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Background: Tumors in the distal esophagus (EAC), gastro-esophageal junction including cardia (GEJAC), and stomach (GAC) develop in close proximity and show strong similarities on a molecular and cellular level. However, recent clinical data showed that the effectiveness of chemo-immunotherapy is limited to a subset of GEAC patients and that EACs and GEJACs generally benefit less from checkpoint inhibition compared to GACs. As the composition of the tumor immune microenvironment drives response to (immuno)therapy we here performed a detailed immune analysis of a large series of GEACs to facilitate the development of a more individualized immunomodulatory strategy. Methods: Extensive immunophenotyping was performed by 14-color flow cytometry in a prospective study to detail the immune composition of untreated gastro-esophageal cancers (n=104) using fresh tumor biopsies of 35 EACs, 38 GEJACs and 31 GACs. The immune cell composition of GEACs was characterized and correlated with clinicopathologic features such as tumor location, MSI and HER2 status. The spatial immune architecture of a subset of tumors (n=30) was evaluated using multiplex immunohistochemistry (mIHC) which allowed us to determine the tumor infiltration status of CD3+, CD8+, FoxP3+, CD163+ and Ki67+ cells. Results: Immunophenotyping revealed that the tumor immune microenvironment of GEACs is heterogeneous and that immune suppressive cell populations such as monocytic myeloid-derived suppressor cells (mMDSC) are more abundant in EACs compared to GACs (p<0.001). In contrast, GACs indicated a proinflammatory microenvironment with elevated frequencies of proliferating (Ki67+) CD4 Th cells (p<0.001), Ki67+ CD8 T cells (p=0.002), and CD8 effector memory-T cells (p=0.024). Differences between EACs and GACs were confirmed by mIHC analyses showing lower densities of tumor- and stroma-infiltrating Ki67+ CD8 T cells in EAC compared to GAC (both p=0.021). Discussions: This comprehensive immune phenotype study of a large series of untreated GEACs, identified that tumors with an esophageal tumor location have more immune suppressive features compared to tumors in the gastro-esophageal junction or stomach which might explain the location-specific responses to checkpoint inhibitors in this disease. These findings provide an important rationale for stratification according to tumor location in clinical studies and the development of location-dependent immunomodulatory treatment approaches. [ABSTRACT FROM AUTHOR]

Identification of molecular predictive markers of response to neoadjuvant chemoradiation could aid clinical decision-making in patients with localized oesophageal cancer. Therefore, we subjected pretreatment biopsies of 75 adenocarcinoma (OAC) and 16 squamous cell carcinoma (OSCC) patients to targeted next-generation DNA sequencing, as well as biopsies of 85 OAC and 20 OSCC patients to promoter methylation analysis of eight GI-specific genes, and subsequently searched for associations with histopathological response and disease-free (DFS) and overall survival (OS). Thereby, we found that in OAC, CSMD1 deletion (8%) and ETV4 amplification (5%) were associated with a favourable histopathological response, whereas SMURF1 amplification (5%) and SMARCA4 mutation (7%) were associated with an unfavourable histopathological response. KRAS (15%) and GATA4 (7%) amplification were associated with shorter OS. In OSCC, TP63 amplification (25%) and TFPI2 (10%) gene promoter methylation were associated with an unfavourable histopathological response and shorter DFS (TP63) and OS (TFPI2), whereas CDKN2A deletion (38%) was associated with prolonged OS. In conclusion, this study identified candidate genetic biomarkers associated with response to neoadjuvant chemoradiotherapy in patients with localized oesophageal cancer., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Lessons Learned: The novel therapeutic vaccine hVEGF 26-104 /RFASE was found to be safe and well tolerated in patients with cancer. hVEGF 26-104 /RFASE failed to induce seroconversion against native hVEGF 165 and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed. Remarkably, hVEGF 26-104 /RFASE induced VEGF 165 -neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates., Background: Targeting vascular endothelial growth factor-A (VEGF) is a well-established anticancer therapy. We designed a first-in-human clinical trial to investigate the safety and immunogenicity of the novel vaccine hVEGF 26-104 /RFASE., Methods: Patients with advanced solid malignancies with no standard treatment options available were eligible for this phase I study with a 3+3 dose-escalation design. On days 0, 14, and 28, patients received intramuscular hVEGF 26-104 , a truncated synthetic three-dimensional (3D)-structured peptide mimic covering the amino acids 26-104 of the human VEGF 165 isoform, emulsified in the novel adjuvant Raffinose Fatty Acid Sulphate Ester (RFASE), a sulpholipopolysaccharide. Objectives were to determine safety, induction of VEGF-neutralizing antibodies, and the maximum tolerated dose. Blood was sampled to measure VEGF levels and antibody titers., Results: Eighteen of 27 enrolled patients received three immunizations in six different dose-levels up to 1,000 μg hVEGF 26-104 and 40 mg RFASE. No dose-limiting toxicity was observed. Although in four patients an antibody titer against hVEGF 26-104 was induced (highest titer: 2.77 10 log), neither a reduction in VEGF levels nor neutralizing antibodies against native VEGF 165 were detected., Conclusion: Despite having an attractive safety profile, hVEGF 26-104 /RFASE was not able to elicit seroconversions against native VEGF 165 and, consequently, did not decrease circulating VEGF levels. Deficient RFASE adjuvant activity, as well as dominant immunoreactivity toward neoepitopes, may have impeded hVEGF 26-104 /RFASE's efficacy in humans., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Radiation therapy has been linked to the induction of an intratumoral type I interferon (IFN) response, which positively affects the response to treatment. This has spiked the interest to combine radiation therapy with IFN-based treatment. Interestingly, this combination treatment has been considered previously, since preclinical studies demonstrated a radiosensitizing effect of interferons. As a result, multiple clinical trials have been performed combining radiation therapy with interferons in different tumor types. Although potential benefit has been suggested, the outcomes of the trials are diverse and challenging to interpret. In addition, increased grade ≥3 toxicity frequently resulted in a negative recommendation regarding the combination therapy. The latter appears premature because many studies were small and several aspects of the combination treatment have not yet been sufficiently explored to justify such a definite conclusion. This review summarizes the available literature on this combination therapy, with a focus on IFN-α and IFN-β. Based on preclinical studies and clinical trials, we evaluated the potential opportunities and describe the current challenges. In addition, we identify several issues that should be addressed to fully exploit the potential benefit of this combinatorial treatment approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Effective combination treatments with fractionated radiotherapy rely on a proper understanding of the dynamic responses that occur during treatment. We explored the effect of clinical fractionated radiotherapy on the development and timing of radioresistance in tumor cells., Methods and Materials: Different colon (HT29/HCT116/COLO320/SW480/RKO) and high-grade astrocytoma (D384/U-251MG) cancer cell lines were treated for 6 weeks with daily fractions of 2 Gy, 5 days per week. Clonogenic survival was determined throughout the treatment period. In addition, the radiosensitivity of irradiated and non-irradiated was compared. Finally, the effect of different dose fractions on the development of radioresistance was determined., Results: All cell lines developed radioresistance within 2-3 weeks during fractionated radiotherapy. This was characterized by the occurrence of a steady state phase of clonogenic survival. In U-251MG cells this was accompanied by increased cell senescence and stemness. After recovering from six weeks of treatment, the radiosensitivity of fractionally irradiated and non-irradiated cells was similar. Including transient radioresistance, described as (α/β) -( , as a factor in the classic LQ model resulted in a perfect fit with the experimental data observed during fractionated radiotherapy. This was confirmed when different dose fractions were applied.d +1) , as a factor in the classic LQ model resulted in a perfect fit with the experimental data observed during fractionated radiotherapy. This was confirmed when different dose fractions were applied., Conclusions: Fractionated irradiation of cancer cells in vitro following clinical radiation schedules induces a reversible radioresistance response. This adaptive response can be included in the LQ model as a function of the dose fraction and the alpha/beta-ratio of a given cell line. These findings warrant further investigation of the mechanisms and clinical relevance of adaptive radioresistance., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The incidence of oesophageal cancer is on the rise, particularly due to an increase in the number of adenocarcinomas of the distal oesophagus. Adenomas and squamous cell carcinomas are the most common histological subtypes; each should be considered as a different entity. The diagnosis 'oesophageal cancer' is confirmed on the basis of histopathological investigation of biopsies, whereas tumour staging is conducted through transoesophageal endoscopic ultrasound and FDG-PET/CT diagnostics. There are various options to treat patients with oesophageal cancer, such as endoscopic resection, multimodal therapy or definitive chemoradiotherapy. Since 2012, neoadjuvant chemoradiotherapy followed by surgery is the standard treatment for oesophageal cancer, except with regard to patients with a T1 or M1 tumour. In the Netherlands, most surgical procedures are now minimally invasive procedures. Despite improved treatment options, mortality rates associated with oesophageal cancer remain high.