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No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1–46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3–36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5–29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0–26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3–4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

The TP53 gene, encoding the critical p53 tumor suppressor, is the most commonly mutated gene in cancer. Intratumoral T cell responses to mutations occurring frequently at certain TP53 positions, termed hot spots, have not been systematically studied. The 8 most commonly mutated positions in TP53 were found in 33 (24%) of 140 common epithelial tumors analyzed. A TP53-specific screening assay was developed to evaluate T cell responses to these p53 neoepitopes presented though intracellular (tandem minigene) and extracellular (pulsed peptide) pathways on autologous antigen-presenting cells expressing all human leukocyte antigen (HLA) class I and II molecules. Tumor-infiltrating lymphocytes (TILs) from 11 patients recognized autologous p53 neoantigens, which accounted for 8% and 39% of all patients sequenced (n = 140) and screened (n = 28), respectively. These responses were restricted by a variety of HLA restriction elements, including common class I (A*02:01) and class II (DPB1*02:01 and DRB1*13:01) alleles. T cell receptors (TCRs) were identified from TP53 mutation-reactive helper (CD4) and cytotoxic (CD8) T cells, and TIL and TCR gene-engineered T cells recognized tumor cell lines endogenously expressing HLA and mutant TP53. Thus, the most commonly mutated gene in cancer, TP53, appears to be immunogenic and represents an attractive candidate for evaluating targeted immune cancer therapies.

Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation.

Purpose To determine whether abagovomab induces protective immune responses in ovarian cancer patients in first clinical remission. The present analysis is a substudy of monoclonal antibody immunotherapy for malignancies of the ovary by subcutaneous abagovomab trial (NCT00418574). Methods The study included 129 patients, 91 in the abagovomab arm and 38 in the placebo arm. Circulating CA125-specific cytotoxic T lymphocytes (CTL) were measured by a flow cytometry-based interferon-γ producing assay. Human antimouse antibody and anti-anti-idiotypic (Ab3) were assessed by ELISA. Patients were evaluated before starting the treatment and at different time points during induction and maintenance phases. Results A similar percentage of patients in both the placebo and abagovomab arms had CA125-specific CTL (26.3 and 31.8 %, respectively; p  = 0.673 by Fisher’s exact test). Patients with CA125-specific CTL in both arms tended to have an increased relapse-free survival (RFS, log-rank test p  = 0.095) compared to patients without. Patients ( n  = 27) in the abagovomab arm without CA125-specific CTL but that developed Ab3 above the cutoff (defined as median Ab3 level at week 22) had a prolonged RFS compared to patients ( n  = 24) that did not develop Ab3 above the cutoff (log-rank test p  = 0.019). Conclusion Abagovomab does not induce CA125-specific CTL. However, patients with CA125-specific CTL perform better than patients without, irrespective of abagovomab treatment. Abagovomab-induced Ab3 associate with prolonged RFS in patients without CA125-specific CTL. Further studies are needed to confirm these data and to assess the potential utility of these immunological findings as a tool for patient selection in clinical trial.

Ectopic germinal centers (GCs) are often formed in the thymus of patients with anti‐acetylcholine receptor antibody (anti‐AChR Ab)‐positive thymic epithelial tumors (TETs) and are considered sites where B cells undergo affinity maturation to produce high‐affinity anti‐AChR Abs, contributing to the development of myasthenia gravis. To evaluate the clinical relevance of these ectopic GCs, we analyzed their distribution and associations with thymic involution and anti‐AChR Ab titers using paraffin‐embedded surgical specimens from 79 TET patients. Thymic involution was scored, and immunohistochemistry was performed to identify cells involved in GC formation. GCs were identified in 32 of the 79 cases. The anti‐AChR Ab+ group had significantly higher frequencies of GCs in the residual thymus compared to the Ab− group. In all cases with GCs in the residual thymus, GCs were found both near the tumor and at distances greater than 1 cm from the tumor. Within the anti‐AChR Ab+ group, GC+ patients were significantly younger and showed milder thymic involution than GC− patients. The number of GCs per unit area positively correlated with serum antibody titer. In Ab+ cases, AChR‐α1 antigens were significantly more frequent in GC+ cases. In mildly involuted thymus, AChR antigens, antigen‐presenting cells, and B cells were detected in the medulla, whereas these were rarely observed in severely involuted thymus. These findings suggest that GC formation occurs preferentially in a less involuted thymus and that surgical resection of at least the extent of a total thymectomy may be indicated in younger patients with anti‐AChR Ab+ TETs. In this study, we demonstrate that ectopic germinal centers were observed in less involuted thymus of thymic epithelial tumors positive for antiacetylcholine receptor antibodies, associating their presence with higher antibody titers and supporting the need for at least a total thymectomy in younger patients.

