Personalized Cancer Vaccines Directed against Tumor Mutations: Building Evidence from Mice to Humans.

Personalized vaccines directed to tumor mutations have recently gained significant momentum. On the basis of the concept of stimulating T-cell responses against neoantigens encoded by a tumor's host of personal mutations, these vaccines utilize genome or exome sequencing, mutation calling, and epitope prediction followed by manufacturing of a customized vaccine for each patient. In their 2012 Cancer Research publication, Castle and colleagues provided evidence that vaccinating with long peptide vaccines encompassing neoantigens can generate robust immune responses and induce antitumor activity in a mouse B16F10 melanoma. This approach, harnessing the exquisite specificity of mutations to the tumor and thus providing an effective target for cancer vaccines, was subsequently shown to be safe and immunogenic in a series of small first in man trials in patients with melanoma. The field has accelerated and expanded substantially over the last 5 years, propelled by increasing evidence for vaccine-mediated clinical efficacy, leading to ongoing registrational trials using personalized RNA neoantigen vaccines in patients with melanoma and several other malignancies. See related article by Castle and colleagues, Cancer Res 2012;72:1081-91.

Recent progress in combination therapy of oncolytic vaccinia virus.

In recent years, oncolytic viruses have emerged as promising agents for treating various cancers. An oncolytic virus is a non-pathogenic virus that, due to genetic manipulation, tends to replicate in and cause lysis of cancerous cells while leaving healthy cells unaffected. Among these viruses, vaccinia virus is an attractive platform for use as an oncolytic platform due to its 190 Kb genome with a high capacity for encoding therapeutic payloads. Combining oncolytic VV therapy with other conventional cancer treatments has been shown to be synergistic and more effective than monotherapies. Additionally, OVV can be used as a vector to deliver therapeutic payloads, alone or in combination with other treatments, to increase overall efficacy. Here, we present a comprehensive analysis of preclinical and clinical studies that have evaluated the efficacy of oncolytic vaccinia viruses in cancer immunotherapy. We discuss the outcomes of these studies, including tumor regression rates, overall survival benefits, and long-term responses. Moreover, we provide insights into the challenges and limitations associated with oncolytic vaccinia virus- based therapies, including immune evasion mechanisms, potential toxicities, and the development of resistance.

Optimal Neoantigen Cancer Vaccines Target CD8+ and CD4+ T Cells with Multiple Antigens.

Cancer vaccines targeting mutated neoantigens offer promise for prevention of cancer recurrence and for treatment of established cancers. Questions remain about whether vaccines need to target multiple neoantigens and whether they need to target both CD8+ and CD4+ T cells. In this issue, Garzia and colleagues demonstrate the importance of including multiple antigens to stimulate both CD4+ T cells and CD8+ T cells for treatment of established cancer. See related article by Garzia et al., p. 440 (4).

CD4+ Regulatory T Cells in Human Cancer: Subsets, Origin, and Molecular Regulation.

CD4+CD25hiFOXP3+ regulatory T cells (Treg) play major roles in the maintenance of immune tolerance, prevention of inflammation, and tissue homeostasis and repair. In contrast with these beneficial roles, Tregs are abundant in virtually all tumors and have been mechanistically linked to disease progression, metastases development, and therapy resistance. Tregs are thus recognized as a major target for cancer immunotherapy. Compared with other sites in the body, tumors harbor hyperactivated Treg subsets whose molecular characteristics are only beginning to be elucidated. Here, we describe current knowledge of intratumoral Tregs and discuss their potential cellular and tissue origin. Furthermore, we describe currently recognized molecular regulators that drive differentiation and maintenance of Tregs in cancer, with a special focus on those signals regulating their chronic immune activation, with relevant implications for cancer progression and therapy.

Identifying cancer patients who received palliative care using the SPICT-LIS in medical records: a rule-based algorithm and text-mining technique.

