mutations, this platform offers a robust way to compare cytotoxic cell efficiency of even closely related cell types, by relying on a multiscale cytometry approach to disentangle complex interactions and to identify the steps that limit the tumor destruction. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer comes in different types, making it hard to treat effectively. One particularly aggressive type, called triple-negative breast cancer, is tough to target with current treatments. Scientists use advanced methods like 3D cultures, which mimic human tissue better than traditional lab methods, to study breast cancer. These 3D cultures help understand how tiny communication structures called exosomes affect cancer growth, spread, and response to therapy. Exosomes are like messengers between cells and can influence cancer's behavior and response to therapy. In this the review, we seek to discuss the effect of 3D cultures on the function of exosomes, which we believe could play an important role in improving exosome-mediated cancer treatment by delivering drugs more precisely and studying how cancer becomes resistant to treatment. This research could lead to better therapies and help us understand how cancer spreads and resists treatment. Breast cancer, a leading cause of cancer-related deaths globally, exhibits distinct subtypes with varying pathological, genetic, and clinical characteristics. Despite advancements in breast cancer treatments, its histological and molecular heterogeneity pose a significant clinical challenge. Triple-negative breast cancer (TNBC), a highly aggressive subtype lacking targeted therapeutics, adds to the complexity of breast cancer treatment. Recent years have witnessed the development of advanced 3D culture technologies, such as organoids and spheroids, providing more representative models of healthy human tissue and various malignancies. These structures, resembling organs in structure and function, are generated from stem cells or organ-specific progenitor cells via self-organizing processes. Notably, 3D culture systems bridge the gap between 2D cultures and in vivo studies, offering a more accurate representation of in vivo tumors' characteristics. Exosomes, small nano-sized molecules secreted by breast cancer and stromal/cancer-associated fibroblast cells, have garnered significant attention. They play a crucial role in cell-to-cell communication, influencing tumor progression, invasion, and metastasis. The 3D culture environment enhances exosome efficiency compared to traditional 2D cultures, impacting the transfer of specific cargoes and therapeutic effects. Furthermore, 3D exosomes have shown promise in improving therapeutic outcomes, acting as potential vehicles for cancer treatment administration. Studies have demonstrated their role in pro-angiogenesis and their innate therapeutic potential in mimicking cellular therapies without side effects. The 3D exosome model holds potential for addressing challenges associated with drug resistance, offering insights into the mechanisms underlying multidrug resistance and serving as a platform for drug screening. This review seeks to emphasize the crucial role of 3D culture systems in studying breast cancer, especially in understanding the involvement of exosomes in cancer pathology. [ABSTRACT FROM AUTHOR]

Introduction: Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy. Methods and results: In the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds' antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells. Discussion: NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer. [ABSTRACT FROM AUTHOR]

Background: The Mixed Lymphocyte Reaction (MLR) consists in the allogeneic co-culture of monocytes derived dendritic cells (MoDCs) with T cells fromanother donor. This in vitro assay is largely used for the assessment of immunotherapy compounds. Nevertheless, the phenotypic changes associated with lymphocyte responsiveness under MLR have never been thoroughly evaluated. Methods: Here, we used multiplex cytokine and chemokine assays, multiparametric flow cytometry and single cell RNA sequencing to deeply characterize T cells activation and function in the context of CD4+- and CD8+-specific MLR kinetics. Results: We showed that CD4+ and CD8+ T cells in MLR share common classical markers of response such as polyfunctionality, increased proliferation and CD25 expression but differ in their kinetics and amplitude of activation as well as their patterns of cytokines secretion and immune checkpoints expression. The analysis of immunoreactive Ki-67+CD25+ T cells identified PBK, LRR1 and MYO1G as new potential markers of MLR response. Using cell-cell communication network inference and pathway analysis on single cell RNA sequencing data, we also highlighted key components of the immunological synapse occurring between T cells and the stimulatory MoDCs together with downstream signaling pathways involved in CD4+ and CD8+ T cells activation. Conclusion: These results provide a deep understanding of the kinetics of the MLR assay for CD4+ or CD8+ T cells and may allow to better characterize compounds impacting MLR and eventually identify new strategies for immunotherapy in cancer. [ABSTRACT FROM AUTHOR]

