In this thesis, the effects of a new form of immunotherapy was investigated and studied how it can be used against different types of cancers. The investigated immunotherapy is based on injecting... Show moreIn this thesis, the effects of a new form of immunotherapy was investigated and studied how it can be used against different types of cancers. The investigated immunotherapy is based on injecting nanoparticles loaded with various immunologically active molecules (immunomodulatory nanoparticles) that can modulate the immune system to attack cancer cells more efficiently. The effectiveness of this immunomodulatory nanoparticles have been studied on different mouse cancer models and investigated as a single treatment or in combination with other known therapies, such as chemotherapy, therapeutic cancer vaccination, or photodynamic therapy. Show less
The anthracycline drug doxorubicin, is one of the most used chemotherapeutic drugs, with over one million patients treated every year. However, the exact molecular mechanism by which this drug kill... Show moreThe anthracycline drug doxorubicin, is one of the most used chemotherapeutic drugs, with over one million patients treated every year. However, the exact molecular mechanism by which this drug kill tumor cells remain unclear. In addition, treatment with anthracyclines coincides with severe adverse effects such as cardiotoxicity, secondary tumor formation and gonadotoxicity. Understanding how these highly effective anticancer drugs function and why they cause these severe toxicities would have tremendous impact on cancer treatment and the quality of life of cancer survivors. Therefore, even today, studying old anticancer drugs has high therapeutic potential and opens new exciting paths to improve currently available treatment options. Show less
In the clinic, several forms of immunotherapy are combined with the standard treatments, including chemotherapy. Translational studies trying to understand the different outcomes in patients have... Show moreIn the clinic, several forms of immunotherapy are combined with the standard treatments, including chemotherapy. Translational studies trying to understand the different outcomes in patients have led to new questions and hypotheses. The studies described in this thesis are to answer some of these questions. We revealed the immunostimulatory effect of the chemotherapy agent; cisplatin. Next, we studied the mechanism of relapse following immunotherapy with HPV16 SLP vaccination in mice. We demonstrated that unsuccessful immunotherapy results in immune editing and secondary resistance. To overcome this, the combination therapies are required. Moreover, we showed the importance of IL-6 producing by tumors in dampening anti-tumor response. To induce a long-term sustained effector T cell response, we examined the potency of mouse cytomegalovirus as a viral vector-based vaccine. We demonstrated that the demarcated thresholds of vaccine-specific T cells correlate to tumor protection. Recognizing the fact that at each phase of the antitumor immune response a different type of help might have to be provided to obtain maximal therapeutic efficacy, the correct timing of various types of chemotherapeutic agents or immune modulators when used in combination is discussed. Finally, we discussed the general aspects and relevance of the studies mentioned in this thesis. Show less
Oncolytic viruses are highly promising agents for cancer therapy. Reovirus type 3 Dearing and adenovirus type 5 are potent representatives of this new type of treatment. They have been tested... Show moreOncolytic viruses are highly promising agents for cancer therapy. Reovirus type 3 Dearing and adenovirus type 5 are potent representatives of this new type of treatment. They have been tested in a multitude of clinical trials. In these studies reovirus and adenovirus display a good safety profile, but anti-tumour efficacy should be improved. The work described in this thesis mainly concentrated on improving the entry and spread of reoviruses and adenoviruses in tumours by means of genetic modification of the viruses. Show less
It can be concluded from this thesis that high-grade osteosarcoma is at clinical, pathological and molecular level a heterogeneous disease. To treat high-grade osteosarcoma, neo-adjuvant... Show moreIt can be concluded from this thesis that high-grade osteosarcoma is at clinical, pathological and molecular level a heterogeneous disease. To treat high-grade osteosarcoma, neo-adjuvant chemotherapy should be combined with radical surgery, irrespective the localization. There are only 4 effective cytostatic agents for osteosarcoma treatment: methotrexate, doxorubicin, cis-platin and ifosfamide. Patients with pulmonary metastases should receive surgery in case of resectable disease, whereas the use of chemotherapy is not of proven value. Patients with irresectable metastatic osteosarcoma should be offered phase-I studies, because no response can be expected from other conventional cytostatic drugs. New drugs, such as the monoclonal antibody trastuzumab against HER2 is not supported by us, because we did not find this receptor on osteosarcoma cells. At molecular level, a disturbed Wnt signalling, an abnormal cell c ycle regulation and a disturbed p53/apoptotic pathway was present in osteosarcoma cells. The hypothesis is that failure of the mesenchymal stem cell to differentiate into the osteoblastic lineage, due to abnormal proliferation and lack of differentiation commitment results in chromosomal instability, which is the hallmark of osteosarcoma. In Patients with an inactive Wnt3a/_-catenin signalling the proteasome inhibitor bortezomib might be a candidate drug, to explore its suggested differentiation inducing properties. Show less
