Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy

Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor-2 (HER2/ErbB-2), has become the mainstay of treatment for HER2-positive breast cancer. Nevertheless, its exact mechanism of action has not been fully elucidated. Although several studies suggest that Fc receptor-expressing immune cells are involved in trastuzumab therapy, the relative contribution of lymphocyte-mediated cellular cytotoxicity and antitumor cytokines remains unknown. We report here that anti-ErbB-2 mAb therapy is dependent on the release of type I and type II IFNs but is independent of perforin or FasL. Our study thus challenges the notion that classical antibody-dependent, lymphocyte-mediated cellular cytotoxicity is important for trastuzumab. We demonstrate that anti-ErbB-2 mAb therapy of experimental tumors derived from MMTV-ErbB-2 transgenic mice triggers MyD88-dependent signaling and primes IFN-γ-producing CD8+ T cells. Adoptive cell transfer of purified T cell subsets confirmed the essential role of IFN-γ-producing CD8+ T cells. Notably, anti-ErbB-2 mAb therapy was independent of IL-1R or IL-17Ra signaling. Finally, we investigated whether immunostimulatory approaches with antibodies against programmed death-1 (PD-1) or 41BB (CD137) could be used to capitalize on the immune-mediated effects of trastuzumab. We demonstrate that anti-PD-1 or anti-CD137 mAb can significantly improve the therapeutic activity of anti-ErbB-2 mAb in immunocompetent mice.     

Seeing the forest and the tree: TILs and PD-L1 as immune biomarkers

Here we will provide an immune-focussed overview of biomarkers in early and advanced stage breast cancer. It should be noted from the outset that all the biomarkers under discussion here have not been tested in prospective clinical trials to determine their predictive performance. Such trials require very large sample sizes due to the statistical burden of testing an interaction between a treatment and a biomarker, which is compounded by the heterogeneous biology of breast cancer (Polley et al. in J Natl Cancer Inst 105:1677–1683 2013 [1]). For a detailed discussion of the immunobiology of breast cancer, analytical aspects of these biomarkers, emerging biomarkers such as tumour mutation burden and detailed immunotherapy clinical trial data, see other articles in this issue.

     

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Purpose

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit.

Methods

We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection.

Results

Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise.

Conclusions

HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of ‘immune cold’ TNBCs.

     

Stereotactic body radiotherapy for oligometastatic soft tissue sarcoma

Background

Stereotactic body radiotherapy (SBRT) is emerging as a novel treatment option in metastatic soft tissue sarcoma (STS). The aim of our study was to evaluate the effectiveness of exclusive SBRT on disease control and survival in oligometastatic (≤?3 synchronous lesions) STS.

Materials and methods

In total, 16 consecutive patients, accounting for 26 metastases (including 21 lung and 5 lymph node or soft tissue metastases), were treated at our institution with SBRT. Patient- and treatment-related characteristics were collected. Local control (LC), overall survival (OS), distant metastases-free survival (DMFS), and time to initiation of chemotherapy or best supportive care (corrected disease-free survival, cDFS) were assessed.

Results

Four-year OS was 54% and median OS was 69 months [95% confidence interval (CI) 20–118 months]. LC of 26 lesions at 4 years was 78%. Median DMFS and cDFS were 17 (95% CI 5–30 months) and 28 months (95% CI 5–52 months), respectively. Disease-free interval <?24 months from primary tumor treatment to first metastasis was the only predictor of reduced LC, cDFS, and OS (p?=?0.022, 0.023, and 0.028, respectively). No acute or chronic grade ≥?3 toxicity was observed. Median follow-up was 36 months (IQR 18–71 months).

Conclusions

In patients with oligometastatic STS, SBRT yields satisfying local control with minimal toxicity. Median OS was 69 months. Repeated SBRT may be considered to extend disease-free and systemic therapy-free interval. Increased time from primary tumor to first metastasis identifies patients with potentially greater benefit from SBRT.

