Immunotherapy Trials Research Articles

An open-label clinical trial of RP2 and RP3 oncolytic immunotherapy in combination with atezolizumab plus bevacizumab for the treatment of patients with advanced colorectal carcinoma.

TPS228 Background: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality worldwide. PD-1/PD-L1 inhibition, in combination with other modalities, has demonstrated significant benefit in patients (pts) with microsatellite instability-high or mismatch repair–deficient CRC. However, these agents have limited, if any, clinical benefit in pts with microsatellite stable (MSS) or mismatch repair–proficient (pMMR) CRC. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 which expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), granulocyte-macrophage colony-stimulating factor (GM-CSF), and an anti–CTLA-4 antibody-like molecule; RP3 additionally expresses 4-1BB and CD40 activating ligands but does not express GM-CSF. Both agents have demonstrated preliminary safety and antitumor activity in pts with solid tumors. This study will evaluate the safety and activity of RP2 and RP3 in combination with atezolizumab (Atezo) plus bevacizumab (Bev) in pts with advanced MSS/pMMR CRC (NCT05733611). Methods: Pts with a histologic diagnosis of unresectable and/or metastatic CRC, with documented MSS or pMMR status, and previously treated with up to 3 standard-of-care systemic regimens will be enrolled in the RP2 + Atezo + Bev or RP3 + Atezo + Bev treatment groups (30 pts per group). Further key inclusion criteria include Eastern Cooperative Oncology Group performance status 0 to 1 and adequate hepatic, renal, and hematologic function. RP2/RP3 will be injected into tumors by direct or image-guided injection. Pts will receive 8 total doses of up to 10 mL of RP2 or RP3, with a first dose concentration of 1 × 106 plaque-forming units (PFU)/mL, followed by 3 doses of 1 × 107 PFU/mL every 2 weeks, and then 4 doses of 1 × 107 PFU/mL every 3 weeks. Pts may receive a second course of up to 8 injections of RP2/RP3 if study criteria are met. Bev will be administered starting on week 1; Atezo will be administered starting week 7. The primary endpoint is objective response rate; secondary endpoints are safety, overall survival, progression-free survival, duration of response, and complete response rate. Antitumor activity will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 as modified for this study. Safety will be assessed by physical examination, clinical laboratory evaluations, vital signs, and monitoring for adverse events (AEs; including serious AEs). Clinical trial information: NCT05733611 .

Sequential or up-front triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma (HCC): MONTBLANC.

TPS574 Background: Escalation of treatment from one to two combined immune checkpoint inhibitors (CPI) has dramatically increased objective and clinical response in advanced hepatocellular carcinoma (HCC) patients. Establishing strategies with more than two CPI agents to further increase response while maintaining a manageable toxicity is therefore a top priority. The upfront simultaneous use of three or more CPI can yield a strong initial response to treatment, but it may also increase treatment-related toxicity. An alternative approach, which prioritizes safety over immediate response, involves utilizing different CPI doublets in a sequential manner. However, this design entails switching to a different combination only after radiological progression is observed, and recurrent progressions may lead to deteriorating liver function and treatment resistance. Trials of immunotherapy of HCC conducted in recent years showed that the efficacy of CPI, when used simultaneously, outweighs the drawbacks of their combined toxicity and that early radiological response to treatment, or the lack thereof, is a predictor of clinical outcome. In addition, failure of trials using broad-spectrum tyrosine kinase inhibitors (TKI) and CPI suggest that antibodies or narrow-spectrum TKI should be used for future CPI-based combinations in HCC studies. Based on these considerations, the MONTBLANC study is the first trial to assess the effectiveness of up-front triple treatment with a combination of the three currently approved immunological agents for HCC and to implement the concept of treatment escalation determined by lack of early radiological response (as opposed to treatment progression). Methods: The MONTBLANC study is a randomized, 2-arm phase II study on the efficacy of combinations of durvalumab, tremelimumab, and bevacizumab in patients with advanced HCC. Patients with preserved liver function (Child-Pugh A) with unresectable tumors or not amenable to local or locoregional treatment are randomized to an early escalation arm (A) or a triple treatment arm (B). Patients in arm A receive combined durvalumab and tremelimumab (STRIDE regimen). Treatment is escalated by the addition of bevacizumab upon detection of disease progression or in the absence of radiological response by the 4th month of treatment. Patients in arm B receive up-front STRIDE and bevacizumab. Treatment will continue until unacceptable toxicity or progression under the Bev-containing regimen. The primary endpoint is overall response rate (ORR). Clinical trial information: NCT05844046 .

