A review of strategies to overcome immune resistance in the treatment of advanced prostate cancer.

Immunotherapy has become integral in cancer therapeutics over the past two decades and is now part of standard-of-care treatment in multiple cancer types. While various biomarkers and pathway alterations such as dMMR, CDK12, and AR-V7 have been identified in advanced prostate cancer to predict immunotherapy responsiveness, the vast majority of prostate cancer remain intrinsically immune-resistant, as evidenced by low response rates to anti-PD(L)1 monotherapy. Since regulatory approval of the vaccine therapy sipuleucel-T in the biomarker-unselected population, there has not been much success with immunotherapy treatment in advanced prostate cancer. Researchers have looked at various strategies to overcome immune resistance, including the identification of more biomarkers and the combination of immunotherapy with existing effective prostate cancer treatments. On the horizon, novel drugs using bispecific T-cell engager (BiTE) and chimeric antigen receptors (CAR) technology are being explored and have shown promising early efficacy in this disease. Here we discuss the features of the tumour microenvironment that predispose to immune resistance and rational strategies to enhance antitumour responsiveness in advanced prostate cancer.

Clinical efficacy and long-term immunogenicity of an early triple dose regimen of SARS-CoV-2 mRNA vaccination in cancer patients.

INTRODUCTION: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. METHOD: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. RESULTS: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P<0.05) and chemotherapy (92.8%±18.1, P<0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection. CONCLUSION: This study demonstrates the benefit of early administration of the third dose among cancer patients.

Real-world outcomes from use of CDK4/6 inhibitors in the management of advanced/metastatic breast cancer in Asia.

Background: Oestrogen receptor positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer (BC) is the most frequently diagnosed BC subtype. Combinations of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with anti-oestrogen therapy have led to improved survival compared with anti-oestrogen therapy alone for advanced/metastatic BC. The evaluation of CDK4/6i in the real-world facilitates treatment planning, insights into the incidence of drug toxicities, dose modifications including dose delays (DDs) and dose reductions (DRs) and improves prognostic accuracy in subgroups, for example geriatric patients, who are under-represented in clinical trials. Methods: This multi-centre study analysed retrospective and prospective data from 456 patients treated with CDK4/6i between January 2015 and December 2020. We examined patient characteristics, variation in prescribing practices, efficacy and toxicity outcomes. Results: In all, 456 patients were included in this study. The median age was 59 (range: 24-92). In total, 85 (19%) were ⩾70 years old. In all, 122 (27%) and 119 (26%) of patients were treated in the first-line and second-line settings, respectively. In total, 25 (5%), 31 (7%) and 145 (32%) of patients had brain, peritoneum and liver metastasis, respectively, at the time of CDK4/6i initiation. On univariate analysis, heavily pre-treated patients and those with distant metastases, involving the liver, brain or peritoneum, had significantly shorter progression-free survival (PFS) and 24-month overall survival (OS). Elderly patients (⩾70) had a shorter PFS; OS results were not mature. Majority of patients (n = 362, 80%) initiated treatment with the United States FDA-approved starting dose of CDK4/6i. In all, 330 (72%) had at least one DD and 217 (48%) patients required at least one DR, but these dose modifications were not associated with poorer survival outcomes. Patients age ⩾70 were more likely to require dose modifications leading to a lower treatment dose. The most common reason for DD/DR was neutropenia (60%) and the incidence of febrile neutropenia was only 2%. Conclusions: Our study indicates CDK4/6i is effective and safe. Age ⩾ 70, distant metastases to liver, peritoneal or brain were negative prognostic factors. Age ⩾ 70 was associated with significantly increased requirement for dose modification; however, this did not impact survival outcomes. These findings provide reassurance that survival outcomes are not adversely affected in elderly patients when DD/DR is indicated.

A new redescription of Daphnia pusilla (Serventy, 1929) (Cladocera: Daphniidae) with emphasis on the thoracic limbs of Daphnia (Ctenodaphnia) Dybowski amp; Grochowski, 1895.

The genus Daphnia O.F. Mller, 1776 (Crustacea: Cladocera) still has a confused taxonomy for several objective and subjective reasons. Still there are many taxa with inadequately described morphology, primarily among the subgenus Daphnia (Ctenodaphnia) Dybowski Grochowski, 1895. We provide a redescription of an Australian endemic taxon Daphnia (Ctenodaphnia) pusilla (Serventy, 1929) according to recent standards of morphological study with special attention to the thoracic limbs. We conclude that main differences between thoracic limbs of the subgenera D. (Ctenodaphnia) and Daphnia s. str. concern the limb I only as it is well-known among the cladocerans of other families. But still only a few species of D. (Ctenodaphnia) have been studied adequately, and efforts to redescribe their morphology need to be continued.

