RESEARCH
Understanding Immunotherapies and Immunotherapy-associated side effects
A simple explanation of immunotherapy by the principal investigator of FLATZ Lab, Prof. Dr. med. Lukas Flatz.
Predicting Response and Outcome of Immunotherapy (IMIT Study)
The arrival of immunotherapy has ushered a new era in cancer treatment, leading to significant and sustained improvement in patient survival. Although checkpoint inhibitors are now regarded pivotal in modern oncology, response rates among patients show inexplicable variation. Our IMIT-project (Immune-Monitoring of Immuno-Therapy) aims at identifying and functionally exploring changes in patients receiving checkpoint inhibitors. In the future, this will help us to tailor individualized therapies for patients by predicting the best response to the growing arsenal of emerging checkpoint inhibitors.
Deciphering the Mechanisms of Toxicity of Immunotherapy
Despite improvement of response rates and survival in several tumor types, there is a potential risk for autoimmune side effects by T-cell infiltration, including skin rash, colitis, pneumonitis, hepatitis, and hypophysitis. As there is evidence of correlation between inflammation in various organs and better response to treatment, we aim to understand the pathogenesis behind these mechanisms. We have recently hypothesized that there may be an association between onset of uveitis and higher response rates in patients with metastatic melanoma (Diem et al., J Immunotherapy, 2016; Nuñez et al., Med. 2023). In patients with non-small cell lung cancer (NSCLC) we described a different histologically-dependent T-cell infiltration in skin rash caused by immunotherapy (Hasan Ali et al., Oncoimmunology, 2016). Furthermore, in patients with NSCLC we showed that C reactive protein flare is a non-invasive, easily determined biomarker to predict response to checkpoint inhibitors (Klümper et al., J Immunother Cancer, 2022).
Identification of previously unknown cancer antigens
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, their use is frequently associated with immune- related adverse events (irAEs) potentially affecting any organ. The mechanisms mediating such irAEs remain poorly understood and biomarkers to predict the development of irAEs are lacking (Berner & Flatz, Immunol Rev, 2023). Therefore, we validated DITAS (discovery of tumor-associated self-antigens) and identified autoreactive napsin-A to be enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade (Berner et al., Sci. Immunol., 2022). Moreover, we could show that autoimmune toxic effects associated with checkpoint blockade may serve as biomarkers for clinical responses and provide opportunities to identify cancer T-cell targets (Berner et al., JAMA Oncology, 2019). To investigate these tumor-associated self-antigens and their role in both toxicity and anti-tumor immune responses, we study in our research melanoma, non-melanoma skin cancers, such as cutaneous squamous cell carcinoma (cSCC), and NSCLC.
The Tumor Microenvironment (TME) Matters
Even though immunotherapies improve survival in many different cancers, a big number of patients fail to respond to immunotherapy. The tumor and its microenvironment are highly complex, consisting of structural components (e.g., extracellular matrix, blood vessels), cellular components (e.g., endothelial, stromal, and immune cells), and soluble factors (e.g., cytokines, growth factors, and metabolites), all of which interact to shape therapy response. To understand how these elements contribute to an anti-tumor or resistant tumor environment, we study the TME in NSCLC, melanoma, cSCC, basal cell carcinoma (BCC), and merkel cell carcinoma (MCC). Identification of potential therapeutic targets within the TME may help overcome poor response and resistance to immunotherapies and increase the efficacy.
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Towards a Cancer Vaccine
The immune system is able to recognize and eliminate cancer cells, however this effector function is usually inhibited by tumor cells. Although great success has been achieved with the development of immune checkpoint inhibitors, only up to 50% of metastatic melanoma patients respond to these therapies. It has been suggested that only patients with pre-existing CD8+ T-cells respond to PD1 blockade (Tumeh et al., Nature, 2014), making it essential to induce tumor-specific T-cell response in patients without such pre-existing T-cells. Many tumor-associated antigens (TAAs) are non-mutated “self-antigens”, which are attractive vaccine targets because they are shared among many patients. In this project we collaborate with other groups including Prof. Stefan Kochanek (University of Ulm), Prof. Karl Lang (University of Essen), and Hookipa Biotech (Vienna) to address the feasibility of a new anti-tumor vaccine against melanoma-associated self-antigens (gp100, TRP-1, TRP-2, TYR). Preliminary data show that immunization of tumor-bearing mice with viruses or recombinant vectors expressing TAAs can initiate potent innate and adaptive immune responses resulting in significantly delayed tumor growth and increased survival (Flatz et al., Nature Medicine, 2010 and Kalkavan et al., Nature Communications, 2017; and Ring et al., Nature Commun., 2021).
