Periodic Reporting for period 1 - Syst-Onco-Herpes (Systemic delivery of oncolytic herpes simplex viruses retargeted to cancer-specific receptors. Virus optimization and business planning.)
Période du rapport: 2022-05-01 au 2023-10-31
Solid tumors that cannot be resected, are metastatic at diagnosis, or progress to metastatic during treatment, are unmet clinical needs and second cause of deaths worldwide (2018). Oncolytic viruses (OVs) are a novel class of replication-competent anti-cancer agents (Lichty, 2014). In simple words, OVs are “good viruses” engineered to selectively kill cancer cells, spread through cancers, and spare normal cells. Their therapeutic effects are exerted through tumor cell lysis and re-establishment of the patient immune response to the tumor (immunotherapy). The tropism-retargeted oncolytic herpes simplex viruses (oHSVs) (ReHVs)(Campadelli-Fiume et al., 2016) developed by the PI in the ERC-AdG grant are genetically engineered Precision Medicine oHSVs in which the virus ability to infect the natural target cells is ablated and replaced with the ability to precisely infect the cancer cells, usually via a Tumor-Associated Antigen (Vannini et al., 2021). ReHVs, and particularly the HER2-retargeted ReHVs (HER2-ReHVs), are superior to the approved attenuated oHSVs with respect to both efficacy and safety.
A Holy Grail in OV field is the possibility to administer them by systemic (i.v.) routes, so that in the human body OVs search for metastases (Hill, 2019). In reality, very few OVs are administered i.v.; they are small viruses with limited genome capacity and are not cancer-specific.
The idea taken to POC was to identify obstacles that constrain the systemic administration of HER2-ReHVs, to develop novel strategies to overcome them and to design initiatives for the development and commercialization of ReHVs. The Syst-Onco-Herpes initiatives were aimed at progressing ReHVs into clinical experimentation and ultimately into their use in patients. The project was divided into 4 Scientific and 3 Business Aims.
A Holy Grail in OV field is the possibility to administer them by systemic (i.v.) routes, so that in the human body OVs search for metastases (Hill, 2019). In reality, very few OVs are administered i.v.; they are small viruses with limited genome capacity and are not cancer-specific.
The idea taken to POC was to identify obstacles that constrain the systemic administration of HER2-ReHVs, to develop novel strategies to overcome them and to design initiatives for the development and commercialization of ReHVs. The Syst-Onco-Herpes initiatives were aimed at progressing ReHVs into clinical experimentation and ultimately into their use in patients. The project was divided into 4 Scientific and 3 Business Aims.
The scientific work conducted under the ERC POC project led to four series of results. Specifically, (i) it was observed that the HER2-ReHV named R-337 could confer some protection even upon systemic i.v.delivery even when administered to already established metastatic tumors. The developed model consisted of immunocompetent BALB/C mice made transgenic tolerant for the human HER2 (the murine strain was developed in the lab for this purpose). The mice bore lung tumors generated by i.v. injection of CT26-HER2 cells, or subcutaneous CT26-HER2 tumors. The anticancer efficacy of the HER2-ReHV was quantified as decrease in the number of lung nodules, or in the s.c tumor growth, and as immune T response to the tumor (Vannini et al., 2023a). (ii) studies on the blood clearance and biodistribution of systemically-administered HER2-ReHV in the above model were carried out in naïve mice and in mice preimmunized) to HSV (herein IMM), a situation that mimics the scenario in the HSV-seroprevalent human population. While HER2-ReHV only populated the tumor, and spare any other organ or tissue, In IMM mice the quantity of HER2-ReHV that populated the tumor and its antitumor efficacy were low. (iii) Our work ascertained that this was mainly due to Complement and to neutralizing antibodies (NAbs). The deleterious effect of complement was counteracted by means of cobra venom factor, especially in combination with Cyclophospamide. Efforts to remove NAbs from circulation were in part effective (Vannini et al., 2023a). (iv) We further explored to what extent the rapid clearance of the HER2-ReHV was the result of the unspecific absorption of the virus to cells expressing broadly distributed heparan sulphates and chondroitin sulphates (cumulatively GlycosAminoGlycans _GAGs) that act as a sink and drain off virus from circulation. To this end, we engineered a variant of R-337 named R-399 in which glycoprotein C (gC) was mutated so as to decrease its ability to interact with cell GAGs. Such modification slowed the blood clearance of R-399, improved the biodistribution and the systemic anticancer efficacy of R-399. This is the first evidence of the role of GAGs in biodistribution of HSV (Vannini et al., 2023c). Cumulatively, the points (i) to (iv) of the project provided instruments to improve the anticancer efficacy of systemically delivered HER2-ReHV. (v) A further key result was the design, analysis of cancer specificity and in vivo anticancer efficacy of a novel ReHV, named R-421, retargeted to nectin4, a novel member of Tumor Associated antigens, highly expressed in bladder and urethral cancer, in pancreas carcinoma. Our studies showed that R-421 is highly specific for the mentioned human cancers, does not exhibit off tumor and off-target activity, and exerts anticancer efficacy and anticancer vaccination (Vannini et al., 2023b). With respect to A#4, augment of the immunotheraputic response and in situ vaccination we observed that efficacy of HER2-ReHV is increased in combination with checkpoint inhibitors ICIs), irrespective of whether the ICIs are inserted in the viral genome, or are administered in combination regimens. We observed strong in situ vaccination to both the selected tumor antigen (e.g. HER2) and to agnostic tumor antigens.