Benefit of immune checkpoint inhibitors (ICI) for patients with advanced esophageal squamous cell carcinoma and low PD-L1 expression: A systematic review and meta-analysis.

346 Background: Immunotherapy has improved survival for patients with advanced esophageal squamous cell carcinoma (aESCC) and currently is the standard of care for patients with a positive PD-L1 status (CPS ≥10; TPS ≥1%) in the first-line setting. For PD-L1 negative/low, treatment options are limited, and chemotherapy is usually the first choice and associated with adverse events that may impair quality of life. Immunotherapy trials harbor conflicting results in this subgroup of patients, therefore, we performed a systematic review and meta-analysis to evaluate the potential benefit of ICI as single treatment for patients with aESCC and a PD-L1 expression negative/low. Methods: Studies that enrolled patients with aESCC treated with ICI versus chemotherapy in first and second-line settings and provided separate outcomes for patients with PD-L1 negative/low were identified by searching the EMBASE, PubMed and Cochrane databases. The outcomes evaluated were Overall Survival (OS), Progression Free-Survival (PFS) and Treatment-Emergent Adverse Events (TEAE). We pooled hazard ratio (HR) for PFS and OS endpoints and odds ratio (OR) with 95% confidence intervals (CI) for TEAE. Statistical analyses were performed using Revman 5.4 and a random-effects model. I² analysis was used to assess heterogeneity. This meta-analysis was recorded on Prospero ID CRD42023411251. Results: We included 6 randomized clinical trials with a total of 674 individuals in the final analysis. Most studies (5/6) included previously treated patients. ICI monotherapy in aESCC patients and PD-L1 expression negative/low was associated with a better OS (HR 0.86; 95% CI 0.76-0.97; p = 0.02; I² = 0%) and worse PFS (HR 1.37; 95% CI 1.10-1.71; p = 0.005; I² = 0%). Regarding the safety profile, it showed higher grade 3-5 toxicity rates (OR 1.8; 95% CI 1.17-2.78; p = 0.007; I² = 85%) for chemotherapy. Conclusions: ICI is effective for patients with aESCC and low/negative PD-L1 expression with an improvement in OS and a favorable safety profile.

A class of constrained optimal control problems arising in an immunotherapy cancer remission process

<p>By considering both the single drug dose and the total drug input during the treatment period, we propose a new optimal control problem by maximizing the immune cell levels and minimizing the tumor cell count, as well as the negative effects of the total drug quantity over time. To solve this problem, the control parameterization technique is employed to approximate the control function by a piecewise constant function, which gives rise to a sequence of mathematical programming problems. Then, we derive gradients of the cost function and/or the constraints in the resulting problems. On the basis of this gradient information, we develop a numerical approach to seek the optimal control strategy for a discrete drug administration. Finally, numerical simulations are conducted to assess the impact of the total drug input on the tumor treatment and to evaluate the rationality of the treatment strategy within the anti-cancer cycle. These results provide a theoretical framework that can guide clinical trials in immunotherapy.</p>

Epithelioid angiosarcoma of the pericardium: Case report of the challenges in the management of a rare malignancy with poor prognosis.

A primary epithelioid angiosarcoma of the pericardium is a rare soft tissue malignancy. This report describes a young adult woman who presented with progressive dyspnea and pericardial effusion. She was found to have pericardial mass on imaging along with extensive myocardial infiltration. The biopsy of the mass revealed epithelioid angiosarcoma, which was CD34 and CD31-immuno-positive. Due to unresectable disease, she was given a trial of immunotherapy followed by conventional chemotherapy. She showed partial response on interim assessment, but progressed soon after the completion of six cycles and succumbed to her rapidly progressive illness within nine months of diagnosis. This report discusses the diagnostic and therapeutic challenges faced while managing this disease of aggressive tumor biology.