BACKGROUND: Due to limited numbers of palliative care specialists and/or resources, accessing palliative care remains limited in many low and middle-income countries. Data science methods, such as rule-based algorithms and text mining, have potential to improve palliative care by facilitating analysis of electronic healthcare records. This study aimed to develop and evaluate a rule-based algorithm for identifying cancer patients who may benefit from palliative care based on the Thai version of the Supportive and Palliative Care Indicators for a Low-Income Setting (SPICT-LIS) criteria. METHODS: The medical records of 14,363 cancer patients aged 18 years and older, diagnosed between 2016 and 2020 at Songklanagarind Hospital, were analyzed. Two rule-based algorithms, strict and relaxed, were designed to identify key SPICT-LIS indicators in the electronic medical records using tokenization and sentiment analysis. The inter-rater reliability between these two algorithms and palliative care physicians was assessed using percentage agreement and Cohen's kappa coefficient. Additionally, factors associated with patients might be given palliative care as they will benefit from it were examined. RESULTS: The strict rule-based algorithm demonstrated a high degree of accuracy, with 95% agreement and Cohen's kappa coefficient of 0.83. In contrast, the relaxed rule-based algorithm demonstrated a lower agreement (71% agreement and Cohen's kappa of 0.16). Advanced-stage cancer with symptoms such as pain, dyspnea, edema, delirium, xerostomia, and anorexia were identified as significant predictors of potentially benefiting from palliative care. CONCLUSION: The integration of rule-based algorithms with electronic medical records offers a promising method for enhancing the timely and accurate identification of patients with cancer might benefit from palliative care.

Mental Health Care Utilization Among Parents of Children With Cancer.

Importance: Caring for children diagnosed with cancer may adversely affect the mental health (MH) of parents. Objective: To characterize utilization of MH services among parents of children with vs without cancer using nationwide commercial claims data. Design, Setting, and Participants: For this cross-sectional study, the Merative MarketScan Commercial Claims Database was used to identify continuously insured families of children treated for cancer (aged ≤21 years at diagnosis) during 2010 to 2018, compared with families who matched eligibility criteria but did not have a child with a cancer history. Parents were assessed from 18 months before to 12 months after their child's cancer diagnosis. Analyses were conducted from February 2022 to September 2023. Exposures: Children's cancer diagnosis. Main Outcomes and Measures: Outcomes included parents' MH-related visits during the first year following their child's cancer diagnosis. Logistic regressions compared outcomes between families of children with vs without cancer, adjusting for sociodemographic and clinical factors. Results: This study included 4837 families of children with cancer (4210 mothers and 4016 fathers) and 24 185 families of children without cancer (21 444 mothers and 19 591 fathers) with continuous insurance enrollment. Most household leads were aged 35 to 54 years (3700 [76.5%] in families of children with cancer vs 17 812 [73.6%] in families of children without cancer) and resided in urban areas (4252 [87.9%] vs 21 156 [87.5%]). The probabilities of parents having anxiety-related visits (10.6% vs 7.0%), depression-related visits (8.4% vs 6.1%), and any MH-related visits (18.1% vs 13.3%) were higher in families of children with vs without cancer. Adjusted analyses showed absolute increases of 3.2 percentage points (95% CI, 2.3 to 4.0; 45.7% relative increase), 2.2 percentage points (95% CI, 1.4 to 3.0; 36.1% relative increase), and 4.2 percentage points (95% CI, 3.1 to 5.3; 31.3% relative increase) in the probabilities of 1 or both parents having anxiety-related visits, depression-related visits, and any MH-related visits, respectively, among families of children with vs without cancer. Such differences were greater in magnitude among mothers than fathers. Conclusions and Relevance: In this cohort study of privately insured parents, those caring for children with cancer had a higher likelihood of utilizing MH care than other parents. These findings underline the importance of interventions toward targeted counseling and support to better meet MH care needs among parents and caregivers of children with cancer.

Utilizing geospatial artificial intelligence to map cancer disparities across health regions.

