Novel strategies for enhancing the efficacy of therapeutic immunization against cancer

In dit proefschrift zijn strategieën beschreven die de effectiviteit van immunotherapie met het SFVeE6,7 kanker vaccin verder verhogen. We laten zien dat lokale tumorbestraling de migratie van tumor-specifieke T cellen naar de tumor verhoogt. Echter ook het aantal immuun-suppressieve cellen, MDSCs, in de tumor neemt toe door deze behandeling. Netto wordt evenwel het antitumor effect versterkt door de combinatie van lokale bestraling met SFVeE6,7 immunisatie. Vervolgens laten we zien dat de behandeling met de tyrosine-kinase remmer sunitib selectief het aantal immuun-suppressieve MDSC’s in de tumor verlaagt en daarmee ook de effectiviteit van SFVeE6,7 verhoogt. Op basis van deze resultaten hebben we een nieuwe behandeling ontworpen en onderzocht die het immuunsysteem sterk activeert, immuuncellen doet migreren en accumuleren in de tumor, en tot slot de immuun suppressieve immuuncellen sterk doet afnemen. Deze combinatie leidt tot een sterk verhoogde verhouding van anti-tumor effectorcellen en immuun-suppressieve cellen in de tumor resulterend in een complete blokkering van tumorgroei. Naast deze functionele studies wordt er in dit proefschrift een geheel nieuwe methode beschreven om de infiltratie van geactiveerde T cellen te visualiseren met behulp van PET.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