Development of novel vaccine platforms for the treatment of cancer

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http://urn.fi/URN:ISBN:978-951-51-4331-0
Julkaisun nimi: Development of novel vaccine platforms for the treatment of cancer
Tekijä: Capasso, Cristian
Muu tekijä: Helsingin yliopisto, farmasian tiedekunta
Lääketutkimuksen tohtoriohjelma
Opinnäytteen taso: Väitöskirja (artikkeli)
Kuuluu julkaisusarjaan: URN:ISSN:2342-317X
Tiivistelmä: With 1 685 210 new cases in 2016 in United States (American Cancer Society), cancer poses a serious challenge for the patients, the healthcare system and families of patients considering that 595 690 people will die from the disease. In the last decades, a new class of therapies raised particular interest thanks to the ability to promote long-lasting complete responses. Immune therapy exploits the patient´s own immune system to find and kill tumor cells. Once immunological memory is established, this can potentially grant long term protection. Nevertheless, the results of immunotherapies are often inconsistent as we observe a number of complete remissions together with patient that completely fail to respond to the therapy. Uncovering the mechanisms of such difference is the primary aim of researchers that try to optimize the strategies to ultimately increase the number of responders. In this thesis three main strategies will be reviewed, studied and finally combined: i) oncolytic adenoviruses; ii) cancer vaccines and iii) immune checkpoint inhibitors. In Study I, we developed an innovative cancer vaccine platform based on oncolytic adenoviruses. We used the adenovirus as a carrier able to deliver peptides to antigen presenting cells. The Virus-peptide complex (i.e. PeptiCRAd) was build with electrostatic interactions, thus preserving the virus ability to infect and kill tumors cells. In addition, we showed that PeptiCRAd was able to reduce the growth of B16OVA and B16F10 tumors by inducing antigen specific responses through the activation of dendritic cells. Ultimately, we showed its potential in humanized mice engrafted with both human melanomas and human peripheral blood mononuclear cells (PBMCs). In Study II we addressed the problem of optimizing the peptides formulations to be used in cancer vaccines. We set up an in silico framework that uses multiple in silico tools such as MHC-I affinity and immunogenicity predictions. This allowed us to directly compare how mutating specific residues would not only change the orientation of the peptide within the MHC-binding pocket, but it would re-shape the whole portion of the MHC molecule that is recognized by the TCRs. This gave us suggestions on the differences in anti-tumor efficacy observed when testing several several improved tumore-specific peptides against both B16OVA and B16F10 tumors. In Study III we used oncolytic vaccines to boost the response to PD-L1 blockade. The Combination proved to increase the survival of melanoma-bearing mice, promoting the presence of TILs with a non-exhausted state (PD-1+ TIM-3-). Hence checkpoint inhibition well synergized with the immune activating properties of the oncolytic vaccine. The findings described in this thesis highlight the necessity of combination therapies to increase the number of responders to immunotherapy. This is a critical aspect to enlarge the number of responding patients and to maximize the benefits of immunotherapies, considering that immunotherapeutic approaches are reaching the market with unprecedented speed.With 1 685 210 new cases in 2016 in United States (American Cancer Society), cancer poses a serious challenge for the patients, the healthcare system and families of patients considering that 595 690 people will die from the disease. In the last decades, a new class of therapies raised particular interest thanks to the ability to promote long-lasting complete responses. Immune therapy exploits the patient´s own immune system to find and kill tumor cells. Once immunological memory is established, this can potentially grant long term protection. Nevertheless, the results of immunotherapies are often inconsistent as we observe a number of complete remissions together with patient that completely fail to respond to the therapy. Uncovering the mechanisms of such difference is the primary aim of researchers that try to optimize the strategies to ultimately increase the number of responders. In this thesis three main strategies will be reviewed, studied and finally combined: i) oncolytic adenoviruses; ii) cancer vaccines and iii) immune checkpoint inhibitors. In Study I, we developed an innovative cancer vaccine platform based on oncolytic adenoviruses. We used the adenovirus as a carrier able to deliver peptides to antigen presenting cells. The Virus-peptide complex (i.e. PeptiCRAd) was build with electrostatic interactions, thus preserving the virus ability to infect and kill tumors cells. In addition, we showed that PeptiCRAd was able to reduce the growth of B16OVA and B16F10 tumors by inducing antigen specific responses through the activation of dendritic cells. Ultimately, we showed its potential in humanized mice engrafted with both human melanomas and human peripheral blood mononuclear cells (PBMCs). In Study II we addressed the problem of optimizing the peptides formulations to be used in cancer vaccines. We set up an in silico framework that uses multiple in silico tools such as MHC-I affinity and immunogenicity predictions. This allowed us to directly compare how mutating specific residues would not only change the orientation of the peptide within the MHC-binding pocket, but it would re-shape the whole portion of the MHC molecule that is recognized by the TCRs. This gave us suggestions on the differences in anti-tumor efficacy observed when testing several several improved tumore-specific peptides against both B16OVA and B16F10 tumors. In Study III we used oncolytic vaccines to boost the response to PD-L1 blockade. The Combination proved to increase the survival of melanoma-bearing mice, promoting the presence of TILs with a non-exhausted state (PD-1+ TIM-3-). Hence checkpoint inhibition well synergized with the immune activating properties of the oncolytic vaccine. The findings described in this thesis highlight the necessity of combination therapies to increase the number of responders to immunotherapy. This is a critical aspect to enlarge the number of responding patients and to maximize the benefits of immunotherapies, considering that immunotherapeutic approaches are reaching the market with unprecedented speed.
URI: URN:ISBN:978-951-51-4331-0
http://hdl.handle.net/10138/235369
Päiväys: 2018-06-08
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