Dendritic cell therapy with CD137L-DC-EBV-VAX in locally recurrent or metastatic nasopharyngeal carcinoma is safe and confers clinical benefit.

INTRODUCTION: Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), and provides a target for a dendritic cell (DC) vaccine. CD137 ligand (CD137L) expressed on antigen presenting cells, costimulates CD137-expressing T cells, and reverse CD137L signaling differentiates monocytes to CD137L-DC, a type of DC, which is more potent than classical DC in stimulating T cells. METHODS: In this phase I study, patients with locally recurrent or metastatic NPC were administered CD137L-DC pulsed with EBV antigens (CD137L-DC-EBV-VAX). RESULTS: Of the 12 patients treated, 9 received full 7 vaccine doses with a mean administered cell count of 23.9 × 106 per dose. Treatment was well tolerated with only 4 cases of grade 1 related adverse events. A partial response was obtained in 1 patient, and 4 patients are still benefitting from a progression free survival (PFS) of currently 2-3 years. The mean pre-treatment neutrophil: lymphocyte ratio was 3.4 and a value of less than 3 was associated with prolonged median PFS. Progressors were characterized by a high frequency of naïve T cells but a low frequency of CD8+ effector T cells while patients with a clinical benefit (CB) had a high frequency of memory T cells. Patients with CB had lower plasma EBV DNA levels, and a reduction after vaccination. CONCLUSION: CD137L-DC-EBV-VAX was well tolerated. The use of CD137L-DC-EBV-VAX is demonstrated to be safe. Consistent results were obtained from all 12 patients, indicating that CD137L-DC-EBV-VAX induces an anti-EBV and anti-NPC immune response, and warranting further studies in patients post effective chemotherapy. PRECIS: The first clinical testing of CD137L-DC, a new type of monocyte-derived DC, finds that CD137L-DC are safe, and that they can induce an immune response against Epstein-Barr virus-associated nasopharyngeal carcinoma that leads to tumor regression or prevents tumor progression.

The Role of Immunotherapy in the Treatment of Advanced Cervical Cancer: Current Status and Future Perspectives.

Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although the majority of patients do not benefit from their use. This review summarises current knowledge and use of immune checkpoint blockade in cervical cancer as well as discussing the challenges faced in their clinical application, namely, the role of biomarker-driven ICI use, potential mechanisms of resistance, strategies to overcome such resistance and additional immunotherapy options beyond ICI.

Exploring physiotherapy practice within hospital-based interprofessional chronic pain clinics in Ontario.

Background: Chronic pain affects one in five persons and is a leading contributor to years lived with disability and high health care costs. In 2016, the government of Ontario increased public funding for pediatric and adult hospital-based interprofessional chronic pain clinics (HICPCs) in Ontario, Canada, expanding the role of physiotherapy in chronic pain management in the province. This role has yet to be described in the literature. Aim: The aim of this study was to explore physiotherapy practice within HICPCs in Ontario. Methods: We conducted an interpretive description qualitative study based on semistructured interviews with physiotherapists employed in pediatric and adult HICPCs in Ontario. Interviews were audio recorded, transcribed verbatim, and reviewed for accuracy. We analyzed interview data using thematic analysis. Results: Ten physiotherapists who practiced in pediatric and adult HICPCs (n = 4 pediatric; n = 6 adult) in Ontario were interviewed between February and April 2020. We constructed five themes related to physiotherapy practice in this setting. Themes included (1) contributing a functional lens to care; (2) empowering through pain education; (3) facilitating participation in physical activity and exercise; (4) supporting engagement in self-management strategies; and (5) implementing a collaborative approach to whole-person care. Conclusions: Our results illuminate how physiotherapy practice within HICPCs in Ontario focuses on providing a collaborative and whole-person approach to care, with an emphasis on supporting patients to increase their functional capacity by promoting engagement in active chronic pain management strategies.

Contexte: La douleur chronique touche une personne sur cinq et est l'un des principaux contributeurs au nombre d'années vécues avec un handicap, ainsi qu'aux coûts de soins de santé élevés. En 2016, le gouvernement de l'Ontario a augmenté le financement public des cliniques interprofessionnelles de la douleur chronique (HICPC) pédiatriques et pour adultes en milieu hospitalier en Ontario, Canada, élargissant le rôle de la physiothérapie dans la prise en charge de la douleur chronique dans la province. Ce rôle n'a pas encore été décrit dans la littérature.Objectif: Le but de cette étude est d'examiner la pratique de la physiothérapie au sein des HICPC en Ontario.Méthodes: Nous avons mené une étude qualitative descriptive interprétative fondée sur des entrevues avec des physiothérapeutes employés dans des HICPC pédiatriques et pour adultes en Ontario. Les entrevues ont fait l'objet d'un enregistrement audio, puis elles ont été transcrites textuellement et vérifiées pour assurer leur exactitude. Nous avons analysé les données des entrevues en ayant recours à une analyse thématique.Résultats: Dix physiothérapeutes qui ont exercé dans des HICPC pédiatriques et pour adultes (n = 4 pédiatriques; n = 6 pour adultes) en Ontario ont été interviewés entre février et avril 2020. Nous avons construit cinq thèmes liés à la pratique de la physiothérapie dans ce contexte. Les thèmes comprenaient (1) l'apport de l'angle fonctionnel aux soins; (2) l'autonomisation grâce à l'éducation sur la douleur; (3) faciliter la participation à une activité physique et à l'exercice; (4) soutenir l'engagement dans des stratégies d'autogestion; et (5) la mise en œuvre d'une approche collaborative des soins à la personne globale.Conclusions: Nos résultats illustrent la façon dont la pratique de la physiothérapie au sein des HICPC en Ontario se concentre sur une approche de soins collaborative et globale, qui met l'accent sur le soutien aux patients pour augmenter leur capacité fonctionnelle en favorisant l'engagement dans les stratégies actives de prise en charge de la douleur chronique.

Low-Dose Nivolumab in Renal Cell Carcinoma: A Real-World Experience.

BACKGROUND: The approved doses of the single agent nivolumab - an anti-programmed cell death protein 1 (PD-1) monoclonal antibody - for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. METHODS: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. RESULTS: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05-1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25-1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48-6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. CONCLUSION: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.

Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies.

The treatment landscape for patients with advanced non-small cell lung cancer has evolved greatly with the advent of immune checkpoint inhibitors. However, many patients do not derive benefit from checkpoint blockade, developing either primary or secondary resistance, highlighting a need for alternative approaches to modulate immune function. In this review, we highlight the absence of a common definition of primary and secondary resistance and summarize their frequency and clinical characteristics. Furthermore, we provide an overview of the biomarkers and mechanisms of resistance involving the tumor, the tumor microenvironment and the host, and suggest treatment strategies to overcome these mechanisms and improve clinical outcomes.

A Model for Rapid Transition to Virtual Care, VA Connecticut Primary Care Response to COVID-19.

INTRODUCTION: Traditionally, health care delivery in the USA has been structured around in-person visits. The COVID-19 pandemic has forced a shift to virtual care models in order to reduce patient exposure to high-risk environments and to preserve valuable health care resources. This report describes one large primary care system's model for rapid transition to virtual care (RTVC). SETTING AND PARTICIPANTS: A RTVC model was implemented at the VA Connecticut Health Care System (VACHS), which delivers care to over 58,000 veterans. PROGRAM DESCRIPTION: The RTVC model included immediate virtual care conversion, telework expansion, implementation of virtual respiratory urgent care clinics, and development of standardized note templates. PROGRAM EVALUATION: Outcomes include the rates of primary encounter types, staff teleworking, and utilization of virtual respiratory urgent care clinics. In under 2 weeks, most encounters were transitioned from in-person to virtual care, enabling telework for over half of the medical staff. The majority of virtual visits were telephone encounters, though rates of video visits increased nearly 18-fold. DISCUSSION: The RTVC model demonstrates expeditious and sustained transition to virtual care during the COVID-19 pandemic. Our experiences help inform institutions still reliant on traditional in-person visits, and future pandemic response.

Craving and opioid use disorder: A scoping review.

INTRODUCTION: The subjective experience of drug craving is a prominent and common clinical phenomenon for many individuals diagnosed with opioid use disorder (OUD), and could be a valuable clinical endpoint in medication development studies. The purpose of this scoping review is to provide an overview and critical analysis of opioid craving assessments located in the published literature examining OUD. METHOD: Studies were identified through a search of PubMed, Embase, and PsychInfo databases and included for review if opioid craving was the focus and participants were diagnosed with or in treatment for OUD. RESULTS: Fifteen opioid craving assessment instruments were identified across the 87 studies included for review. The most common were the Visual Analog Scale (VAS, 41 studies), Desires for Drug Questionnaire (DDQ, 12 studies), Heroin Craving Questionnaire (HCQ, 10 studies), and Obsessive-Compulsive Drug Use Scale (OCDUS, 10 studies). Craving assessments varied considerably in their format, content, time frame, and underlying subscales, and only 6 of 15 had been psychometrically evaluated. DISCUSSION: This review identified a variety of opioid craving assessments, but few had been evaluated for their psychometric properties making it difficult to ascertain whether craving is being assessed optimally in studies of OUD. Thus, the development of a reliable and valid opioid craving assessment would be worthwhile and could be guided by recently published Food and Drug Administration Clinical Outcome Assessment (COA) guidelines. Importantly, a COA focused on opioid craving could be a valuable addition to research studies designed to evaluate novel treatments for OUD.

The evolving immuno-oncology landscape in advanced lung cancer: first-line treatment of non-small cell lung cancer.

Lung cancer is the most common cancer and leading cause of cancer death. While targeted therapies have redefined treatment options for non-small cell lung carcinoma (NSCLC) with genetic aberrations such as epidermal growth factor and anaplastic lymphoma kinase, many patients do not harbour these oncogenic drivers. Cancer immunology has enabled the development of immune modulators that has dramatically altered the therapeutic landscape of advanced NSCLC. The success of immune-checkpoint inhibitors in pretreated NSCLC has led to the conduct of multiple studies exploring their role in the first-line setting. This article provides an overview of the evolving landscape of immune-checkpoint inhibitors with a focus on the programmed cell-death 1 (PD-1; pembrolizumab, nivolumab) and programmed cell-death ligand 1 (PD-L1; atezolizumab, durvalumab, avelumab) immune-checkpoint inhibitors as single agent or in combination with either chemotherapy or with another immune-checkpoint inhibitor in the treatment of NSCLC, the challenges faced, as well as future perspectives.

Population diversity in oncology drug responses and implications to drug development.

Cancer drug development is proceeding at a rapid pace, with drug approvals in oncology outpacing the other disease indications. With high population growth and economic development of Asian countries, access to cancer drugs becomes a paramount necessity. Approval of these drugs is dependent on establishing their safety and efficacy in populations living in these countries. Ethnic and racial differences in drug pharmacokinetics, or drug receptor sensitivities may lead to differences in drug responses between populations. These differences may be due to intrinsic or extrinsic factors, and understanding of the magnitude of these differences and their etiologies is important. One key pharmacogenetic reason for ethnic variability of drug response arises from the different allelic frequencies of polymorphic drug-metabolising enzyme genes, resulting in altered drug disposition. Using race or ethnicity as a "biomarker" for pharmacotherapeutics is fraught with issues as they are difficult to define scientifically, and are considered more social constructs. Nonetheless, studying the genetics of ethno-geographical variability of drug response will allow genetic biomarkers to be uncovered, which would greatly facilitate precision medicine, and should justify broadening the involvement and accrual of patients from global diverse populations during the early phases of drug development for an oncology drug.

Anti-inflammatory Trained Immunity Mediated by Helminth Products Attenuates the Induction of T Cell-Mediated Autoimmune Disease.

Recent studies have suggested that the innate immune system can display characteristics of immunological memory and this has been called "innate immune memory" or "trained immunity." Certain fungal products have been shown to induce epigenetic imprinting on monocytes/macrophages that results in heightened inflammatory responses to subsequent stimuli. Here we report that innate immune cells can be trained to be more anti-inflammatory following exposure to products of a helminth pathogen. Macrophages trained in vitro with Fasciola hepatica total extract (FHTE) had enhanced IL-10 and IL-1RA, but reduced TNF production upon re-stimulation with FHTE or TLR ligands and this was reversed by inhibitors of DNA methylation. In contrast, macrophages trained with ß-glucan or Bacillus Calmette-Guérin had enhanced TNF production upon re-stimulation with Pam3cys or LPS. Furthermore, FHTE-trained macrophages had enhanced expression of markers of alternative activated macrophages (AAM). Macrophages from mice treated with FHTE expressed markers of AAM and had heightened IL-10 and IL-1RA production in response to FHTE or TLR ligands and had suppressed TNF and IL-12p40 production. Macrophages from mice treated with FHTE had reduced APC function and inhibited IL-17 production and the encephalitogenic activity of T cells in the experimental autoimmune encephalomyelitis (EAE) model. In addition, mice pre-treated with FHTE were resistant to induction of EAE and this was associated with a significant reduction in IL-17-producing γδ and CD4 T cells infiltrating the CNS. Our findings reveal that cells of the innate immune system can be trained in vitro or in vivo to be more anti-inflammatory by exposure to helminth products and this protects mice against the induction of a T cell-mediated autoimmune disease.