Development of innovative cancer treatment modalities with enhanced performance through the integration of viral vector platform technologies

Japan's own oncolytic virus therapy takes the next step — Combining with gene therapy to transform "cancer treatment"

—Professor Tomoki Todo, Division of Innovative Cancer Therapy, Advanced Clinical Research Center, the Institute of Medical Science, the University of Tokyo

Cancer mortality rates continue to rise, and the need for new treatments is growing ever greater. This research aims to create and enhance innovative cancer treatment modalities by integrating two viral vector-based platform technologies.

The first platform technology is "oncolytic virus therapy," which uses replication-competent viruses to directly destroy cancer cells. Because cancer cells universally lack defense mechanisms against viral infection, viral replication is inherently amplified in cancer cells. However, engineering viruses that replicate selectively in cancer cells while showing no replication in normal cells requires advanced platform technologies involving careful design of the viral genome and genetic engineering. Cancer cell-selective viral replication not only directly kills the cells but also induces specific antitumor immunity as the immune system clears the virus together with the destroyed cancer cells.

The second platform technology is "in vivo gene therapy," in which a viral vector is used to introduce and express therapeutic genes in cancer cells inside the body. Various therapeutic genes, including suicide genes and angiogenesis-inhibiting genes, have been explored through in vivo gene therapy against cancer, but from the standpoint of combining this with oncolytic virus technology, it is rational to make use of therapeutic genes that enhance specific antitumor immune stimulation.

Herpes simplex virus type 1 (HSV-1) has many properties that make it advantageous as a vector for cancer treatment. In particular, the third-generation oncolytic HSV-1 (G47Δ) that we developed through oncolytic virus technology achieves both high safety and potent antitumor activity through three artificially introduced mutations. We were pioneers worldwide in academia-led clinical development, and a Phase II investigator-initiated clinical trial targeting glioblastoma (brain tumor) demonstrated high therapeutic efficacy, including multiple cases of cure, as well as safety. In 2021, this product, Japan's first domestically developed oncolytic virus product, became the first in the world to be granted manufacturing and marketing approval with malignant glioma (brain tumor) as the indication. Demonstrating that six intratumoral administrations of G47Δ combined with surgery are feasible and effective has had a major impact on brain tumor treatment worldwide and represents a paradigm shift.

Meanwhile, we have developed a breakthrough technology that allows any therapeutic gene to be inserted accurately and rapidly into the HSV-1 genome as a platform technology for in vivo gene therapy. Using this system, it is possible to develop "armed" oncolytic HSV-1 variants in which genes with various specialized functions are inserted into the established G47Δ backbone, whose clinical safety has been confirmed. These armed oncolytic HSV-1 variants "combine" in vivo gene therapy functionality with cancer cell-selective HSV-1 replication, utilizing the replication-competent virus as a tool for gene delivery. Because the viral vector carrying the therapeutic gene replicates within cancer cells and expresses the therapeutic gene each time it infects surrounding cancer cells, the concentration of therapeutic gene products rises in a tumor-localized manner. The therapeutic gene can be freely chosen, and multiple armed oncolytic HSV-1 variants can also be used in combination. By integrating the two platform technologies, a synergistic effect of oncolytic virus therapy and in vivo gene therapy is achieved without the side effects caused by systemic administration.

We have already developed a human interleukin-12 (IL-12)-expressing oncolytic HSV-1 (T-hIL12) and are conducting an investigator-initiated clinical trial targeting malignant melanoma. An interim analysis of the Phase II trial showed that four intratumoral administrations of T-hIL12 in treatment-naive patients produced a markedly higher response rate compared with standard therapy. We have also developed multiple armed oncolytic HSV-1 variants that express immune checkpoint modifiers. In this research, we aim to combine the IL-12-expressing type and the immune checkpoint-modifying type in particular, and to bring this into society as a new cancer treatment modality. By combining two biopharmaceutical platform technologies using the HSV-1 vector, we will promote and advance virus-based cancer treatment, and connect this research to innovation in cancer medicine and the development of new industries.