Oncolytic Virotherapy Development for Genitourinary Malignancies
Generally, genitourinary (GU) system is the organ system of the reproductive organs and the urinary system. In GU oncology, bladder cancer, prostate cancer and renal cell carcinoma (RCC) have been at the forefront of immune-oncology for decades, and immunotherapy will continue to be a cornerstone of therapy, particularly in the treatment of metastatic disease. With the approval of immunotherapy agents by FDA, such as interleukin-2 for the treatment of metastatic renal cell carcinoma (mRCC), Bevacizumab for the treatment of mRCC, Atezolizumab for the treatment of platinum-resistant bladder cancer, and Sipuleucel-T for the treatment of prostate cancer, as well as a number of ongoing trials of vaccines and checkpoint inhibitors, immunotherapies have expanded the treatments available for patients with GU malignancies, and have significantly impacted the treatment of these malignancies. Refueled by advances in biotechnology, oncolytic virotherapy has promoted the development of cancer immunotherapy as a sophisticated method. Specifically, characterized by the features of specific genetic mutations and cell surface marker, urological cancer is suitable to be treated by oncolytic virus for which it is possible to improve both effectiveness and safety.
Fig. 1 Schematic view of OV-mediated effects in tumor (E. Antonio Chiocca, 2014)
For oncolytic virus development of GU cancers, Creative Biolabs can provide virus vector construction and validation services on the basis of following options:
Genetic Mutations
Genetic mutations in urological cancer cells provides opportunities to design effective and cancer-specific oncolytic viruses. For instance, in advanced prostate cancer, frequent genetic mutations are found in AR, ETS genes, TP53 and PTEN. Specifically, mutations or deletions of TP53 occur in various cancerous cells, and might be permissive for replication of particular viruses; in bladder cancer, there are also alterations of multiple genes responsible for malignancy being discovered, like mutations in gene FGFR3, HRAS, PTEN, PIK3CA, etc. Furthermore, viral expression of tumour suppressor genes can also be exploited to increase oncolytic activity.
Virus Tropism
To render oncolytic viruses more specific in binding and attacking cancer cells, cancer-specific cell surface markers can be exploited, such as PSMA and PSCA, against which the antibodies can be incorporated into the envelope or capsid of oncolytic viruses to alter their tropism. In addition, modification of viral envelope protein with cell surface receptor to target cancer cell markers is another promising approach to increase virus tropism toward cancer cell types.
Arming Virus
In numerous cases, oncolytic virus can be engineered to be armed with transgene to enhance the host immune system against cancer. To induce tumor-specific T cell responses, for example, GM-CSF could be co-expressed from virus to recruit and activate antigen-presenting cell and thus eradicate tumor and develop immune responses. One successful case is the first FDA-approved oncolytic virotherapy, Talimogene laherparepvec, which is a HSV-1 based oncolytic virus armed with GM-CSF. In addition to dendritic cells and macrophages, natural killer cells and T cell are also able to be stimulated to improve the clinical efficacy of oncolytic virus therapy.
Beyond the above options, more strategies are available in Creative Biolabs regarding the enhancement of clinical efficacy of oncolytic virus, such as combination of oncolytic virus with gene therapy, coat modification of oncolytic virus to minimize the antiviral response, delivery of oncolytic virus with carrier cells. Please contact us and find your custom oncolytic virotheray for GU malignancy.
Reference:
- Zahid D., (2016). "Oncolytic virotherapy for urological cancers." Nature reviews Urology, 13, 334–352
- E. Antonio Chiocca, (2014). "Oncolytic Viruses and Their Application to Cancer Immunotherapy." Cancer Immunol Res, 2:295-300