MGFB: Vaccinating Against Tumor Antigen Escape

by | Dec 1, 2022

The Greenfire Bio subsidiary is developing xenogenic tumor antigen libraries delivered via engineered viruses.

Article by Richard Guy, Biopharma Analyst

MGFB is developing virus-based cancer vaccines for solid tumors that prime the immune system against hundreds of tumor antigens, including ones that arise during tumor escape, and aims to achieve stronger immune responses by tapping non-human cDNA systems.

The clinical-stage company, a subsidiary of Greenfire Bio, launched Nov. 8 with technology licensed from Richard Vile’s lab at the Mayo Clinic.

The company is using engineered vesicular stomatitis viruses (VSV) to deliver up to 400 different tumor epitopes to stimulate T cell responses in patient lymph nodes. “The plan is to bomb the tumors with everything and hopefully minimize tumor escape,” MGFB CBO Sanjeev Munshi told BioCentury.

The company’s strategy is founded on the observation that tumors quickly lose tumor-specific antigens in response to evolutionary pressure from the immune system.

“Historically, people have developed directed therapies against tumor-specific antigens,” he said. “The problem is that those therapies only go after the cell types in the tumor that present the antigen. The rest of the cells expand and contribute to tumor growth, so the overall response to therapy is minimal, and the tumors recur.”

MGFB’s library approach, he said, addresses both the propensity of tumors to become resistant to therapies and the need to target tumors in multiple ways.

“Individually, the T cells are only weakly active against the tumor antigens,” said Munshi. “But together, as a constellation, they make the tumor more susceptible to the T cell activation process. By including tumor- associated antigens and neoantigens in the library, you can knock out as many cells of the tumor as possible and minimize its ability to escape.”

The company believes tumor-associated antigens found in patient samples are not immunogenic enough to kill tumors because the human proteins are still considered “self ” by the immune system. Instead, the company is turning to xenogenic libraries of tumor antigens from dogs.

Because the cDNA the company is using to build its libraries is not human, Munshi said some of the epitopes will look sufficiently different to the immune system for it to prime a T cell response. The company is banking on those subtle differences, and the size of the antigen library, to stimulate immune responses against the human counterparts of the non-human antigens.

MGFB has two strategies to diversify its library: sourcing cDNA from multiple dogs, and tapping APOBEC3B-induced mutagenesis.

APOBEC3B, an enzyme that causes C-to-T or C-to-G point mutations, is upregulated in multiple tumor types and generates mutations that frequently lead to drug resistance.

MGFB is using APOBEC3B-induced mutagenesis as part of its neoantigen discovery process by harvesting tumor cells from dogs that are treatment-naive, treatment-experienced and relapsed, or treatment refractory. The goal is to develop a library that accounts for tumors’ tendency to mutate in response to therapy.

The library is then packaged in VSV particles. “A single virus particle cannot accommodate more than about 3.5 kilobases, but we have a collection of these VSV particles that together represent the library of antigens,” Munshi said.

Munshi said MFGB’s technology can simultaneously deliver more epitopes than other companies’ technologies.
The optimal number of antigens to deliver is a subject of debate in the cancer vaccine field, with some arguing that too many antigens can cause competitive inhibition. Other companies in the camp of more-is-better include Nouscom AG, whose lead product delivers 209 shared neoantigens via a great apes adenovirus vector, followed by a vaccinia vector.

MFGB also plans to combine its viruses with checkpoint inhibitors. In a proof-of-concept study, 12 melanoma
patients refractory to checkpoint inhibitors were treated with pembrolizumab and a version of the company’s vaccine encoding a single tumor-associated antigen to TYRP1. Detailed results were not available, but Munshi said the response was “encouraging.” The company also has pre-clinical data establishing the efficacy of its multi-epitope strategy in glioblastoma and melanoma mouse models.

MFGB chief corporate development officer Chris Searcy said the company is planning to raise a round of venture financing but declined to disclose a specific amount or timeline for its closing. The company is targeting indications in melanoma, glioma, colorectal cancer, and hepatocellular carcinoma.