We have developed an innovative tool, the Intelligent Catchment Analysis Tool (iCAT), designed to identify and address healthcare disparities across specific regions. Powered by Artificial Intelligence and Machine Learning, our tool employs a robust Geographic Information System (GIS) to map healthcare outcomes and disease disparities. iCAT allows users to query publicly available data sources, health system data, and treatment data, offering insights into gaps and disparities in diagnosis and treatment paradigms. This project aims to promote best practices to bridge the gap in healthcare access, resources, education, and economic opportunities. The project aims to engage local and regional stakeholders in data collection and evaluation, including patients, providers, and organizations. Their active involvement helps refine the platform and guides targeted interventions for more effective outcomes. In this paper, we present two sample illustrations demonstrating how iCAT identifies healthcare disparities and analyzes the impact of social and environmental variables on outcomes. Over time, this platform can help communities make decisions to optimize resource allocation.

Immunogenetic Diversity and Cancer Immunotherapy Disparities.

SUMMARY: The success of checkpoint blockade cancer immunotherapies has unequivocally confirmed the critical role of T cells in cancer immunity and boosted the development of immunotherapeutic strategies targeting specific antigens on cancer cells. The vast immunogenetic diversity of human leukocyte antigen (HLA) class I alleles across populations is a key factor influencing the advancement of HLA class I-restricted therapies and related research and diagnostic tools.

From Base Pairs to City Squares: Comprehensive Precision Oncology for the Future.

SUMMARY: An increased understanding of the role of the social determinants of health in cancer prevention, cancer care, and outcomes can lead to their integration into genetics and genomics as well as informing interventions and clinical trials, creating a comprehensive precision oncology framework.

Phase-Separated Biomolecular Condensation in Cancer: New Horizons and Next Frontiers.

SUMMARY: Beyond lipid membrane compartments, cells including cancer cells utilize various membraneless compartments, often termed biomolecular condensates, to regulate or organize key cellular processes underlying physiologic or pathologic phenotypes. In this commentary, the emergence of biomolecular condensation in cancer biology is highlighted, with a focus on key unanswered questions and with implications for improving the understanding of cancer pathogenesis and developing innovative cancer management strategies.

Using the National Cancer Plan to Drive Innovation in Cancer Research.

SUMMARY: The NCI director presents her vision of the National Cancer Plan as an integrated framework that can help drive innovation in cancer research to speed progress toward ending cancer as we know it.

Chemotherapy and the Extra-Tumor Immune Microenvironment: EXTRA-TIME.

SUMMARY: Understandably, conventional therapeutic strategies have focused on controlling primary tumors. We ask whether the cost of such strategies is actually an increased likelihood of metastatic relapse.

Is there scope to do better? Clinical communication with adolescents and young adults with cancer-A scoping review.

INTRODUCTION: How to communicate effectively with adolescent and young adults with cancer (AYACs) is a research priority. In a UK-wide survey of young people with cancer's research priorities, communication was a striking cross-cutting theme. It is increasingly recognised that AYACs have experiences and communication needs that differ significantly from those of younger children and older adults. The purpose of this review is to explore the features of effective clinical communication with AYACs. METHODS: A literature search was undertaken to identify and map the available evidence using a broad scope to get an overview of the pertinent literature, identify knowledge gaps and clarify concepts. The searches yielded 5825 records, generating 4040 unique articles. These were screened and 71 full articles were read by four researchers with disagreements resolved by discussion leaving 29 included articles. Narrative synthesis was undertaken in relation to each of the research questions. RESULTS: Three key themes were identified: being an adolescent/young adult, supporters, and healthcare professionals (HCPs). AYACs need to feel that HCPs understand their unique perspective. They want to be involved, this changes over time and in different contexts. Supporters are a central tenet, are most often parents and undertake several roles which are not always universally supportive. HCPs enable involvement of AYACs, and this needs to be actively promoted. AYACs preference for their level of involvement requires continual assessment. The three themes are interlinked and exist within the wider scope of the triadic encounter and cancer experience. CONCLUSION: Supporters, most often parents were a key feature across the data and were seemingly paradoxical in nature. Triadic communication, the presence of a third person, is a central tenet of communication with AYACs and we propose a conceptual model to represent the nuances, components, and facets of this complex communication.

