Immunological boosting and personalization of oncolytic virotherapies for cancer treatment

Cancer is the leading cause of death worldwide creating a need for novel cancer treatments that are more efficient but also safer and more specific. Oncolytic viruses (OVs) have shown a solid safety profile in clinical trials. OVs are nowadays considered immunotherapies because of to their ability to stimulate the host immune system to fight against cancer. Promising efficacy has been seen in some trials, however, efficacy is often seen only in a small group of patients. The purpose of the thesis was to improve the efficacy of OV therapies by boosting the immunogenicity of the viruses, and to optimize the therapeutic efficacy by selecting favorable patient populations and by developing a method to tailor the drug individually for each patient. In the first study, an oncolytic adenovirus (OAd) was modified to express human tumor necrosis factor alpha (hTNFα), a potent immunomodulatory cytokine. The TNFα-virus showed effective tumor cell killing associated with signs of immunogenic cell death and enhanced recruitment of immune cells to the infection site. We also saw potential for combining the TNFα-virus therapy with radiation. In another study the immunogenicity of an oncolytic vaccinia virus was enhanced by modifying it to express DNA-dependent activator of interferon-regulatory factors (DAI), a potent inducer of innate immune responses during virus infection. We showed that the DAI-virus induces expression of genes involved in immune responses, and treatments with the virus showed improved cancer-killing efficacy and immunogenicity in murine and human melanoma models, suggesting applicability also in vaccine design. Response rates after virotherapies vary between patients, and there is a lack of markers that would help predict the patient cohorts who would benefit from the therapy. We screened over 200 cancer patients treated with OAds for two Fc gamma receptor (FcγR) polymorphisms to determine if these polymorphisms would affect the responsiveness to the treatments. We observed a certain FcγR genotype combination (FcγRIIIa-VV + FcγRIIa-HR) to be predictive of poor overall survival after OAd treatments. To tailor the OV therapy for enhanced specificity, we developed a novel platform (PeptiCRAd) to coat a virus with tumor-specific antigens (peptides) for improved induction of cancer-specific immunity. Efficacy and immunogenic potency of the PeptiCRAd were shown in several in vivo models. Our results suggest that administration of tumor-specific peptides on the surface of OVs increases the anti-tumor efficacy compared to treatments with viruses or peptides alone. This platform has potential to be used as a carrier and adjuvant for patient-specific peptides to trigger anti-tumor immunity in a personalized manner.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2016

Author dc:creator

• Hirvinen, Mari

• biofarmasia

Statement dc:rights

• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
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• Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/160244

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F160244