The business part of the project was quite successful and indeed put the basis for the translation of ReHVs to clinical experimentation (Development) and ultimately for their future commercialization and for societal benefit. Ultimately, this should increase therapeutic options for specific metastatic diseases. In practice, we carefully detailed the plan of the activities required to bring ReHVs to the IND deposit for authorization of clinical experimentation; (ii) carried out a Market analysis finalized to the benchmarking and positioning of ReHVs in the competitive landscape. (iii) Designed a Business Plan and strategies to search for investors/partners and further funding. The overall result of the Business activities is that the University of Bologna, that is the owner of the IP, signed an Agreement with a international biotech company to bring ReHVs to IND deposit, and, subsequently to further development and deposit of protocols for clinical studies.
The business part of the project was quite successful and indeed put the basis for the translation of ReHVs to clinical experimentation (Development) and ultimately for their future commercialization and for societal benefit. Ultimately, this should increase therapeutic options for specific metastatic diseases. In practice, we carefully detailed the plan of the activities required to bring ReHVs to the IND deposit for authorization of clinical experimentation; (ii) carried out a Market analysis finalized to the benchmarking and positioning of ReHVs in the competitive landscape. (iii) Designed a Business Plan and strategies to search for investors/partners and further funding. The overall result of the Business activities is that the University of Bologna, that is the owner of the IP, signed an Agreement with a international biotech company to bring ReHVs to IND deposit, and, subsequently to further development and deposit of protocols for clinical studies.
Key needs to ensure further Development of SYS ReHVs and ultimately to bring them to the authorization of clinical experimentation center on additional research on biodistribution and toxicology in higher animals (primates); such studies are required to define safety profile of ReHVs in higher animals.
(2018). WHO - Latest global cancer data: https://www.who.int/cancer/PRGlobocanFinal.pdf
Campadelli-Fiume, G., et al (2016). Viruses 8.
Hill, C., and Carlisle, R. (2019). Expert Op drug delivery 16, 607-620.
Lichty, B.D. et al (2014). Nat Rev Cancer 14, 559-567.
Vannini, A., … and Campadelli-Fiume, G. (2021). Immunotherapeutic Efficacy of Retargeted oHSVs Designed for Propagation. Cancers 13, 266.
Vannini, A., … Campadelli-Fiume, G., (2023a). Efficacy of Systemically Administered Retargeted Oncolytic Herpes Simplex Viruses—Clearance and Biodistribution in Naïve and HSV-Preimmune Mice. Cancers 15, 4042.
Vannini, A.,..Campadelli-Fiume G.. (2023b). Innovative retargeted oncolytic herpesvirus against nectin4-positive cancers. Frontiers in Molecular Biosciences 10, 1149973.
Vannini, A., Campadelli-Fiume, G. (2024). Decrease in heparan sulphate binding in tropism-Retargeted oncolytic Herpes simplex Virus (ReHV) improves blood clearance and the systemic anticancer efficacy. Cancers (MDPI) 16, 1143.
(2018). WHO - Latest global cancer data: https://www.who.int/cancer/PRGlobocanFinal.pdf
Campadelli-Fiume, G., et al (2016). Viruses 8.
Hill, C., and Carlisle, R. (2019). Expert Op drug delivery 16, 607-620.
Lichty, B.D. et al (2014). Nat Rev Cancer 14, 559-567.
Vannini, A., … and Campadelli-Fiume, G. (2021). Immunotherapeutic Efficacy of Retargeted oHSVs Designed for Propagation. Cancers 13, 266.
Vannini, A., … Campadelli-Fiume, G., (2023a). Efficacy of Systemically Administered Retargeted Oncolytic Herpes Simplex Viruses—Clearance and Biodistribution in Naïve and HSV-Preimmune Mice. Cancers 15, 4042.
Vannini, A.,..Campadelli-Fiume G.. (2023b). Innovative retargeted oncolytic herpesvirus against nectin4-positive cancers. Frontiers in Molecular Biosciences 10, 1149973.
Vannini, A., Campadelli-Fiume, G. (2024). Decrease in heparan sulphate binding in tropism-Retargeted oncolytic Herpes simplex Virus (ReHV) improves blood clearance and the systemic anticancer efficacy. Cancers (MDPI) 16, 1143.