Targeting DNA vaccination and patient specific cancer vaccines
Multiple myeloma (MM) is a relatively frequent hematologic malignancy with a poor prognosis – despite recent advances in treatment. It has become clear that tumor-specific T cells can reject cancers; such T cells recognize mutated tumor-specific antigens that are presented by HLA molecules to T cells. We therefore want to generate cancer vaccines that elicit cytotoxic T cell responses towards cancer-specific mutated sequences that are unique to each MM patient.
We have previously shown that targeted DNA vaccines, called vaccibodies, can protect against cancer in a mouse model of MM developed by Professor Bjarne Bogen (Fredriksen et al., Mol Ther 2006, Fredriksen et al., Blood, 2007). We have developed a new generation of targeted DNA vaccines, with two different chains combined in one heterodimer. In this project, we would like to compare the heterodimer with the vaccibody for its ability to induce immune responses to the antigen as well as to provide protection against MOPC315 tumor in BALB/c mice and a novel MOPC315.BM. Luc (Hofgaard et al., PloS-One, 2012), a MM mouse model that home to the bone marrow (BM) and thereby a more clinically relevant tumor model. We would like to induce CD8+ T cell responses by vaccination and study the role of these cells in protection against tumor. We would also like to vaccinate with targeted vaccines that have modification in the antigenic part in order to find the exact epitope that the CD8+ T cells recognize.
All vaccines are characterized in vitro, but to study the immunogenicity of new vaccines, animal experiments are the only alternative available. The immune system is complex, and it will be impossible to fully predict the effect of a vaccine in physiological conditions without experiments in mice. We therefore apply for 3028 mice (2242 of BALB/c or C57BL, 336 of the BALB/c Rag1-/-, 100 of the Welles x Bette, a BCR KI mice, 100 of the BALB/c Batf3 KO mice and 150 of tg46 mice and 100 of Island, Nocturne, Dolby mice and their crosses). These mice will be vaccinated and the immune responses are followed. Mice will also be challenge with the MM (MOPC315) mouse models. The experiments were designed to minimize the number of mice by including enough animals in each experiment to gain significantly relevant results. These numbers were based on power calculations and experience with previous experiments in our group. To minimize discomfort, mice are anesthesized before vaccination. Little adverse effects are expected after vaccination. To study the protective effect of a vaccine, it is important to challenge the mice with the MM tumor. For mice that develop tumor, these experiments are expected to cause moderate pain and discomfort. They will become less active, their fur will bristle, and they can loose weight. Depending on the model used, the mice will develop either a tumor s.c. or paralysis. When the end point symptoms occur mice will be euthanized.
The new mice strain (Batf3KO) added will confirm the role of the CD8 T cells in protection induced by the vaccination against the tumor. Tg46 mice will be used to study the response of CD4+ T cells to cancer vaccines.
The Island, Nocturne and Dolby are tg for a part of the BCR to get a known specificity of the BCR introduced. These mice will be used to study activation of T cells after vaccination.
Our aim is to understand what immune responses are necessary to protect against tumor. Therefore it is necessary to challenge vaccinated mice with tumors. Our goal is to transfer this knowledge to human vaccine that can protect against MM in patients.
New coworkers are added.
We have previously shown that targeted DNA vaccines, called vaccibodies, can protect against cancer in a mouse model of MM developed by Professor Bjarne Bogen (Fredriksen et al., Mol Ther 2006, Fredriksen et al., Blood, 2007). We have developed a new generation of targeted DNA vaccines, with two different chains combined in one heterodimer. In this project, we would like to compare the heterodimer with the vaccibody for its ability to induce immune responses to the antigen as well as to provide protection against MOPC315 tumor in BALB/c mice and a novel MOPC315.BM. Luc (Hofgaard et al., PloS-One, 2012), a MM mouse model that home to the bone marrow (BM) and thereby a more clinically relevant tumor model. We would like to induce CD8+ T cell responses by vaccination and study the role of these cells in protection against tumor. We would also like to vaccinate with targeted vaccines that have modification in the antigenic part in order to find the exact epitope that the CD8+ T cells recognize.
All vaccines are characterized in vitro, but to study the immunogenicity of new vaccines, animal experiments are the only alternative available. The immune system is complex, and it will be impossible to fully predict the effect of a vaccine in physiological conditions without experiments in mice. We therefore apply for 3028 mice (2242 of BALB/c or C57BL, 336 of the BALB/c Rag1-/-, 100 of the Welles x Bette, a BCR KI mice, 100 of the BALB/c Batf3 KO mice and 150 of tg46 mice and 100 of Island, Nocturne, Dolby mice and their crosses). These mice will be vaccinated and the immune responses are followed. Mice will also be challenge with the MM (MOPC315) mouse models. The experiments were designed to minimize the number of mice by including enough animals in each experiment to gain significantly relevant results. These numbers were based on power calculations and experience with previous experiments in our group. To minimize discomfort, mice are anesthesized before vaccination. Little adverse effects are expected after vaccination. To study the protective effect of a vaccine, it is important to challenge the mice with the MM tumor. For mice that develop tumor, these experiments are expected to cause moderate pain and discomfort. They will become less active, their fur will bristle, and they can loose weight. Depending on the model used, the mice will develop either a tumor s.c. or paralysis. When the end point symptoms occur mice will be euthanized.
The new mice strain (Batf3KO) added will confirm the role of the CD8 T cells in protection induced by the vaccination against the tumor. Tg46 mice will be used to study the response of CD4+ T cells to cancer vaccines.
The Island, Nocturne and Dolby are tg for a part of the BCR to get a known specificity of the BCR introduced. These mice will be used to study activation of T cells after vaccination.
Our aim is to understand what immune responses are necessary to protect against tumor. Therefore it is necessary to challenge vaccinated mice with tumors. Our goal is to transfer this knowledge to human vaccine that can protect against MM in patients.
New coworkers are added.