Anti-PD-1 Monoclonal Antibodies (mAbs) Are Superior to Anti-PD-L1 mAbs When Combined with Chemotherapy in First-Line Treatment for Metastatic Non-Small Cell Lung Cancer (mNSCLC): A Network Meta-Analysis.

Platinum-based chemotherapy combined with anti-PD-1 or PD-L1 monoclonal antibodies (mAbs) is now standard first-line therapy for mNSCLC patients without sensitizing driver mutations. Anti-PD-1 and anti-PD-L1 mAbs are considered to be equivalent in efficacy. In the absence of head-to-head randomized control trials (RCTs), we utilized network meta-analysis (NWM) to provide an indirect comparison of their efficacy. A systematic literature review and NWM were performed using RCTs that investigated anti-PD-1 or PD-L1 mAbs ± chemotherapy in patients with mNSCLC in the first-line setting. The primary outcome was comparative overall survival (OS), while secondary outcomes were comparative progression-free survival (PFS), objective response rate (ORR), and rate of grade 3 and higher toxicities. We identified 24 RCTs. Patients treated with anti-PD-1 mAb + chemotherapy compared with anti-PD-L1 mAb + chemotherapy showed superior mOS, mPFS, and ORR with a similar rate of grade 3 and higher toxicities. This difference in mOS was most pronounced in the PD-L1 TPS 1-49% population. The two mAbs were equivalent as single agents. Anti-PD-1 mAb + chemotherapy improved mOS when compared to anti-PD-1 mAb monotherapy, whereas anti-PD-L1 mAbs + chemotherapy did not when compared to anti-PD-L1 mAb monotherapy. Head-to-head RCTs are warranted in the future.

CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review.

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations-heterozygous deletions (HeD), point mutations, and promoter methylation-is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.

Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas.

Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes.

Dynamic quantification of MHC class I-peptide presentation to CD8+ T cells via intracellular cytokine staining.

In order to further our basic understanding of antigen processing and presentation as well as to translate that knowledge into clinically effective vaccines and immunotherapies, having appropriate tools to study MHC class I-peptide presentation is highly desirable. Current methods are based upon HPLC fractionation of extracted peptides, monoclonal Ab, multivalent T cell receptors (TCR), T cell hybridomas, TCR transgenic cells, and T cell lines. However, each of these is associated with problems that make them either difficult to apply generally or too insensitive to adequately quantitate antigen presentation. We have developed a method based upon intracellular cytokine staining (ICS) that dynamically and relatively quantitates MHC class I-peptide presentation to CD8+ T cells in a manner that is both widely applicable and highly sensitive. It is well-suited to assess antigen presentation in its early stages, does not require fixation nor labeling of antigen presenting cells (APC), can be used to examine cross-presentation, and is able to directly employ ex vivo T cells which obviates the need for the development and maintenance of T cell lines and hybridomas. Our method represents a simple yet powerful tool that others interested in studying antigen processing and presentation should find of great practical value.