Immuno-oncology has revolutionized cancer care, drug development, the design of clinical trials, standard treatment paradigms, and the evaluation of response to therapy. These are all areas, however, that have not fully incorporated principles of tumor immunology. Insufficient emphasis is put on the effect drugs have on the immune system, and specifically, the impact that multiple lines of therapy can have on the functioning of the immune system, hindering a robust anti-tumor immune response. A paradigm shift in how we approach the development of novel immunotherapeutic agents is necessary to facilitate the effective improvements in patient outcomes. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors (ICIs) in combination with tyrosine kinase inhibitors or other ICIs has significantly improved the prognosis for patients with mccRCC. This marks a major milestone in the treatment of mccRCC. Nonetheless, most patients will discontinue first-line therapy. In this narrative review, we analyze the different patterns of treatment discontinuation in the four pivotal phase III trials that have shown an improvement in overall survival in mccRCC first-line therapy, starting from 1 January 2017 to 1 June 2023. We highlight the different discontinuation scenarios and their influences on subsequent treatment options, aiming to provide more data to clinicians to navigate a complex decision-making process through a narrative review approach. We have identified several causes for discontinuations for patients treated with ICI-based combinations, such as interruption for drug-related adverse events, ICI treatment completion, treatment discontinuation due to complete response or maximum clinical benefit, or due to progression (pseudoprogression, systemic progression, and oligoprogression); for each case, an extensive analysis of the trials and current medical review has been conducted. [ABSTRACT FROM AUTHOR]

Simple Summary: It is well recognized now that the development of drug resistance is one of the leading causes of treatment failure in conventional therapies. In comparison, recent improvements in immunotherapy showed promising results in eradicating cancer. Chimeric antigen receptor (CAR)-T-cell therapy is one of the cancer immunotherapies that uses patient's T cells and genetically modifies them to target cancer cells. Although CAR-T-cell therapy has shown remarkable success in treating blood cancer, it has proven far more limited in the treatment of solid tumors in different organs. This review article discussed the chronological development of CAR-T-cell therapies and their treatment options in different types of cancers. This article also addresses the current clinical challenges in CAR-T-cell therapy and recent advancements in developing novel therapeutic strategies with fewer side effects. In recent years, chimeric antigen receptor (CAR)-T-cell therapy has emerged as the most promising immunotherapy for cancer that typically uses patients' T cells and genetically engineered them to target cancer cells. Although recent improvements in CAR-T-cell therapy have shown remarkable success for treating hematological malignancies, the heterogeneity in tumor antigens and the immunosuppressive nature of the tumor microenvironment (TME) limits its efficacy in solid tumors. Despite the enormous efforts that have been made to make CAR-T-cell therapy more effective and have minimal side effects for treating hematological malignancies, more research needs to be conducted regarding its use in the clinic for treating various other types of cancer. The main concern for CAR-T-cell therapy is severe toxicities due to the cytokine release syndrome, whereas the other challenges are associated with complexity and immune-suppressing TME, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T-cell exhaustion, and reduced cytotoxicity in the tumor site. This review discussed the latest discoveries in CAR-T-cell therapy strategies and combination therapies, as well as their effectiveness in different cancers. It also encompasses ongoing clinical trials; current challenges regarding the therapeutic use of CAR-T-cell therapy, especially for solid tumors; and evolving treatment strategies to improve the therapeutic application of CAR-T-cell therapy. [ABSTRACT FROM AUTHOR]

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumor-specific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient’s clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-γ following onco-virotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to onco-virotherapy at the early stage of the preclinical phases.

Ravi K Goyal,1 Jingchuan Zhang,2 Keith L Davis,1 Martina Sluga-O’Callaghan,1 Peter A Kaufman3 1Health Economics, RTI Health Solutions, Research Triangle Park, NC, USA; 2Eisai Inc., Nutley, NJ, USA; 3Larner College of Medicine, Division of Hematology/Oncology, University of Vermont Cancer Center, Burlington, VT, USACorrespondence: Peter A Kaufman, Larner College of Medicine, Division of Hematology/Oncology, University of Vermont Cancer Center, 111 Colchester Avenue, EP2, Burlington, VT, 05401, USA, Email Peter.Kaufman@uvmhealth.orgIntroduction: Eribulin was approved by the FDA in 2010 for the treatment of metastatic breast cancer (MBC) in the United States (US). More recently, several immuno-oncology (IO) and antibody–drug conjugate (ADC) regimens have been approved for MBC. We assessed the treatment patterns and clinical outcomes in MBC patients treated with eribulin following treatment with an IO or ADC in US clinical practice.Materials and Methods: In a retrospective patient medical chart review study, patients with MBC, aged ≥ 18 years, who initiated eribulin therapy between March 1, 2019, and September 30, 2020, treated with either prior IO or ADC in the metastatic setting were included. Patient demographics, treatment characteristics, and clinical outcomes were analyzed descriptively. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan–Meier analyses.Results: In the study population (N=143), median age at eribulin initiation was 62 years; 64% were Caucasian, and 67% had triple-negative MBC (TNBC). Eribulin therapy was used in the second to fifth line of therapy in the metastatic setting; median treatment duration was 7.2 months. The overall response rate for eribulin was 59.4%. Median rwPFS and OS from eribulin initiation were 21.4 months (95% CI, 12.9-not estimable [NE]) and 24.2 months (95% CI, 17.5-NE), respectively. In patients with TNBC, median rwPFS and OS from eribulin initiation were 12.0 months (95% CI, 8.8-NE) and 18.3 months (95% CI, 14.9-NE), respectively.Conclusion: These real-world data provide evidence for the clinical effectiveness outcomes of eribulin treatment among MBC patients previously treated with an IO or ADC.Keywords: real world evidence, metastatic breast cancer, immuno-oncology, antibody drug conjugates, eribulin, patient medical chart review

