Abstract
Our aim was to develop new methods for enhancing the efficacy of cancer immunotherapy. Therapeutic cancer vaccines that have proven effective in animal tumor models are being studied in clinical trials. The high pre-clinical efficacy of these vaccines is not achieved in clinical results. Two main reasons can be envisioned for the sub-optimal clinical immune responses: insufficient intra-tumoral migration of antigen-specific immune effector cells or inactivation of their anti-tumoral functions due to intra-tumoral immune suppressive cells. Combinations of therapeutic vaccines with strategies that enhance intra-tumoral migration / activity of vaccine-induced immune effector cells are expected to enhance the efficacy of cancer immunotherapy.
The vaccine used here is based on a recombinant vector system derived from Semliki Forest virus (rSFV) and encodes a fusion protein of E6 and E7 from human papilloma virus (HPV) type 16 (SFVeE6,7), one of the main HPV strains responsible for development of cervical cancer. In a mouse model of cervical cancer, we studied the effects of combined SFVeE6,7 immunization with low-dose local tumor irradiation and/or sunitinib, two antitumor treatments already used in the clinic. We demonstrated that combined multi-therapy with SFVeE6,7, low-dose local tumor irradiation and sunitinib enhances immunotherapy efficacy and blocks tumor development. Additionally, we used a novel positron emission tomography (PET) tool to monitor the total body distribution of activated T cells induced by low-dose local tumor irradiation and SFVeE6,7 immunization. Lastly, in a retrospective study of locally advanced cervical cancer patients treated with radio(chemo)therapy we evaluated the independent prognostic values of tumor-infiltrating lymphocytes.
The vaccine used here is based on a recombinant vector system derived from Semliki Forest virus (rSFV) and encodes a fusion protein of E6 and E7 from human papilloma virus (HPV) type 16 (SFVeE6,7), one of the main HPV strains responsible for development of cervical cancer. In a mouse model of cervical cancer, we studied the effects of combined SFVeE6,7 immunization with low-dose local tumor irradiation and/or sunitinib, two antitumor treatments already used in the clinic. We demonstrated that combined multi-therapy with SFVeE6,7, low-dose local tumor irradiation and sunitinib enhances immunotherapy efficacy and blocks tumor development. Additionally, we used a novel positron emission tomography (PET) tool to monitor the total body distribution of activated T cells induced by low-dose local tumor irradiation and SFVeE6,7 immunization. Lastly, in a retrospective study of locally advanced cervical cancer patients treated with radio(chemo)therapy we evaluated the independent prognostic values of tumor-infiltrating lymphocytes.
| Translated title of the contribution | Nieuwe strategieën voor het verbeteren van de efficaciteit van therapeutische immunisatie tegen kanker |
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| Original language | English |
| Qualification | Doctor of Philosophy |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 14-Jan-2015 |
| Place of Publication | [S.l.] |
| Publisher | |
| Print ISBNs | 978-90-367-7317-1 |
| Electronic ISBNs | 978-90-367-7316-4 |
| Publication status | Published - 2015 |