Infectious Diseases and Their Role in Neuroimmune Disease

Recent findings suggest a relationship between a post-infectious immune response and neurologic changes. These changes, manifesting as various neurological symptoms, including memory issues and cognitive alterations, may be linked to a form of post-infectious autoimmunity. We have coined the term “Alzheimer’s of the Immune System,” or AIS, to describe this syndrome and various immune partners that may play a role in this immune dysfunction have been identified. Here, we will discuss several clinical presentations that feed into the hypothesis of infectious-immune axis and its mechanism of action. We propose that these disorders fall under the umbrella of AIS and discuss the role of immuno therapy in their management. First, we consider pediatric acute-onset neuropsychiatric syndrome (PANS), a broad diagnostic criterion created to describe children with severe, sudden onset of neuropsychiatric changes. Research exploring the link between immune dysregulation in PANS and its amelioration with intravenous immunoglobulin treatment strongly suggests the association of PANS with a pro-inflammatory state. Next, we delve into autism spectrum disorder (ASD), characterizing it as a neuroimmune disorder. ASD marked by communication and social skill deficits, as well as repetitive and stereotypical behaviors, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both the mother’s and child’s immune systems, and their potential role in diagnosis and treatment. Lastly, we discuss post-viral fatigue syndrome in patients who have recovered from SARS-CoV-2 infection as another example of neuroimmune condition recently added to the growing list. Further research is needed to validate our hypothesis of AIS, including large scale randomized control trials of different immuno therapies. By unravelling the infectious-immune axis and its mechanism of action, we equip physicians with valuable tools for identifying optimal forms of treatment and management for these conditions.

The transcriptomic expression pattern of immune checkpoints shows heterogeneity between and within cancer types.

Transcriptomic expression profiles of immune checkpoint markers are of interest in order to decipher the mechanisms of immunotherapy response and resistance. Overall, 514 patients with various solid tumors were retrospectively analyzed in this study. The RNA expression levels of tumor checkpoint markers (ADORA2A, BTLA, CD276, CTLA4, IDO1, IDO2, LAG3, NOS2, PD-1, PD-L1, PD-L2, PVR, TIGIT, TIM3, VISTA, and VTCN) were ranked from 0-100 percentile based on a reference population. The expression of each checkpoint was correlated with cancer type, microsatellite instability (MSI), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) by immunohistochemistry (IHC). The cohort included 30 different tumor types, with colorectal cancer being the most common (27%). When RNA percentile rank values were categorized as "Low" (0-24), "Intermediate" (25-74), and "High" (75-100), each patient had a distinctive portfolio of the categorical expression of 16 checkpoint markers. Association between some checkpoint markers and cancer types were observed; NOS2 showed significantly higher expression in colorectal and stomach cancer (P < 0.001). Principal component analysis demonstrated no clear association between combined RNA expression patterns of 16 checkpoint markers and cancer types, TMB, MSI or PD-L1 IHC. Immune checkpoint RNA expression varies from patient to patient, both within and between tumor types, though colorectal and stomach cancer showed the highest levels of NOS2, a mediator of inflammation and immunosuppression. There were no specific combined expression patterns correlated with MSI, TMB or PD-L1 IHC. Next generation immunotherapy trials may benefit from individual analysis of patient tumors as selection criteria for specific immunomodulatory approaches.

The pathophysiology of sepsis and precision-medicine-based immunotherapy.

Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations.

Genetic and T2 biomarkers linked to the efficacy of HDM sublingual immunotherapy in asthma

BackgroundHypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT).ObjectiveTo investigate whether genetic and type 2...

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy

Background and objectiveNeoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. MethodsPatients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, <ypT2N0 rates, 2-yr recurrence-free survival (RFS), and OS. Key findings and limitationsAmong 43 patients enrolled (n = 13, cohort 1; n = 30, cohort 2), 13 and 29 completed intended neoadjuvant therapy, respectively, in cohorts 1 and 2, and 41 underwent RC. The median time from the last dose to RC was 4 wk. The G3 TRAEs occurred in 0% (90% confidence interval [CI] 0–21%) of patients in cohort 1 and 7% (90% CI 1–20%) in cohort 2; all these TRAEs resolved and no G4/5 TRAEs occurred. No patient had delayed RC for >6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, <ypT2N0 rates were 25% and 32%, 2-yr RFS rates were 73% and 71%, and 2-yr OS rates were 82% and 89%, respectively. CD8+ T-cell density increased significantly from TURBT to RC in cohort 2. Conclusions and clinical implicationsNeoadjuvant nivolumab-based immunotherapy was safe, feasible, and well tolerated in cisplatin-ineligible patients with MIBC. Although ypT0N0 rates were lower than expected, 2-yr survival rates seem to be comparable with those of other neoadjuvant immunotherapy trials. Nivolumab is being evaluated in the CA-017-078 trial (NCT03661320). Patient summaryFor patients with muscle-invasive bladder cancer unable to receive cisplatin-based chemotherapy, treatment with nivolumab without and with lirilumab prior to radical cystectomy was safe, feasible, and well tolerated. Nivolumab-based immunotherapy showed lower pathologic response rates than but similar survival rates to other neoadjuvant immunotherapy trials.

