| 1. |
- Ellingsen, Espen Basmo, et al.
(författare)
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Characterization of the T cell receptor repertoire and melanoma tumor microenvironment upon combined treatment with ipilimumab and hTERT vaccination
- 2022
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Ingår i: Journal of Translational Medicine. - : Springer Nature. - 1479-5876 .- 1479-5876. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: This clinical trial evaluated a novel telomerase-targeting therapeutic cancer vaccine, UV1, in combination with ipilimumab, in patients with metastatic melanoma. Translational research was conducted on patient-derived blood and tissue samples with the goal of elucidating the effects of treatment on the T cell receptor repertoire and tumor microenvironment.Methods: The trial was an open-label, single-center phase I/11a study. Eligible patients had unresectable metastatic melanoma. Patients received up to 9 UV1 vaccinations and four ipilimumab infusions. Clinical responses were assessed according to RECIST 1.1. Patients were followed up for progression-free survival (PFS) and overall survival (OS). Whole-exome and RNA sequencing, and multiplex immunofluorescence were performed on the biopsies. T cell receptor (TCR) sequencing was performed on the peripheral blood and tumor tissues.Results: Twelve patients were enrolled in the study. Vaccine-specific immune responses were detected in 91% of evaluable patients. Clinical responses were observed in four patients. The mPFS was 6.7 months, and the mOS was 66.3 months. There was no association between baseline tumor mutational burden, neoantigen load, IFN-gamma gene signature, tumor-infiltrating lymphocytes, and response to therapy. Tumor telomerase expression was confirmed in all available biopsies. Vaccine-enriched TCR clones were detected in blood and biopsy, and an increase in the tumor IFN-gamma gene signature was detected in clinically responding patients.Conclusion: Clinical responses were observed irrespective of established predictive biomarkers for checkpoint inhibitor efficacy, indicating an added benefit of the vaccine-induced T cells. The clinical and immunological read-out warrants further investigation of UV1 in combination with checkpoint inhibitors.
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| 2. |
- Kerzeli, Iliana Kyriaki
(författare)
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Dissecting the Microenvironment of Urothelial Bladder Cancer : Therapy, Modelling and Biomarkers
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The complexity of the tumor microenvironment (TME) impacts therapy responses and the survival of cancer patients. The scope of this thesis is to study the effects of immune modulation on tumor-infiltrating leukocytes, and to explore the TME of urothelial cancer to provide the research society with new knowledge and potential therapeutic targets.In paper I, a small molecule MALT1 inhibitor demonstrated in vitro selective inhibition of immune suppressive T regulatory cells (Tregs). However, the inhibitor failed to demonstrate anti-tumor therapeutic effects in vivo. The effect of the MALT1 inhibitor was assessed on immune cell subsets in tumors, as well as in secondary lymphoid organs. Ultimately, the inhibitor was found to have a depleting effect on antigen-specific T cells.Paper II describes the development and characterization of a novel murine urothelial cancer model in both sexes by using a low-dose carcinogen exposure via drinking water combined with a unique transgenic strain. The model recapitulates the profile of basal histology subtype urothelial cancer with a progression outcome, presents transcriptomic tumor heterogeneity, and displays early immune activation signatures despite its failure to respond to checkpoint blockade immunotherapy. Moreover, the study demonstrates that the female sex displayed accelerated tumor development, but also benefited from therapeutic TLR9 stimulation in contrast to males.Therefore, in paper III, an in-depth transcriptomic analysis of the immune cell compartment of the TME was performed in both sexes by using this novel model of urothelial cancer. Infiltrating immune cell subsets varied between stages, while cell communication analysis pinpointed distinct interactions among immune and tumor cells and pathways of immune regulation suitable for therapeutic targeting. Also, differentially expressed genes in immune cell subsets of the TME between sexes revealed higher immune responsiveness in some female immune cell subsets and higher metabolic activity in several male immune cell subsets.In paper IV, proximity extension assay (PEA) analysis of urine and plasma was assessed for liquid biopsy biomarker discovery. Samples from patients at first diagnosis revealed that high MMP12 plasma levels were associated with poor survival. This finding was reproduced in serum PEA analysis of an independent urothelial cancer patient cohort. Single cell transcriptomic analysis of public datasets demonstrated that the production of MMP12 in urothelial cancer could be attributed to tumor-infiltrating macrophages.In conclusion, this thesis illustrates the multi-faceted opportunities and challenges of targeting and studying the microenvironment of urothelial cancer in murine models and human patients.
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| 3. |
- Lauren, Ida, et al.
(författare)
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Long-term SARS-CoV-2-specific and cross-reactive cellular immune responses correlate with humoral responses, disease severity, and symptomatology
- 2022
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Ingår i: Immunity, Inflammation and Disease. - : John Wiley & Sons. - 2050-4527. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses. Methods: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFN gamma) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array. Results: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFN gamma and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFN gamma in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion. Conclusion: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses.
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