Turnstone Biologics Inc. has found a major backer for its preclinical vaccinia-based oncolytic virus platform for cancer immunotherapy. Takeda Pharmaceutical Co. Ltd. is paying $120 million in up-front, near-term milestones and equity investment and could pay $900 million more in development, regulatory and commercial milestones to enter a strategic alliance with the New-York-based firm.

The two companies will co-develop and co-commercialize on a 50:50 basis Turnstone’s lead program Rival-01 (formerly TBio-6517) and will collaborate on the discovery of an undisclosed number of additional product candidates. Each firm will be entitled to select a subset of these for future development. The early milestones have not been disclosed. “They are very near-term and, of course, we believe they’re very attainable,” Turnstone CEO Sammy Farah told BioWorld Asia.

It’s Turnstone’s first deal for its second platform. The company was originally founded to take forward a modified Maraba vesiculovirus strain, MG1, which is hypervirulent in cancer cells. That brought in a multiproduct deal with North-Chicago-based Abbvie Inc two years ago. That collaboration is ongoing, although the partners’ thinking about how best to deploy the technology is evolving, said Farah. “It continues to be an important part of what Turnstone is doing,” he said.

Sammy Farah, CEO, Turnstone

Its vaccinia platform, like the Maraba technology, came from the lab of Turnstone’s scientific founder John Bell, of The Ottawa Hospital Research Institute and the University of Ottawa. Turnstone is not the first company to explore the potential of vaccinia as a cancer immunotherapy, but it has modified the platform to enhance its properties. “DNA viruses tend to be immunosuppressive,” Mike Burgess, president of R&D at Turnstone, told BioWorld Asia. Bell and colleagues have introduced a 25kb deletion at two loci in the vaccinia genome to eliminate genes that help the virus to evade the host immune response. “These are genes that are not required for viral replication,” Burgess said.

It can further modify the vaccinia backbone to introduce additional properties, in order to mount what Farah called “a multipronged” attack on the cancer. Rival-01 carries three additional genes that encode an anti-CTLA-4 antibody, FMS-like tyrosine kinase 3 (Flt3) ligand and interleukin-12 (IL-12). Collectively, they are designed to boost the immune response within the tumor microenvironment. “CTLA-4 [inhibition] lowers the threshold for T-cell activation,” Burgess said. Flt3 signaling is important for expanding the population of antigen-presenting dendritic cells. IL-12 activates both natural killer cells and CD8 cytotoxic T lymphocytes.

Mike Burgess, president of R&D, Turnstone

The design strategy is similar to that pursued by Cambridge, Mass.-based Oncorus Inc., which recently raised $79.5 million to take forward an oncolytic herpes virus encoding the same three genes, as well as genes expressing a PD-1 inhibitor and the chemokine CCL4. That construct is limited to intratumoral delivery, however. Turnstone’s vaccinia viruses are designed for systemic delivery, although it will also explore intratumoral administration.

Turnstone and Osaka, Japan-based Takeda plan to test Rival-01 in several solid tumor indications and in non-Hodgkin lymphoma. They have yet to disclose the timing of a first clinical trial. “We are marching towards the clinic quite rapidly,” Farah said. The additional constructs that Turnstone and Takeda will work on have not yet been defined, but the general principle is the same – to engineer viruses with several synergistic properties. “Our focus is on understanding the biology and which biology we’re trying to modulate,” Burgess said. “You may be tempted to put things in because you can.” They will combine them with other agents, but the aim is to develop viruses that are also active as monotherapies. Turnstone retains ownership of the vaccinia platform and has several other programs underway, including a second, undisclosed program, which is also nearing the clinic.

The present deal is evidence of big pharma’s ongoing interest in using viruses as vehicles for cancer immunotherapy. Their inherent immunogenicity and selectivity for cancer cells – which generally lose their antiviral defences during oncogenic transformation – combined with their ability to express genes carrying additional payloads offer a ready-made route to delivering multiple immunomodulatory activities directly to the tumor. The field has yet to deliver in terms of clear-cut evidence of meaningful clinical activity, however. A recent casualty was Transgene SA’s TG4010, an engineered vaccinia virus expressing the oncoprotein mucin-1 and IL-2, which failed a phase II combination trial with the PD-1 inhibitor Opdivo (nivolumab) plus chemotherapy in non-small-cell lung cancer.

Although Amgen Inc., of Thousand Oaks, Calif., gained approval in melanoma for Imlygic (talimogene laherparepvec), a live attenuated herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF), the product has been a commercial failure. It has been unable to compete with immune checkpoint inhibitors, which are more active. Its necessity for intratumoral delivery hasn’t helped either, Burgess said.

The main development risks attached to Rival-01 are the “inherent uncertainties” attached to taking a new platform into human studies for the first time, Farah said. At the same time, vaccinia virus strains have a long history of use in smallpox vaccines. “The dots connect well,” Farah said.

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