A novel, high-performance, low-volume, rapid luciferase immunoprecipitation system (LIPS) assay to detect autoantibodies to zinc transporter 8.

Zinc transporter 8 autoantibodies (ZnT8A) are thought to appear close to type 1 diabetes (T1D) onset and can identify high-risk multiple (≥2) autoantibody positive individuals. Radiobinding assays (RBA) are widely used for ZnT8A measurement but have limited sustainability. We sought to develop a novel, high-performance, non-radioactive luciferase immunoprecipitation system (LIPS) assay to replace RBA. A custom dual C-terminal ZnT8 (aa268-369; R325/W325) heterodimeric antigen, tagged with a NanoluciferaseTM (Nluc-ZnT8) reporter, and LIPS assay was developed. Assay performance was evaluated by testing sera from new onset T1D (n = 573), healthy schoolchildren (n = 521), and selected first-degree relatives (FDRs) from the Bart's Oxford family study (n = 617; 164 progressed to diabetes). In new-onset T1D, ZnT8A levels by LIPS strongly correlated with RBA (Spearman's r = 0.89; P < 0.0001), and positivity was highly concordant (94.3%). At a high specificity (95%), LIPS and RBA had comparable assay performance [LIPS pROC-AUC(95) 0.032 (95% CI: 0.029-0.036); RBA pROC-AUC(95) 0.031 (95% CI: 0.028-0.034); P = 0.376]. Overall, FDRs found positive by LIPS or RBA had a comparable 20-year diabetes risk (52.6% and 59.7%, respectively), but LIPS positivity further stratified T1D risk in FDRs positive for at least one other islet autoantibody detected by RBA (P = 0.0346). This novel, high-performance, cheaper, quicker, higher throughput, low blood volume Nluc-ZnT8 LIPS assay is a safe, non-radioactive alternative to RBA with enhanced sensitivity and ability to discriminate T1D progressors. This method offers an advanced approach to current strategies to screen the general population for T1D risk for immunotherapy trials and to reduce rates of diabetic ketoacidosis at diagnosis.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450μg (n=42) or placebo (n=23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months. CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P<0.001), and three amyloid-related imaging abnormality cases (one symptomatic). Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Reaching Communities Through Food Allergy Advocacy, Research, and Education: A Comprehensive Analysis

This article explores the multifaceted approach of food allergy (FA) advocacy, research, and education to address the diverse challenges associated with FA, such as disparities in socioeconomic status, food security, quality of life, and the overall burden of the disease. Advocacy initiatives are instrumental in driving policy changes, raising public awareness, and directing substantial research funding, with a focus on reducing disparities. They have influenced allergen labeling regulations and improved access to epinephrine, emphasizing the importance of school-based management plans, especially in underserved communities. Research in FA informs medical practices and offers them hope for improved treatments. Recent breakthroughs in peanut allergy prevention and oral immunotherapy trials exemplify the potential for advancements while highlighting the need to address disparities in health care access. Education is a critical tool for prevention, raising awareness, and reducing the risk of allergic reactions. Efforts should be tailored to reach marginalized communities, particularly in schools where education on FA management is essential. Collaborating directly with communities is imperative to ensure inclusivity and address disparities. Barriers such as mistrust, language and cultural differences, and lack of diversity among researchers must be overcome to encourage diverse participation in research studies. This article concludes by emphasizing the significance of a comprehensive approach to FA research that prioritizes equity and inclusivity. The call to action highlights the need for global initiatives to reshape the landscape of FA care and address disparities in health care access and outcomes.

