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Other viral infections
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Human papillomavirus (HPV) is an icosahedral, non-enveloped, double-stranded deoxyribonucleic acid (DNA) virus of approximately 55nm in diameter (1). The genome of HPVs consists of approximately 8 kilobase paired molecules of circular, double-stranded DNA. All the proteins are encoded on one of the two DNA strands. All papilloma viruses share a similar genomic organization consisting of an early (E) gene region, a late (L) gene region, and a regulatory region. The five “early” proteins (E1, E2, E5, E6, E7) are required for viral replications and/or cellular transformation. Transformation of the “late” structural L1 and L2 transcripts and of the E1 to E4 spliced transcript is restricted to differentiating epithelium where viral assembly occurs (2,3). The L1 protein comprises the majority of the virus shell. The L1 gene is the most highly conserved gene among individual types. The L2 protein of 77 kDa is known as the minor capsid protein because it contributes a smaller percentage of the capsid mass than does the L1 protein.
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The classification of IO agents is challenging, and there is significant cross-over and ambiguity in the classification of these emerging agents. For example, some observers classify “immune checkpoint inhibitors (ICPis)” separately to monoclonal antibodies (mAbs). For the main families of IO agents, the anti-CTLA-4 (Cytotoxic T-Lymphocyte-Associated protein-4), anti-PD-1 (Programmed Cell Death Protein-1) and PD-L1 (Programmed Death-Ligand 1) agents, the clinical data relating to target expression and response to therapy is complex. For example, there are reports of responses to treatment irrespective of PD-L1 expression. There is also ambiguity around the thresholds used to define “positive” and “negative” biomarker expression values. The single antibodies targeting the CTLA-4, PD-1, and PD-L1 antigens are described below in more detail.
Lung Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
A discrepancy between FDA and EMA durvalumab licensing and PACIFIC trial inclusion criteria with regard to specific PD-L1 cutoff points has created some conflict as to what the eligibility criteria are in different countries. In the United Kingdom, a PD-L1 expression of >1% is required prior to Cancer Drugs Fund approval. It is still not clear whether PD-L1 expression is a relevant biomarker in Stage III disease.
PD-L1 and PD-L2 Mutations in Pediatric Hodgkin Lymphoma: Do They Have Any Prognostic Significance?
Published in Fetal and Pediatric Pathology, 2022
Gülen Gül, Dilek Ince, Nur Olgun, Erdener Ozer
In the analysis section of the sequenced exon and intron junction regions of PD-L1 and PD-L2 genes, only two separate mutational variants were found in the exome 5 of PD-L1 gene. Eight (20.5%) tumors showed a p.R260C mutation (Figure 2), and three (7.7%) tumors showed an additional p.R234L mutation. None of the tumors had PD-L2 mutations. The relationship between PD-L1 mutational status and clinicopathological parameters is demonstrated in Table 2. Seven of eight cases with PD-L1 mutation were either older than 14 years or of nodular sclerosing subtype. Of the eight cases with PD-L1 mutation, four patients were male and four female. In statistical analysis p.R260C mutation exhibited a significant relationship with older age and nodular sclerosing histological subtype (p = 0.04 and p = 0.04, respectively). However PD-L1 mutation did not statistically correlate with other parameters such as gender, presence of B symptoms and bulky disease, tumor stage, serum LDH and ESR levels, bone marrow involvement, disease relapse and outcome. ESR was relatively higher than 20 mm/h and serum LDH level was lower than 500 U/L in cases with PD-L1 mutations. Four patients with bone marrow involvement had no mutation. Overall eight cases with PD-L1 mutations were alive. Only one of those had disease relapse and four of these eight cases were without bone marrow involvement.
Radiation therapy and immunotherapy in breast cancer treatment: preliminary data and perspectives
Published in Expert Review of Anticancer Therapy, 2021
Kim Cao, Louisa Abbassi, Emanuela Romano, Youlia Kirova
The IMpassion 130 study was a phase III trial that has included 902 patients treated with atezolizumab or placebo in combination with first-line chemotherapy. At the first interim analysis (median follow-up of 12.9 months), the median PFS was significantly higher with atezolizumab plus nab-paclitaxel (7.2 months) compared with placebo plus nab-paclitaxel (5.5 months) (HR for progression or death: 0.80, 95%CI 0.69–0.92, p= 0.002) [41]. Of interest, atezolizumab associated with CT prolonged OS in the subgroup of patients with PD-L1 positive tumors. Updated results from the second interim analysis with a median follow-up of 18 months showed that this benefit in OS was maintained but with a smaller magnitude in this specific subgroup: median OS was 25.0 months (95%CI 19.6–30.7) with atezolizumab versus 18.0 months (13.6–20.1) with placebo (HR 0.71 [0.54–0.94]) [42]. This study led to the FDA-approval of atezolizumab in patients with PD-L1-positive metastatic TNBC. Final OS analysis recently presented at virtual ESMO this year, confirms this significant survival advantage with atezolizumab–nab-paclitaxel versus placebo in PD-L1+ patients: 25.4 (19.6, 30.7) versus 17.9 months (13.6, 20.3), HR 0.67 [0.53–0.86] (Ermens et al., LBA16). Importantly, this OS benefit was maintained at 3 years. However, there was still no survival benefit in PD-L1 negative patients.
An Open–Label, Randomized, Multi–Center Study Comparing the Sequence of High Dose Aldesleukin (Interleukin–2) and Ipilimumab (Yervoy) in Patients with Metastatic Melanoma
Published in OncoImmunology, 2021
Merve Hasanov, Denái R. Milton, William H. Sharfman, Bret Taback, Lee D. Cranmer, Gregory A Daniels, Lawrence Flaherty, Sigrun Hallmeyer, Mohammed Milhem, Lynn Feun, Ralph Hauke, Gary Doolittle, Nancy Gregory, Sapna Patel
The baseline characteristics of the patients in the ITT are described in Table 1. In ITT, there were 17 (58.6%) patients that had mutation testing. BRAF was the most frequent mutation identified, as it was reported by 9 (31.0%) patients. Additionally, two patients (6.9%), one from each treatment arm, tested positive for an NRAS mutation. Twenty-two out of 29 (75.9%) patients in ITT, 11 patients from each treatment arm received prior treatment before enrolling in the clinical trial. None of the patients received prior dacarbazine, temozolomide, platinum, vinca alkaloids, paclitaxel, or nitrosourea. No patients had prior treatment with antibodies against PD-1 or PD-L1. Details of the treatments are given in Table 1. The most common metastatic sites were lymph nodes (44.8%), lung (37.9%), liver (17.2%), and bone (13.8%), similar in both treatment arms (Table 1).