     

A Survey on Coronary Atherosclerotic Plaque Tissue Characterization in Intravascular Optical Coherence Tomography

Purpose of Review

Atherosclerotic plaque deposition within the coronary vessel wall leads to arterial stenosis and severe catastrophic events over time. Identification of these atherosclerotic plaque components is essential to pre-estimate the risk of cardiovascular disease (CVD) and stratify them as a high or low risk. The characterization and quantification of coronary plaque components are not only vital but also a challenging task which can be possible using high-resolution imaging techniques.

Recent Finding

Atherosclerotic plaque components such as thin cap fibroatheroma (TCFA), fibrous cap, macrophage infiltration, large necrotic core, and thrombus are the microstructural plaque components that can be detected with only high-resolution imaging modalities such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Light-based OCT provides better visualization of plaque tissue layers of coronary vessel walls as compared to IVUS. Three dominant paradigms have been identified to characterize atherosclerotic plaque components based on optical attenuation coefficients, machine learning algorithms, and deep learning techniques.

Summary

This review (condensation of 126 papers after downloading 150 articles) presents a detailed comparison among various methodologies utilized for plaque tissue characterization, classification, and arterial measurements in OCT. Furthermore, this review presents the different ways to predict and stratify the risk associated with the CVD based on plaque characterization and measurements in OCT. Moreover, this review discovers three different paradigms for plaque characterization and their pros and cons. Among all of the techniques, a combination of machine learning and deep learning techniques is a best possible solution that provides improved OCT-based risk stratification.

     

A multi-institutional experience in adventitial cystic disease

Background

Adventitial cystic disease (ACD) is an unusual arteriopathy; case reports and small series constitute the available literature regarding treatment. We sought to examine the presentation, contemporary management, and long-term outcomes using a multi-institutional database.

Study of impulse-control disorders among alcohol-dependent patients.

BACKGROUND: Impulse-control disorders (ICDs) include intermittent explosive disorder, kleptomania, trichotillomania, pyromania, and pathological gambling. Several studies have suggested that the incidence of pathological gambling is substantially higher in alcoholics than in the general population. The rate of co-occurrence of other ICDs and alcohol dependence has never been systematically investigated. In our study, we assessed the frequency of all ICDs in a population of alcohol-dependent patients. We also examined the possibility that the presence of an ICD can correspond to earlier onset and more severe forms of alcoholism, which have a greater association with antisocial personality. METHOD: All patients hospitalized at our psychiatric unit for detoxification between January and August 1997 met DSM-IV criteria for alcohol dependence and were included in this study. Diagnosis of alcohol dependence was confirmed with the Mini-International Neuropsychiatric Interview. ICDs were investigated using the Minnesota Impulsive Disorders Interview. All patients completed the Michigan Alcoholism Screening Test. RESULTS: Among the 79 patients included in the study, 30 (38.0%) met criteria for an ICD. Included in the study were 19 cases of intermittent explosive disorder, 7 cases of pathological gambling, 3 cases of kleptomania, and 1 case of trichotillomania. Patients with co-occurring ICDs were significantly younger than patients without an ICD (mean age = 40.7 vs. 44.5 years; p = .03). Patients with co-occurring pathological gambling were significantly younger at the onset of alcohol dependence than patients without ICDs (mean age = 19.5 vs. 25.9 years; p = .0008). Pathological gamblers had significantly longer duration of alcohol dependence compared with patients without ICDs (26.0 vs. 17.9 years; p = .02). Patients with co-occurring intermittent explosive disorder had the shortest duration of alcohol dependence of all patients (9.9 years). Prevalence of antisocial personality disorder was no different in patients with or without co-occurring ICDs. CONCLUSION: Thirty-eight percent of the alcohol-dependent patients studied presented with an ICD. Patients with ICDs were younger than those without an ICD. The presence of an ICD was not associated with a specific form of alcohol dependence or with antisocial personality. Co-occurrence of pathological gambling, however, was associated with lower age at onset of alcohol dependence, a higher number of detoxifications, and a longer duration of alcohol dependence than was absence of an ICD.