Have the recent advancements in cancer therapy and survival benefitted patients of all age groups across the Nordic countries? NORDCAN survival analyses 2002-2021.

BACKGROUND: Since the early 2000s, overall and site-specific cancer survival have improved substantially in the Nordic countries. We evaluated whether the improvements have been similar across countries, major cancer types, and age groups. MATERIAL AND METHODS: Using population-based data from the five Nordic cancer registries recorded in the NORDCAN database, we included a cohort of 1,525,854 men and 1,378,470 women diagnosed with cancer (except non-melanoma skin cancer) during 2002-2021, and followed for death until 2021. We estimated 5-year relative survival (RS) in 5-year calendar periods, and percentage points (pp) differences in 5-year RS from 2002-2006 until 2017-2021. Separate analyses were performed for eight cancer sites (i.e. colorectum, pancreas, lung, breast, cervix uteri, kidney, prostate, and melanoma of skin). RESULTS: Five-year RS improved across nearly all cancer sites in all countries (except Iceland), with absolute differences across age groups ranging from 1 to 21 pp (all cancer sites), 2 to 20 pp (colorectum), -1 to 36 pp (pancreas), 2 to 28 pp (lung), 0 to 9 pp (breast), -11 to 26 pp (cervix uteri), 2 to 44 pp (kidney), -2 to 23 pp (prostate) and -3 to 30 pp (skin melanoma). The oldest patients (80-89 years) exhibited lower survival across all countries and sites, although with varying improvements over time. INTERPRETATION: Nordic cancer patients have generally experienced substantial improvements in cancer survival during the last two decades, including major cancer sites and age groups. Although survival has improved over time, older patients remain at a lower cancer survival compared to younger patients.

[Palliative care in paediatric oncology - a national parental perspective]. / Palliativ vård av barn med cancer.

The WHO definition of paediatric palliative care (PPC) emphasises the role of active multidimensional care, carried out with interdisciplinary competence, and providing support to the entire family. The aim of the current national study was to investigate whether parents perceived that their child received palliative care (PC) before the child died of cancer and the parent's view of the care during the child's last month of life. In 2016, parents (n=226) completed a study-specific survey, and a majority reported that their child had received PC with good professional competence. However, many parents reported that the child was greatly affected by pain in the last month of life. Geographical differences indicated that parents who live in sparsely populated areas to a lesser extent reported that their child received PC. Lastly, our conclusion is that access to equal PPC and improved symptom control is crucial for children and their families.

STING pathway as a cancer immunotherapy: Progress and challenges in activating anti-tumor immunity.

The stimulator of the interferon genes (STING) signaling pathway plays a crucial role in innate immunity by detecting cytoplasmic DNA and initiating antiviral host defense mechanisms. The STING cascade is triggered when the enzyme cyclic GMP-AMP synthase (cGAS) binds cytosolic DNA and synthesizes the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum adaptor STING, leading to the activation of kinases TBK1 and IRF3 that induce interferon production. Secreted interferons establish an antiviral state in infected and adjacent cells. Beyond infections, aberrant DNA in cancer cells can also activate the STING pathway. Preclinical studies have shown that pharmacological STING agonists like cyclic dinucleotides elicit antitumor immunity when administered intratumorally by provoking innate and adaptive immunity. Combining STING agonists with immune checkpoint inhibitors may improve outcomes by overcoming tumor immunosuppression. First-generation STING agonists encountered challenges like poor pharmacokinetics, limited tumor specificity, and systemic toxicity. The development of the next-generation STING-targeted drugs to realize the full potential of engaging this pathway for cancer treatment can be a solution to overcome the current challenges, but further studies are required to determine optimal applications and combination regimens for the clinic. Notably, the controlled activation of STING is needed to preclude adverse effects. This review explores the mechanisms and effects of STING activation, its role in cancer immunotherapy, and current challenges.

Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application.

