To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
The aim of this thesis was to investigate if a text-mining tool is suitable for collecting real-world data from electronic health records to evaluate cancer treatments in clinical practice. By... Show moreThe aim of this thesis was to investigate if a text-mining tool is suitable for collecting real-world data from electronic health records to evaluate cancer treatments in clinical practice. By investigating a range of use cases including treatments of patients with renal cell carcinoma, hepatocellular carcinoma, melanoma, breast cancer, and COVID-19, it showed that the text-mining tool is a suitable method of data needed for the evaluation of treatment patterns, effectiveness, safety, prognostic factors, and guideline adherence. The discussion showed that enhancing the data quality and actively using real-world data for treatment evaluation regarding treatment policies are some of the next steps. Show less
This thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the... Show moreThis thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the etiology of mismatch repair deficiency (MMRd) in intermediate and high risk endometrial cancer; and the combination of immunotherapy and PARP inhibition for the treatment of recurrent or metastatic endometrial cancer.The overall aims of this thesis were:• To evaluate health-related quality of life up to 5 years after chemoradiotherapy compared with pelvic radiotherapy alone in the adjuvant treatment of high risk endometrial cancer in the PORTEC-3 trial;• To investigate the preferences of patients and clinicians regarding the benefit-risk trade-off of the addition of chemotherapy to adjuvant pelvic radiotherapy;• To investigate the prevalence and prognosis of Lynch syndrome-associated endometrial cancer among MMRd endometrial cancers;• To evaluate the role of combined checkpoint inhibition and PARP inhibition in women with metastatic or recurrent endometrial cancer in terms of progression-free survival and toxicity in the DOMEC trial. Show less
This thesis aims to improve the treatment of patients with stage III melanoma. The first part describes different aspects of treatment with Talimogene Laherparepvec (T-VEC), a genetically modified... Show moreThis thesis aims to improve the treatment of patients with stage III melanoma. The first part describes different aspects of treatment with Talimogene Laherparepvec (T-VEC), a genetically modified herpes virus, which is used as oncolytic immunotherapy for skin and lymph node metastases in melanoma patients. We show that patients with a low tumor burden have the best outcomes, suggesting T-VEC should be used earlier on in the course of the disease. We present a prediction model, allowing a more accurate selection of patients for T-VEC monotherapy. Two studies focused on the use of T-VEC in clinical practice and the results allowed us to make recommendations on the use of PET/CT and dermoscopy during T-VEC treatment. Part two focuses on the value of surveillance and screening imaging in high-risk melanoma patients. We show that FDG-PET/CT is a valuable imaging tool to detect recurrence after complete resection of stage III disease, even shortly after surgery (before starting adjuvant therapy). Finally, we conclude that nodal staging with US as adjunct to SLNB is useful in the work- up of stage IIB/C melanoma, as it can lead to alterations in treatment and prevent unnecessary surgery. Show less
Monique Krystyna van der Kooij shows that a combination of treatments enhancing the immune system can conquer metastasized melanoma in heavily pre-treated patients. Immunotherapy is not a new... Show moreMonique Krystyna van der Kooij shows that a combination of treatments enhancing the immune system can conquer metastasized melanoma in heavily pre-treated patients. Immunotherapy is not a new concept. However, in Leiden a milder, and therefore better tolerated preconditioning regimen is used before the immune cells are administered. This milder preconditioning, in combination with the patient’s own immune cells and an immune checkpoint inhibitor is unique. This thesis shows that this combination is safe and preliminary data also show that some patients have (lasting) clinical responses. A second important finding described in this thesis is that treatment with immune checkpoint inhibitors can safely be prescribed to patients with common autoimmune diseases. Approximately 1 in 10 metastatic melanoma patients suffer from such an autoimmune disease. Until now clinicians were hesitant to prescribe these immune checkpoint inhibitors out of fear of unleashing the autoimmune disease. Showing that this is not the case made it possible for this large group of patients to gain access to this often-successful treatment. However, immune checkpoint inhibitor monotherapy is not indicated for all patients with metastatic melanoma. Patients with uveal melanoma do not benefit from this type of treatment, and do suffer from the adverse events. Show less
In this thesis, we start with a general introduction in Chapter 1 to briefly present the state of PDT, immune therapies, and nanotechnology in the field of cancer. PDT is a well-established... Show moreIn this thesis, we start with a general introduction in Chapter 1 to briefly present the state of PDT, immune therapies, and nanotechnology in the field of cancer. PDT is a well-established approach in superficial cancer treatment. The aim of my Ph.D. research work has been to improve therapeutic responses in solid tumors by novel combinatorial strategies based on PDT and the utilization of nanotechnology. Insights and concepts in these works are expected to help to design personalized therapeutic interventions in cancer progression. In Chapter 2, we focused on the combination of PDT with a stimulator of interferon genes (STING) agonist: ADU-S100. We investigated the anti-tumor efficiency and survival time after this combined treatment in colon tumor mice models. We found that ADU-S100 post-PDT treatment could enhance PDT-induced inflammation and immune responses, which lead to abscopal effects in a distal untreated tumor. The combination also protected cured mice from tumor recurrence through memory T cell anti-tumor immune responses with high probability. In Chapter 3, we found that PDT in combination with viral core particles could prime systematic immune responses and serum antibody intensity to against colon cancer process in MC38 tumor-bearing mice. In Chapter 4, we reviewed the current challenges facing the combination of PDT and multiple cancer treatment options based on current published literature. We highlighted the opportunities of nanoparticle-based PDT in cancer therapies. In Chapter 5, we investigated how hydrogel-supported near-infrared (NIR) -PDT with improved therapy potential in tumor-bearing mice by combining it with immune checkpoint inhibitors. In addition to the improved tumor growth inhibitory effects and prolonged survival time, immune mechanisms were also studied. We found that hydrogel-supported NIR-PDT by multi-stimulation could induce a higher level of lymphocytes in the circulating blood and increased lymphocytes infiltration into tumor site. A general discussion of overall data observed in this work, and clinical and research prospects related to this thesis are provided in Chapter 6. Show less
The immune system plays a dual role in cancer development. Besides the potential to eliminate cancer cells, immunoregulatory mechanisms exist that counteract anti-tumor immunity.Research in this... Show moreThe immune system plays a dual role in cancer development. Besides the potential to eliminate cancer cells, immunoregulatory mechanisms exist that counteract anti-tumor immunity.Research in this thesis focusses on the role of regulatory T cells (Tregs), a type of adaptive immune cell that plays a major role in tumor-associated immunosuppression. Specifically, the role of Tregs was investigated during the development of primary- and metastatic breast cancer, and in the context of novel immunotherapeutics. This was done by using advanced genetically engineered mouse models that recapitulate human breast cancer.The results in this thesis describe that breast tumors are, already early in their development, able to mobilise Tregs in the tumor-draining lymph nodes, thereby creating a local immunosuppressive niche leading to increased lymph node metastasis. In addition, it was found that the immunotherapeutic treatments anti-PD1 and anti-CTLA4 inadvertently activate Tregs, resulting in a diminished efficacy of this treatment in mice bearing breast tumors. Finally, we describe a mechanism by which intratumoral macrophages are critical promote the intratumoral accumulation of Tregs in breast tumors.Insights from this thesis may eventually contribute to the development of therapeutic applications that are aimed at overcoming immunoregulatory mechanisms in breast cancer. Show less