Sequential monitoring of cancer immunotherapy trial with random delayed treatment effect

ABSTRACT Cancer immunotherapy trials are frequently characterized by a delayed treatment effect that violates the proportional hazards assumption. The log-rank test (LRT) suffers a substantial loss of statistical power under the nonproportional hazards model. Various group sequential designs using weighted LRTs (WLRTs) have been proposed under the fixed delayed treatment effect model. However, patients enrolled in immunotherapy trials are often heterogeneous, and the duration of the delayed treatment effect is a random variable. Therefore, we propose group sequential designs under the random delayed effect model using the random delayed distribution WLRT. The proposed group sequential designs are developed for monitoring the efficacy of the trial using the method of Lan-DeMets alpha-spending function with O’Brien-Fleming stopping boundaries or a gamma family alpha-spending function. The maximum sample size for the group sequential design is obtained by multiplying an inflation factor with the sample size for the fixed sample design. Simulations are conducted to study the operating characteristics of the proposed group sequential designs. The robustness of the proposed group sequential designs for misspecifying random delay time distribution and domain is studied via simulations.

A Composite Decision Rule of CD8+ T-cell Density in Tumor Biopsies Predicts Efficacy in Early-stage, Immunotherapy Trials.

To examine whether CD8+ T-cell numbers in paired tumor biopsies in early-stage clinical trials can be used as an early indicator of clinical benefit for cancer immunotherapies. Paraffin sections of tumor biopsies were stained immunohistochemically for CD8+ T cells, which were digitally enumerated. The tumor biopsies were from cancer patients in early-phase trials testing novel immunotherapeutic agents. Paired biopsies taken before the start of treatment and on-treatment were compared. A total of 155 patients were used as the training set and an additional 221 patients were used as the validation set. Using the Cox proportional hazard model, a ≥0.9- increase in fold change (FC) on a ln scale in CD8+ T cells (corresponding to a 2.5-fold increase on the linear scale), from baseline, demonstrated a greater association with prolonged progression-free survival and allowed improved differentiation between groups above and below the threshold. Similarly, a ≥6.2 threshold in geometric mean of the on-treatment density (OTD) of T cells, which approximately corresponds to 500 cells/mm2, correlated with longer PFS. The combination of both criteria (FC and OTD) provided the best discrimination between clinically nonactive and active compounds. We propose that a composite score of CD8+ T-cell density in paired biopsies taken before and on-treatment may be a new biomarker to inform on clinical outcomes in early immunotherapy clinical trials.

Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study

The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. French National Cancer Institute.

Facts and Hopes on Biomarkers for Successful Early Clinical Immunotherapy Trials: Innovative Patient Enrichment Strategies.

Despite the clinical validation and unequivocal benefit to patients, the development of cancer immunotherapies is facing some key challenges and the attrition rate in early phases of development remains high. Identifying the appropriate patient population that would benefit most from the drug is on the critical path for successful clinical development. We believe that a systematic implementation of patient enrichment strategies early in the drug development process and trial design, is the basis for an innovative, more efficient, and leaner clinical development to achieve earlier a clear proof of concept or proof of failure. In this position article, we will describe and propose key considerations for the implementation of patient enrichment strategies as an opportunity to provide decision-enabling data earlier in the drug development process. We introduce an innovative multidimensional tool for immuno-oncology drug development that focuses on facilitating the identification and prioritization of enrichment-relevant biomarkers, based on the drug mechanism of action. To illustrate its utility, we discuss patient enrichment examples and use a case in the field of cancer immunotherapy, together with technical and regulatory considerations. Overall, we propose to implement fit for purpose enrichment strategies for all investigational drugs as early as possible in the development process. We believe that this will increase the success rate of immuno-oncology clinical trials, and eventually bring new and better medicines to patients faster.

A Human Adenovirus C Infection-Related Gene Panel for Predicting Survival and Treatment Responsiveness in Glioma Patients

Viruses are critical for the regulation of cancer development and for therapy. Human adenovirus C (HadVC) has been detected in central nervous system and glioma tissue. The objective of the present study was the development of a robust prognostic model based on HadVC infection (HadVCi)-relevant genes. The genome, transcriptome, and virome were systemically analyzed using The Cancer Genome Atlas dataset for training and 2 cohorts from the Chinese Glioma Genome Atlas and an immunotherapy trial cohort with 17 patients receiving anti-PD-1 treatment for validation. HadVCi-relevant gene selection from differentially expressed genes between HadVC-infected and non-HadVC-infected glioma patients using least absolute shrinkage and selection operator regression was followed by Cox regression modeling to establish a prognostic HadVCi score. Kaplan-Meier and receiver operating characteristic curve analyses were performed to estimate the predictive capacity of the HadVCi score. The χ2, Spearman, and Mann-Whitney U tests were used to identify the correlation with the clinicopathological parameters, treatment responsiveness, and immune landscape. Temozolomide-resistant glioma cells were established and analyzed at the transcriptional level using RNA sequencing data. The HadVCi score was (-0.2526673∗TRPC6)+(-0.2244276∗RNF207)+ (-0.0894468∗SEC31B)+ (-0.0190214∗ZCRB1)+ (-0.017122∗DNPH1)+ (0.0495818∗CCDC34)+ (0.1196349∗PURG)+ (0.1778997∗LILRA5). The score possesses a strong ability to predict overall survival. Further analysis revealed a higher HadVCi score correlated with a malignant phenotype and poorer treatment responsiveness to temozolomide-based chemotherapy and combined therapies. Additionally, transcriptomic analysis showed malignancy-, stemness-, and radioresistant-related gene activation in the HadVCi group, which characterized the poor outcomes and limited sensitivity to standard therapy. The HadVCi score could be an effective tool for survival prediction and treatment guidance for patients with glioma.