Abstract Objective The impact of inflammatory response on tumor development and therapeutic response is of significant importance in clear cell renal cell carcinoma (ccRCC). The customization of specialized prognostication approaches and the exploration of supplementary treatment options hold critical clinical implications in relation to the inflammatory response. Methods In the present study, unsupervised clustering was implemented on TCGA-KIRC tumors using transcriptome profiles of inflammatory response genes, which was then validated in two ccRCC datasets (E-MATB-1980 and ICGC) and two immunotherapy datasets (IMvigor210 and Liu et al.) via SubMap and NTP algorithms. Combining co-expression and LASSO analyses, inflammatory response-based scoring system was defined, which was evaluated in pan-cancer. Results Three reproducible inflammatory response subtypes (named IR1, IR2 and IR3) were determined and independently verified, each exhibiting distinct molecular, clinical, and immunological characteristics. Among these subtypes, IR2 had the best OS outcomes, followed by IR3 and IR1. In terms of anti-angiogenic agents, sunitinib may be appropriate for IR1 patients, while axitinib and pazopanib may be suitable for IR2 patients, and sorafenib for IR3 patients. Additionally, IR1 patients might benefit from anti-CTLA4 therapy. A scoring system called IRscore was defined for individual ccRCC patients. Patients with high IRscore presented a lower response rate to anti-PD-L1 therapy and worse prognostic outcomes. Pan-cancer analysis demonstrated the immunological features and prognostic relevance of the IRscore. Conclusion Altogether, characterization of inflammatory response subtypes and IRscore provides a roadmap for patient risk stratification and personalized treatment decisions, not only in ccRCC, but also in pan-cancer.

The role of the tumor microenvironment (TME) in immuno‐oncology has driven demand for technologies that deliver in situ, or spatial, molecular information. Compartmentalized heterogeneity that traditional methods miss is becoming key to predicting both acquired drug resistance to targeted therapies and patient response to immunotherapy. Here, we describe a novel method for assay‐agnostic spatial profiling and demonstrate its ability to detect immune microenvironment signatures in breast cancer patients that are unresolved by the immunohistochemical (IHC) assessment of programmed cell death ligand‐1 (PD‐L1) on immune cells, which represents the only FDA microenvironment‐based companion diagnostic test that has been approved for triple‐negative breast cancer (TNBC). Two distinct physiological states were found that are uncorrelated to tumor mutational burden (TMB), microsatellite instability (MSI), PD‐L1 expression, and intrinsic cancer subtypes.

This study aimed to identify the 25 most prevalent adverse events (AEs) associated with FDA-approved immune checkpoint inhibitors (ICIs)—specifically, PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors—using data from the FDA Adverse Events Reporting System (FAERS), a publicly available repository of reported drug adverse events, and AERSMine, an open-access pharmacovigilance tool, to investigate these adverse events. For PD-1 inhibitors, the most common AEs were diarrhea, fatigue, and pyrexia, with notable instances of neutropenia and hypothyroidism, particularly with toripalimab and dostarlimab. PD-L1 inhibitors also frequently caused pyrexia, diarrhea, and fatigue, with interstitial lung disease and hypothyroidism showing a class effect, and drug-specific AEs such as hepatotoxicity and chills. CTLA-4 inhibitors predominantly resulted in diarrhea and colitis, with ipilimumab frequently causing pyrexia and rash, while tremelimumab exhibited unique AEs such as biliary tract infection. The LAG-3 inhibitor relatlimab reported fewer AEs, including pyrexia and pneumonia. Rare but significant AEs across all inhibitors included myocarditis and myasthenia gravis. This study provides a detailed overview of the 25 most common AEs associated with ICIs, offering valuable insights for clinical decision-making and AE management. Further research is necessary to elucidate the mechanisms underlying these AEs and to develop targeted interventions to enhance the safety and efficacy of ICI therapy in patients with cancer.

