Development of novel oncolytic viruses for the treatment of glioblastoma
1. Forsøkets formal
Oncolytic viruses (OVs) are of growing interest as cancer therapeutics for their ability to kill tumour cells both directly by inducing oncolysis and indirectly by activating antitumour immune responses. One of the oncolytic viruses currently under clinical development is the rat parvovirus H-1PV. The virus has been recently evaluated as a monotherapy in a phase I/IIa clinical trials in patients with glioblastoma, the most common and lethal form of brain tumour. Virus treatment was demonstrated to be safe, well tollerated and associated with first evidence of the efficacy. However H-1PV therapy needs further development to improve its clinical outcome further. To this end, we have developed a first generation of Ad-PV chimeras in which an engineered version of the H-1PV genome was inserted into the Ad5 genome (see below). In this study we plan to evaluate the efficacy of these novel anticancer agents alone or in combination with drugs (VPA and ABT-737) previously identified to synergize with H-1PV wild type. In addition, as H-1PV is able to induce immunogenic cell death we will combine the virus with immune-checkpoint blockade. Our ambition is to produce the necessary proof(s)-of- concept necessary to move most promising therapies from the bench into the clinic. To this end experimentation in animal models of cancer is absolutely required.
In order to achieve our ultimate goal, for the preclinical in vivo validation we plan to use immunocompetent and immunodeficient rat models of glioblastoma. In this way we will have the possibility to distinguish between the anticancer activities directly induced by the virus (virus oncolysis) or those mediated by the immuno-system.
2. forventede skadevirkninger på dyrene
We will implant brain tumor cells into the brain of nude rats or Wistar rats. Tumors will develop and imaged regularly by MRI. Upon tumor development, oncolytic virus will be injected into the tumors. From our previous experiences, these treatments are well tolerated by the animals. When tumors reach a big size on MRI, animals will be euthanized, preferably before symptoms develop.
3. forventet vitenskapelig eller samfunnsmessig nytteverdi
Glioblastoma is a highly aggressive tumor of the brain with dismal prognosis. Thus new treatment strategies are needed to improve the survival of these patients.
4. Antall dyr og art
Wistar rotter; Antall: 222
Nakne rotter (rnu-/rnu-); Antall: 96
5. Erstatning, reduksjon, forbedring
This a preclinical therapeutic study which has to be performed in animals. The therapeutic efficacy is highly dependent on the tumor microenvironment, which is very complex and cannot be fully mimicked in vitro. We have an extensive experience with the intracranial injection technique; we are able to perform the procedure in a safe and fast manner. During operatrion, Marcain will be given as local anesthesia. Marcain has a long lasting effect, so that animals will have less pain right after they wake up. In addition, 0.1 ml temgesic will be given to all animals as postoperative analgesia.
Oncolytic viruses (OVs) are of growing interest as cancer therapeutics for their ability to kill tumour cells both directly by inducing oncolysis and indirectly by activating antitumour immune responses. One of the oncolytic viruses currently under clinical development is the rat parvovirus H-1PV. The virus has been recently evaluated as a monotherapy in a phase I/IIa clinical trials in patients with glioblastoma, the most common and lethal form of brain tumour. Virus treatment was demonstrated to be safe, well tollerated and associated with first evidence of the efficacy. However H-1PV therapy needs further development to improve its clinical outcome further. To this end, we have developed a first generation of Ad-PV chimeras in which an engineered version of the H-1PV genome was inserted into the Ad5 genome (see below). In this study we plan to evaluate the efficacy of these novel anticancer agents alone or in combination with drugs (VPA and ABT-737) previously identified to synergize with H-1PV wild type. In addition, as H-1PV is able to induce immunogenic cell death we will combine the virus with immune-checkpoint blockade. Our ambition is to produce the necessary proof(s)-of- concept necessary to move most promising therapies from the bench into the clinic. To this end experimentation in animal models of cancer is absolutely required.
In order to achieve our ultimate goal, for the preclinical in vivo validation we plan to use immunocompetent and immunodeficient rat models of glioblastoma. In this way we will have the possibility to distinguish between the anticancer activities directly induced by the virus (virus oncolysis) or those mediated by the immuno-system.
2. forventede skadevirkninger på dyrene
We will implant brain tumor cells into the brain of nude rats or Wistar rats. Tumors will develop and imaged regularly by MRI. Upon tumor development, oncolytic virus will be injected into the tumors. From our previous experiences, these treatments are well tolerated by the animals. When tumors reach a big size on MRI, animals will be euthanized, preferably before symptoms develop.
3. forventet vitenskapelig eller samfunnsmessig nytteverdi
Glioblastoma is a highly aggressive tumor of the brain with dismal prognosis. Thus new treatment strategies are needed to improve the survival of these patients.
4. Antall dyr og art
Wistar rotter; Antall: 222
Nakne rotter (rnu-/rnu-); Antall: 96
5. Erstatning, reduksjon, forbedring
This a preclinical therapeutic study which has to be performed in animals. The therapeutic efficacy is highly dependent on the tumor microenvironment, which is very complex and cannot be fully mimicked in vitro. We have an extensive experience with the intracranial injection technique; we are able to perform the procedure in a safe and fast manner. During operatrion, Marcain will be given as local anesthesia. Marcain has a long lasting effect, so that animals will have less pain right after they wake up. In addition, 0.1 ml temgesic will be given to all animals as postoperative analgesia.