Immunity in malignant brain tumors: Tumor entities, role of immunotherapy, and specific contribution of myeloid cells to the brain tumor microenvironment.

Malignant brain tumors lack effective treatment, that can improve their poor overall survival achieved with standard of care. Advancement in different cancer treatments has shifted the focus in brain tumor research and clinical trials toward immunotherapy-based approaches. The investigation of the immune cell landscape revealed a dominance of myeloid cells in the tumor microenvironment. Their exact roles and functions are the subject of ongoing research. Current evidence suggests a complex interplay of tumor cells and myeloid cells with competing functions toward support vs. control of tumor growth. Here, we provide a brief overview of the three most abundant brain tumor entities: meningioma, glioma, and brain metastases. We also describe the field of ongoing immunotherapy trials and their results, including immune checkpoint inhibitors, vaccination studies, oncolytic viral therapy, and CAR-T cells. Finally, we summarize the phenotypes of microglia, monocyte-derived macrophages, border-associated macrophages, neutrophils, and potential novel therapy targets.

Cerebral amyloid angiopathy frequency at baseline and after 4 years of follow‐up in the INSIGHT‐preAD study

AbstractBackgroundCerebral amyloid angiopathy (CAA) diagnostic is of special interest due to its association with cognitive impairment, Alzheimer disease (AD) and Amyloid‐Related Imaging Abnormalities (ARIA) in trials with anti‐amyloid immunotherapies. We aimed to assess the frequency of CAA diagnosis and associated lesions in subjects with cognitive complaint and normal cognition enrolled in the INSIGHT‐preAD study.MethodCognitively normal elderly with memory complaint included in the INSIGHT‐preAD study were assessed with multimodal explorations for 5 years follow‐up. 3T MRI‐scans were performed at baseline and during follow‐up at 2 and 4 years. Lobar cerebral microbleeds (CMB), cortical superficial siderosis (CSS), enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) were rated according to validated scales and guidelines. Boston criteria V2.0 were applied to diagnose possible and probable CAA.ResultAmong the 318 subjects (median [Q1, Q3] age: 76.4 [74.1, 78.5] years, 201 (63.2%) women) enrolled at baseline, 41 (12.9%) had at least one lobar CMB, 4 (1.3%) CSS, 68 (21.7%) severe EPVS in the centrum semi‐ovale and 245 (77%) WMH with a spot pattern ≥10. The median FAZEKAS score was 2.0 [1.0, 2.0]. At baseline, 251 (78.9%) subjects had CAA: 218 (68.5%) possible CAA and 33 (10.4%) probable CAA with a median number of CMB of 1.0 [1.0, 1.0]. Compared to non‐CAA subjects (n = 67), those with probable CAA at baseline were not different on demographics and vascular risk factor, had more executive dysfunction, and tended to be associated with Apoe4 status and lower hippocampal volume. After 2‐ and 4‐ years of follow‐up, 81.2% and 81.3% of the subjects still in the study had CAA, with 13.3% and 14.1% of probable CAA respectively, and the number of subjects with CMB increased to 15.9% and 18.3%.ConclusionIn the INSIGHT‐preAD study, the high frequence of CAA, with minimal change after 4 years follow‐up, was essentially due to the non‐hemorrhagic lesions. The hemorrhagic lesions (CMB and CSS) were uncommon, probably underestimated by the MRI T2* sequence. These results have implications in clinical setting and could be useful in pre‐symptomatic AD anti‐amyloid immunotherapy trial.