The advancement of immuno-oncology has brought about a significant shift in cancer treatment methods, with antibody-based immune checkpoint inhibitors like atezolizumab leading the way in this regard. However, the use of this checkpoint blockade can result in immune-related adverse events due to increased T-cell activity. The full spectrum of these events is not yet completely understood. In this study, the United States FDA Adverse Event Reporting System (FAERS) was utilized to investigate immune-related adverse events linked with the use of atezolizumab. The study identified forty-nine immune-related adverse events that affected multiple organ systems, including cardiovascular, respiratory, hematologic, hepatic, renal, gastrointestinal, neurologic, musculoskeletal, dermatologic, endocrine, and systemic disorders. The strongest signals for relative risk occurred for immune-mediated encephalitis (RR = 93.443), autoimmune myocarditis (RR = 56.641), immune-mediated hepatitis (RR = 49.062), immune-mediated nephritis (RR = 40.947), and autoimmune arthritis (RR = 39.382). Despite the morbidity associated with these adverse events, emerging evidence suggests potential associations with improved survival outcomes. Overall, this report sheds light on the widespread immune-related adverse events that cause significant morbidity and mortality in patients with cancer being treated with atezolizumab and brings attention to them for the clinicians treating these patients.

For mammary carcinomas in pet rabbits, prognostic biomarkers are poorly defined, and treatment is limited to surgical excision. Additional treatment options are needed for rabbit patients for which surgery is not a suitable option. In human breast cancer, the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) represents a prognostic biomarker and possible therapeutic target. This retrospective immunohistochemical study examined IDO1 in 96 pet rabbit mammary carcinomas with known mitotic count, hormone receptor status, and percentage of stromal tumor infiltrating lymphocytes (TILs). Tumors were obtained from 96 pet rabbits with an average of 5.5 years. All rabbits with reported sex (n = 88) were female or female-spayed. Of the carcinomas, 94% expressed IDO1, and 86% had sparse TILs consistent with cold tumors. Statistically significant correlations existed between a higher percentage of IDO1-positive tumor cells, lower mitotic counts, and increased estrogen receptor expression. The threshold for significance was IDO1 staining in >10% of tumor cells. These results lead to the assumption that IDO1 expression contributes to tumorigenesis and may represent a prognostic biomarker and possible therapeutic target also in pet rabbit mammary carcinomas. They also support the value of rabbits for breast cancer research.

Abstract Background The mechanisms whereby CYFIP2 acts in tumor development and drives immune infiltration have been poorly explored. Thus, this study aimed to identifying the role of CYFIP2 in tumors and immune response. Methods In this study, we first explored expression patterns, diagnostic role and prognostic value of CYFIP2 in cancers, particularly in lung adenocarcinoma (LUAD). Then, we performed functional enrichment, genetic alterations, DNA methylation analysis, and immune cell infiltration analysis of CYFIP2 to uncover its potential mechanisms involved in immune microenvironment. Results We found that CYFIP2 significantly differentially expressed in different tumors including LUAD compared with normal tissues. Furthermore, CYFIP2 was found to be significantly correlated with clinical parameters in LUAD. According to the diagnostic and survival analysis, CYFIP2 may be employed as a potential diagnostic and prognostic biomarker. Moreover, genetic alterations revealed that mutation of CYFIP2 was the main types of alterations in different cancers. DNA methylation analysis indicated that CYFIP2 mRNA expression correlated with hypomethylation. Afterwards, functional enrichment analysis uncovered that CYFIP2 was involved in tumor-associated and immune-related pathways. Immune infiltration analysis indicated that CYFIP2 was significantly correlated with immune cells infiltration. In particular, CYFIP2 was strongly linked with immune microenvironment scores. Additionally, CYFIP2 exhibited a significant relationship with immune regulators and immune-related genes including chemokines, chemokines receptors, and MHC genes. Conclusion Our results suggested that CYFIP2 may serve as a prognostic cancer biomarker for determining prognosis and might be a promising therapeutic strategy for tumor immunotherapy.

Abstract Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno‐oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child–Pugh–Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3–5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape.