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Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.

Immune-related adverse events (irAEs) secondary to immune checkpoint inhibitor (ICI) therapy reportedly improve overall survival (OS) in patients with non-small cell lung cancer (NSCLC). However, studies have been small and the association between irAE severity and OS remains poorly defined. To examine the association between irAEs and their severity with OS in patients with locally advanced or metastatic NSCLC receiving ICIs. This retrospective observational cohort study included patients with NSCLC receiving ICIs between March 1, 2014, and November 30, 2021, with follow-up until March 31, 2023. Data analysis was completed April 26, 2023. The Alberta Immunotherapy Database, a provincial, multicenter cohort, was used to capture data from patients receiving ICIs in Alberta, Canada. Participants included 803 patients 18 years or older who received at least 1 cycle of ICI (alone or with chemotherapy), agnostic to treatment line. Developing an irAE mandating delay or discontinuation of ICI therapy and/or systematic corticosteroids for management of toxic effects (hereinafter referred to as clinically meaningful irAEs). The primary outcome was association between irAEs and OS according to Kaplan-Meier analysis. Clinically meaningful irAEs were identified. Patients with poor prognosis (survival <3 months) who may have died prior to irAE development were excluded from OS analysis, mitigating immortal time bias. Adjusted Cox proportional hazards regression analyses ascertained variables associated with OS. Among the 803 patients included in the analysis, the median age of patients with irAEs was 69.7 (IQR, 63.1-75.2) years and the median age of those without irAEs was 67.5 (IQR, 60.4-73.3) years, with comparable sex distribution (139 of 295 men [47.1%] and 156 of 295 women [52.9%] with irAEs vs 254 of 505 men [50.3%] and 251 of 505 women [49.7%] without irAEs). Mitigating immortal time bias (n = 611), irAEs were associated with OS (median OS with irAEs, 23.7 [95% CI, 19.3-29.1] months; median OS without irAEs, 9.8 [95% CI, 8.7-11.4] months; P < .001). No OS difference was associated with treatment in hospital vs as outpatients for an irAE (median OS, 20.8 [95% CI, 11.7-30.6] vs 25.6 [95% CI, 20.1-29.8] months; P = .33). Developing irAEs remained associated with OS in the total cohort after Cox proportional hazards regression with known prognostic characteristics (hazard ratio, 0.53 [95% CI, 0.40-0.70]; P < .001). In this cohort study of 803 patients with locally advanced or metastatic NSCLC receiving ICIs, developing a clinically meaningful irAE was associated with improved OS. This association was not compromised by hospitalization for severe toxic effects. Whether and how ICI therapy resumption after an irAE is associated with OS warrants further study.

Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival. A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs. A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01). Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of several solid tumor types. However, as patient outcomes are heterogeneous, clinical tools to aid in prognostication are needed. The Lung Immune Prognostic Index (LIPI) correlates with outcomes in patients with non-small cell lung cancer (NSCLC) treated with ICI, but its applicability beyond NSCLC is poorly defined. We sought to determine whether LIPI is associated with overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in a pooled, real-world, retrospective cohort of patients with solid tumors treated with ICI. Of the total pooled cohort (N = 578), 47.2%, 38.2% and 14.5% of patients were stratified into good, intermediate and poor LIPI group, respectively. Median OS were 22.8 (95% CI 17.4–29.5), 7.8 (95% CI 6.6–9.6), and 2.5 months (95% CI 1.4–3.4) (p < 0.0001). Median PFS were 9.9 (95% CI 7.2–11.5), 3.6 (95% CI 2.7–4.3), and 1.4 months (95% CI 1.2–2.2) (p < 0.0001). ORR was also associated with LIPI group (p < 0.001). Intermediate and poor LIPI were independently prognostic of OS compared to good LIPI, with hazard ratios (HR) of 1.8 (95% CI 1.4–2.3, p < 0.001) and 3.6 (95% CI 2.5–5.1, p < 0.001), respectively. These data are the first to suggest that in a real-world setting, the prognostic value of LIPI may be tumor agnostic.

Ki67 is a commonly used marker of cancer cell proliferation, and has significant prognostic value in breast cancer. In spite of its clinical importance, assessment of Ki67 remains a challenge, as current manual scoring methods have high inter- and intra-user variability. A major reason for this variability is selection bias, in that different observers will score different regions of the same tumor. Here, we developed an automated Ki67 scoring method that eliminates selection bias, by using whole-slide analysis to identify and score the tumor regions with the highest proliferative rates. The Ki67 indices calculated using this method were highly concordant with manual scoring by a pathologist (Pearson's r = 0.909) and between users (Pearson's r = 0.984). We assessed the clinical validity of this method by scoring Ki67 from 328 whole-slide sections of resected early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. All patients had Oncotype DX testing performed (Genomic Health) and available Recurrence Scores. High Ki67 indices correlated significantly with several clinico-pathological correlates, including higher tumor grade (1 versus 3, P<0.001), higher mitotic score (1 versus 3, P<0.001), and lower Allred scores for estrogen and progesterone receptors (P = 0.002, 0.008). High Ki67 indices were also significantly correlated with higher Oncotype DX risk-of-recurrence group (low versus high, P<0.001). Ki67 index was the major contributor to a machine learning model which, when trained solely on clinico-pathological data and Ki67 scores, identified Oncotype DX high- and low-risk patients with 97% accuracy, 98% sensitivity and 80% specificity. Automated scoring of Ki67 can thus successfully address issues of consistency, reproducibility and accuracy, in a manner that integrates readily into the workflow of a pathology laboratory. Furthermore, automated Ki67 scores contribute significantly to models that predict risk of recurrence in breast cancer.

As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus (RV) for the treatment of breast cancer (BrCa). In vitro, oncolysis and cytokine production were assessed in human and murine BrCa cell lines following RV exposure. Furthermore, RV-induced upregulation of tumor cell PD-L1 was evaluated. In vivo, the immunocompetent, syngeneic EMT6 murine model of BrCa was employed to determine therapeutic and tumor-specific immune responses following treatment with RV, anti-PD-1 antibodies or in combination. RV-mediated oncolysis and cytokine production were observed following BrCa cell infection and RV upregulated tumor cell expression of PD-L1. In vivo, RV monotherapy significantly reduced disease burden and enhanced survival in treated mice, and was further enhanced by PD-1 blockade. RV therapy increased the number of intratumoral regulatory T cells, which was reversed by the addition of PD-1 blockade. Finally, dual treatment led to the generation of a systemic adaptive anti-tumor immune response evidenced by an increase in tumor-specific IFN-γ producing CD8+ T cells, and immunity from tumor re-challenge. The combination of PD-1 blockade and RV appears to be an efficacious immunotherapeutic strategy for the treatment of BrCa, and warrants further investigation in early-phase clinical trials.

Reovirus is a ubiquitous RNA virus that exploits aberrant signaling pathways for its replication. The oncolytic potential of reovirus against numerous cancers under pre-clinical/clinical conditions has been documented by us and others. Despite its proven clinical activity, the underlying mechanisms of reovirus oncolysis is still not well elucidated. If reovirus therapy is to be optimized for cancer, including breast cancer patients, it is imperative to understand the mechanisms of reovirus oncolysis, especially in treatment of resistant tumour. In the present study global gene expression profiling was utilized as a preliminary roadmap to tease-out pivotal molecules involved in reovirus induced apoptosis in breast cancer. Reovirus treated HTB133 and MCF7 breast cancer cells revealed transcriptional alteration of a defined subset of apoptotic genes and members of the nuclear factor-kappa B (NF-kB) family and p53 upregulated modulator of apoptosis (PUMA) were prominent. Since NF-kB can paradoxically suppress or promote apoptosis in cancer, the significance of NF-kB in reovirus oncolysis of breast cancer was investigated. Real time PCR analysis indicated a 2.9-4.3 fold increase in NF-kB p65 message levels following reovirus infection of MCF7 and HTB133, respectively. Nuclear translocation of NF-kB p65 protein was also dramatically augmented post reovirus treatment and correlated with enhanced DNA binding. Pharmacologic inhibition of NF-kB lead to oncolytic protection and significant down regulation of PUMA message levels. PUMA down regulation using siRNA suppressed reovirus oncolysis via significantly repressed apoptosis in p53 mutant HTB133 cells. This study demonstrates for the first time that a prominent pathway of reovirus oncolysis of breast cancer is mediated through NF-kB and that PUMA upregulation is dependent on NF-kB activation. These findings represent potential therapeutic indicators of reovirus treatment in future clinical trials.

Evidence suggests that the expression of certain cytokine receptors increases with lung cancer evolution. Overexpression of the cytokine receptor CXCR4 is associated with poor outcomes in stage IV non-small cell lung cancer (NSCLC), with shorter survival in females with high CXCR4 expression. This study quantifies CXCR4 expression in early stage disease and evaluates its association with gender-specific recurrence-free (RFS) and overall survival (OS) in resected stage I-III NSCLC patients. Patient characteristics and clinical outcomes were obtained from the Glans-Look Lung Cancer (G-LLC) database for early stage NSCLC patients diagnosed between 2003-2006 at the Tom Baker Cancer Centre (TBCC). CXCR4 expression was quantified on tissue microarrays (TMA). Median RFS and OS were evaluated by gender using Kaplan-Meier analyses. CXCR4 expression and outcome data were analyzed using Cox proportional hazards (PH) and multi-state models (MSM). 176 stage I-III NSCLC patients were identified. CXCR4 expression was lower in early stage NSCLC patients, with a mean CXCR4 expression of 1729 (SD 1083) compared to 2640 (SD 1541) in stage IV patients. On Kaplan-Meier, median RFS by gender was similar (male 52.8 months vs. female 54.5 months) as was median OS (male 80.9 months vs. female 89.0 months), and there was no significant difference in RFS (p = 0.60) or OS (p = 0.30) by gender and CXCR4 groups over follow-up. By multivariable analysis, CXCR4 expression was not prognostic for RFS (Hazard Ratio (HR) = 1.00, p = 0.73) or OS (HR = 1.00, p = 0.44), and no gender difference was observed. CXCR4 expression increases with stage progression in NSCLC but is not prognostic in early stage NSCLC patients of either gender. Mechanisms by which CXCR4 expression increases during lung carcinogenesis warrant further exploration and testing in clinical trials.

Summary Purpose This open-labeled, phase I clinical trial was designed to determine the safety and tolerability of percutaneous intralesional administration of wild-type oncolytic revovirus type 3 Dearing (Reolysin®) in cancer patients with accessible and evaluable disease, who had otherwise failed to improve on standard cancer interventions. Experimental Design An escalating dose of Reolysin® starting from up to 10 10 plague forming units (PFU) was administered to each cohort of three patients per dose level. Viral shedding, reovirus neutralizing antibody response, toxicity and clinical response were assessed. Results Nineteen patients with various advanced solid tumors were treated. The most common toxicities related to treatment were grade 2 (or less) local erythema and transient flu like symptoms. Viral shedding was not seen in cerebral spinal fluid (CSF), urine and stool samples in all patients. Rising viral antibody titres were seen in all patients. In addition, we observed some evidence of local target tumor response activity in 7/19 patients (37 %) at the end of six or more weeks follow-up, with one patient exhibiting a complete response (CR), two a partial response (PR), and four stable disease (SD) to the local injected lesion. Conclusions Reolysin® is well tolerated given intralesionaly, with DLT/MTD not reached at a dose of 10 10 PFU. The favorable toxicity profile, lack of viral shedding and possible therapeutic activity has made this unattenuated oncolytic reovirus an attractive cancer therapeutic agent for ongoing clinical studies, including in the setting of locally advanced accessible disease for palliation of symptoms.

Multiple Myeloma (MM), a clonal malignancy of antibody-producing plasma cells, is the second most common hematologic malignancy and results in significant patient morbidity and mortality. The high degree of immune dysregulation in MM, including T cell imbalances and up-regulation of immunosuppressive checkpoint proteins and myeloid derived suppressor cells, allows this malignancy to escape from host immune control. Despite advances in the therapeutic landscape of MM over the last decade, including the introduction of immunomodulatory drugs, the prognosis for this disease is poor, with less than 50% of patients surviving 5 years. Thus, novel treatment strategies are required. Oncolytic viruses (OV) are a promising new class of therapeutics that rely on tumour specific oncolysis and the generation of a potent adaptive anti-tumour immune response for efficacy. To date, a number of OV have shown efficacy in pre-clinical studies of MM with three reaching early phase clinical trials. OVs represent a rational therapeutic strategy for MM based on (1) their tumour tropism, (2) their ability to potentiate anti-tumour immunity and (3) their ability to be rationally combined with other immunotherapeutic agents to achieve a more robust clinical response.