Macrophage polarization is relevant for tumor biology. M2 polarized macrophages favor tumor growth and survival, while M1 macrophages support tumor destruction and antigen presentation. Markers identifying M1/M2 polarization are a subject of debate. We conducted a systematic review and meta-analysis to investigate the association of proposed macrophage markers with prognosis across epithelial tumors and melanoma. The Medline search engine was used and 195 articles were recovered for full review. Only articles which measured markers using immunohistochemistry or immunofluorescence and had overall survival (OS) as the primary endpoint were included. One hundred and thirteen articles were finally accepted for analysis. CD68 was associated with worse survival across tumors (hazard ratio (HR) = 1.24, 95% CI = 1.11–1.37). Tumor anatomical location influenced this association. Colorectal tumors showed an inverse association between CD68 and OS in contrast to the rest of cancer types (HR = 0.56 vs. 1.34). The approach taken to measure CD68 had an impact on prognosis; when macrophages were measured at the tumor invasion front prognosis was more favorable than when they were measured intratumorally (HR = 0.94 vs. 1.4). CD163, CD204, and CD206 showed a robust association with worse OS (HR = 1.63, 1.95, 1.65, respectively). Tumors arising in the lung and the liver showed a weaker association between CD163 and OS as compared with other locations ( β  = −0.5401 for the lung and −0.5940 for the liver compared with other anatomical locations). The counting strategy also had an impact on CD163 association with OS, with hot-spot counting having higher HRs compared with averaging macrophage counts across spots or absolute cell counting ( β  = −0.4678). In conclusion, proposed M2 markers are associated with worse survival across epithelial tumors and melanoma. The anatomical origin of tumors influences this association. The compartment where the macrophages were scored and counting strategy influenced the association with OS of CD68 and CD163, respectively.

Programmed death-ligand 1 (PD-L1) expression in various tumors is known to correlate with the efficacy of immune checkpoint inhibitors; however, evaluation of PD-L1 expression in thymic epithelial tumors (TETs) using multiple antibodies are limited. We retrospectivity evaluated PD-L1 expression in thymomas and thymic carcinomas using two antibodies, SP142 and SP263, and compared their expression rates in each type of TETs. We retrospectively included 37 cases of thymoma and 11 cases of thymic carcinoma that were histologically diagnosed between January 2000 and December 2020. PD-L1 expression was assessed using SP142 and SP263 antibodies with semi-quantitative scoring. The concordance rate for PD-L1 positivity between SP142 and SP263 was 81.2%, whereas the concordance rate for high PD-L1 expression was 83.3%. SP142 showed positive PD-L1 expression in 23 (62%) thymoma cases and eight (73%) thymic carcinoma cases. In contrast, SP263 antibody showed positive PD-L1 expression in 31 (84%) cases of thymoma and 9 (82%) cases of thymic carcinoma. In addition, type B thymomas exhibited significantly higher PD-L1 positivity than other thymoma types. The tumor-infiltrating lymphocytes were mostly CD3 and CD8 positive. No significant difference in overall survival was observed between the high and low PD-L1 expression groups in thymic carcinoma. PD-L1 expression rate was high in TETs, with variations depending on the antibody used and histological subtype. SP263 showed higher PD-L1 expression compared to SP142. The type of the antibody used should be considered when evaluating PD-L1 expression in TETs.

