Georg-Speyer-Haus
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Background: The inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system.
Methods: We screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria.
Results: We identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern.
Conclusion: Cerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions.
Purpose: Recent advances in the treatment algorithm of locally advanced rectal cancer (LARC) have significantly improved complete response (CR) rates and disease-free survival (DFS), but therapy resistance, with its substantial impact on outcomes and survival, remains a major challenge. Our group has recently unraveled a critical role of interleukin-1α (IL-1α) signaling in activating inflammatory cancer-associated fibroblasts (iCAFs) and mediating radiation-induced senescence, extracellular matrix (ECM) accumulation, and ultimately therapy resistance. We here summarize the recently initiated ACO/ARO/AIO-21 phase I trial, testing the IL-1 receptor antagonist (IL-1 RA) anakinra in combination with fluoropyrimidine-based chemoradiotherapy (CRT) for advanced rectal cancer.
Methods/Design: The ACO/ARO/AIO-21 is an investigator-driven, prospective, open-labeled phase I drug-repurposing trial assessing the maximum tolerated dose (MTD) of capecitabine administered concurrently to standard preoperative radiotherapy (45 Gy in 25 fractions followed by 9 Gy boost in 5 fractions) in combination with fixed doses of the IL-1RA anakinra (100 mg, days −10 to 40). Capecitabine will be administered using a 3 + 3 dose-escalation design (500 mg/m2 bid; 650 mg/m2 bid; 825 mg/m2 bid, respectively) from day 1 to day 40. Response assessment including digital rectal examination (DRE), endoscopy and pelvic magnetic resonance imaging (MRI) is scheduled 10 weeks after completion of CRT. For patients achieving clinical complete response (cCR), primary non-operative management is provided. In case of non-cCR immediate total mesorectal excision (TME) will be performed. Primary endpoint of this phase I trial is the MTD of capecitabine.
Discussion: Based on extensive preclinical research, the ACO/ARO/AIO-21 phase I trial will assess whether the IL-1RA anakinra can be safely combined with fluoropyrimidine-based CRT in rectal cancer. It will further explore the potential of IL-1 inhibition to overcome therapy resistance and improve response rates. A comprehensive translational research program will expand our understanding from a clinical perspective and may help translate the results into a randomized phase II trial.
Radiobiology research in rectal cancer has been limited to cell lines, patient-derived organoids (PDOs), or xenografts. Here, we describe a protocol which recapitulates more efficiently the complex contributions of the tumor microenvironment. This approach establishes a preclinical mouse model of rectal cancer by intrarectal transplantation of genetically modified organoids into immunocompetent mice followed by precise image-guided radiotherapy (IGRT) of organoid-induced tumors. This model represents a useful platform to study the cellular and molecular determinants of therapy resistance in rectal cancer.
Specialized surveillance mechanisms are essential to maintain the genetic integrity of germ cells, which are not only the source of all somatic cells but also of the germ cells of the next generation. DNA damage and chromosomal aberrations are, therefore, not only detrimental for the individual but affect the entire species. In oocytes, the surveillance of the structural integrity of the DNA is maintained by the p53 family member TAp63α. The TAp63α protein is highly expressed in a closed and inactive state and gets activated to the open conformation upon the detection of DNA damage, in particular DNA double-strand breaks. To understand the cellular response to DNA damage that leads to the TAp63α triggered oocyte death we have investigated the RNA transcriptome of oocytes following irradiation at different time points. The analysis shows enhanced expression of pro-apoptotic and typical p53 target genes such as CDKn1a or Mdm2, concomitant with the activation of TAp63α. While DNA repair genes are not upregulated, inflammation-related genes become transcribed when apoptosis is initiated by activation of STAT transcription factors. Furthermore, comparison with the transcriptional profile of the ΔNp63α isoform from other studies shows only a minimal overlap, suggesting distinct regulatory programs of different p63 isoforms.