Tertiary lymphoid structures (TLS) are clusters of immune cells that resemble and function similarly to secondary lymphoid organs (SLOs). While TLS is generally associated with an anti-tumour immune response in most cancer types, it has also been observed to act as a pro-tumour immune response. The heterogeneity of TLS function is largely determined by the composition of tumour-infiltrating lymphocytes (TILs) and the balance of cell subsets within the tumour-associated TLS (TA-TLS). TA-TLS of varying maturity, density, and location may have opposing effects on tumour immunity. Higher maturity and/or higher density TLS are often associated with favorable clinical outcomes and immunotherapeutic response, mainly due to crosstalk between different proportions of immune cell subpopulations in TA-TLS. Therefore, TLS can be used as a marker to predict the efficacy of immunotherapy in immune checkpoint blockade (ICB). Developing efficient imaging and induction methods to study TA-TLS is crucial for enhancing anti-tumour immunity. The integration of imaging techniques with biological materials, including nanoprobes and hydrogels, alongside artificial intelligence (AI), enables non-invasive in vivo visualization of TLS. In this review, we explore the dynamic interactions among T and B cell subpopulations of varying phenotypes that contribute to the structural and functional diversity of TLS, examining both existing and emerging techniques for TLS imaging and induction, focusing on cancer immunotherapies and biomaterials. We also highlight novel therapeutic approaches of TLS that are being explored with the aim of increasing ICB treatment efficacy and predicting prognosis.

How does the frame of communication affect cancer patients' decisions?-from a behavioral economics point of view.

BACKGROUND: It has been said that physicians should provide their patients with accurate evidence in terms of information on treatment options. However, in some cases, although the physician provides accurate and sufficient information, the patient still chooses the medically not-recommended treatment. The purpose of this research is to clarify how patients' decisions differ when a physician changes the frame of an explanation when he/she provides information about cancer treatment. METHODS: An online questionnaire survey was conducted in March 2017. Through the aid of a survey company, we emailed questionnaires to 1,360 cancer patients who received treatment within the last 2 years. We randomly assigned participants to 6 hypotheticals scenario of a terminal cancer patient, and presented hypothetical evidence in different ways. Subsequently, we asked survey participants whether they would choose to receive additional anti-cancer treatment. RESULTS: Although there was no statistically significant difference between scenarios, the "social burden" groups showed a lower rate of patients who preferred to continue a medically ineffective anti-cancer treatment than the control group, at a 10% significance level. The scenario significantly affected the patients' sense of abandonment [F(5, 1,354)=5.680, P<0.001], sense of distress [F(5, 1,354)=3.920, P=0.002], and necessity of improvement [F(5, 1,354)=2.783, P=0.017]. CONCLUSIONS: Nudges were not shown to be effective in situations where discontinuation of anticancer treatment was being considered. On the other hand, some nudges were found to be invasive and should be used with caution.

Generative artificial intelligence and non-pharmacological bias: an experimental study on cancer patient sexual health communications.

Objectives The objective of this study was to explore the feature of generative artificial intelligence (AI) in asking sexual health among cancer survivors, which are often challenging for patients to discuss.Methods We employed the Generative Pre-trained Transformer-3.5 (GPT) as the generative AI platform and used DocsBot for citation retrieval (June 2023). A structured prompt was devised to generate 100 questions from the AI, based on epidemiological survey data regarding sexual difficulties among cancer survivors. These questions were submitted to Bot1 (standard GPT) and Bot2 (sourced from two clinical guidelines).Results No censorship of sexual expressions or medical terms occurred. Despite the lack of reflection on guideline recommendations, 'consultation' was significantly more prevalent in both bots' responses compared with pharmacological interventions, with ORs of 47.3 (p<0.001) in Bot1 and 97.2 (p<0.001) in Bot2.Discussion Generative AI can serve to provide health information on sensitive topics such as sexual health, despite the potential for policy-restricted content. Responses were biased towards non-pharmacological interventions, which is probably due to a GPT model designed with the 's prohibition policy on replying to medical topics. This shift warrants attention as it could potentially trigger patients' expectations for non-pharmacological interventions.