Summary Thymomas and thymic carcinomas are the most prevalent tumors that develop in the thymus’s epithelial tissue. Thymomas are malignant tumors that develop from the epithelial cells of the thymus and frequently include mixed populations of lymphocytes. In contrast, thymic carcinomas are also tumors of the thymic epithelium, but they are characterized by a lack of lymphocytes, exhibit more aggressive behavior, and are associated with a poorer prognosis. Surgical intervention is the primary approach for managing resectable cases, while advanced, unresectable tumors are treated with platinum-based chemotherapy. The recurrence of the disease can happen months to years after initial treatment. Some patients do benefit from biologic therapies, but there is still a significant need for new treatment options. Immune checkpoint inhibitors have proven safe and clinically effective, improving survival in various cancers. However, their use in thymic cancers is currently limited to treating recurrent thymic carcinoma due to potential immune toxicity risks. This manuscript reviews the current applications of immunotherapy for thymic epithelial tumors and discusses strategies to enhance safety and expand treatment options for patients with these cancers.

Patients with thymic epithelial tumors (TET), who have a high risk of developing immunological disorders such as immunodeficiency and autoimmunity, were included among frail patients eligible for the COVID-19 vaccinal program. We previously found an increase of serum biomarkers of inflammation in 25 of 44 (56,8%) TET patients after the second dose (T2) of mRNA vaccine (BNT162b2 from Pfizer-BioNTech), although none developed immune-related complications at this time point. In this study we have investigated the metabolic process of high-density lipoproteins (HDL) that are among the main players in inflammatory and immune modulation. To verify the impact of the vaccine on HDL metabolism in TET patients, we prospectively evaluated serum HDL and HDL subfractions at baseline and T2. Among the 45 TET patients, we observed two different trends: 24 ones (53.3%, subgroup 1) showed a significant decrease of serum small HDL ( p  < 0.0001) class and/or HDL 10 subfraction (HDL 10) ( p  < 0.0001) at T2 as compared to baseline values (T0), the other 21 patients (subgroup 2) did not show significant variations. Serum values of small HDL class in subgroup 1 at T2 were inversely correlated with serum interleukin (IL)-6, activated T lymphocytes and regulatory T cells. These findings suggested that the COVID-19 vaccine-related inflammation induces the HDL remodeling with a reduction of anti-inflammatory small HDL class. Further studies need to clarify why the vaccine causes inflammation in about 50% of TET patients and whether such response is peculiar to COVID-19 vaccine or if it would be induced also by other mRNA vaccines.

Background There is evidence that some ovarian tumours evoke an immune response, which can be assessed by tumour infiltrating lymphocytes (TILs). To facilitate adoption of TILs as a clinical biomarker, a standardised method for their H&E visual evaluation has been validated in breast cancer. Methods We sought to investigate the prognostic significance of TILs in a study of 953 invasive epithelial ovarian cancer tumour samples, both primary and metastatic, from 707 patients from the prospective population-based SEARCH study. TILs were analysed using a standardised method based on H&E staining producing a percentage score for stromal and intratumoral compartments. We used Cox regression to estimate hazard ratios of the association between TILs and survival. Results The extent of stromal and intra-tumoral TILs were correlated in the primary tumours ( n  = 679, Spearman’s rank correlation = 0.60, P  < 0.001) with a similar correlation in secondary tumours ( n  = 224, Spearman’s rank correlation = 0.62, P  < 0.001). There was a weak correlation between stromal TIL levels in primary and secondary tumour samples (Spearman’s rank correlation = 0.29, P  < 0.001) and intra-tumoral TIL levels in primary and secondary tumour samples (Spearman’s rank correlation = 0.19, P  = 0.0094). The extent of stromal TILs differed between histotypes (Pearson chi2 (12d.f.) 54.1, P  < 0.0001) with higher levels of stromal infiltration in the high-grade serous and endometriod cases. A significant association was observed for higher intratumoral TIL levels and a favourable prognosis (HR 0.74 95% CI 0.55–1.00 p  = 0.047). Conclusion This study is the largest collection of epithelial ovarian tumour samples evaluated for TILs. We have shown that stromal and intratumoral TIL levels are correlated and that their levels correlate with clinical variables such as tumour histological subtype. We have also shown that increased levels of both intratumoral and stromal TILs are associated with a better prognosis; however, this is only statistically significant for intratumoral TILs. This study suggests that a clinically useful immune prognostic indicator in epithelial ovarian cancer could be developed using this technique.