When Off-Target is a Win: MBL-UChicago Collaboration Takes Aim at Cancer Immunotherapy
Those “Aha!” moments when unrelated ideas merge into a fantastic new insight do happen in science. And they’re not so rare in the interdisciplinary air at the Marine Biological Laboratory (MBL).
Case in point: Such a moment arose during a casual conversation between bioengineer Jeffrey Hubbell and neurobiologist Joshua Rosenthal in 2018. Hubbell was in Woods Hole meeting MBL scientists, including Rosenthal, on the occasion of being named the inaugural Eugene Bell Professor in Tissue Engineering at University of Chicago's Pritzker School of Molecular Engineering (see story here).
As Hubbell and Rosenthal chatted, talk turned to their research interests, which on the surface seemed dissimilar. But today, the two scientists are deep into a collaboration to improve the efficiency of immunotherapies to treat cancer (the focus of Hubbell’s lab) using directed RNA editing, a technology pioneered by Rosenthal’s lab. They’ve filed for a patent on their approach, and are collecting data to explore its potential for clinical translation.
“It’s exciting, looking forward,” says Rosenthal. “If this approach keeps showing as efficacious and it works on several tumor models, it may be fertile grounds for starting a biotech [company].”
Ironically, it was a “failed” experiment in Rosenthal’s lab that inspired the idea to apply RNA editing to immunotherapies (see sidebar).
“We have generated a lot of different directed-RNA editing systems over the years. One was particularly bad because it made lots of mistakes -- essentially, we thought it was worthless,” Rosenthal says. “But in talking to Jeff, there was a Eureka moment where we realized it might be really valuable in the context of immunotherapies.”
Weaponizing the immune system against cancer
Some of the most promising modern approaches to treating cancer involve harnessing the patient’s own immune system to fight the disease. Therapeutics that “release the brakes” on the immune system to attack cancer cells, called immune checkpoint inhibitors (ICIs), have revolutionized the treatment of certain kinds of tumors.
But there is plenty of room for improvement. Our immune system works by recognizing foreign proteins, and then eliminating the cells that express those proteins. A central challenge to immunotherapy is that normal cells and cancer cells express very similar proteins, and thus look much the same to the immune system. The big exception is cancer cells contain mutated proteins (called neoantigens) that caused the cells to become cancerous in the first place.
“It’s known that tumors that have more neoantigens – a higher so-called ‘mutational burden’ – are more responsive to immunotherapies,” Hubbell says. “A typical melanoma tumor may have 5,000 neoantigens, and those are relatively responsive to immunotherapy. But other types of tumors, such as breast and prostate, have only one or a few protein mutations. These ‘cold tumors’ are really hard to treat by immunotherapy.”
Meanwhile Rosenthal, a few years ago, accidentally found a way to make thousands of protein mutations in a cell, in an RNA editing experiment that had a completely different aim and seemed to be “a total failure.”
But in talking to Hubbell, something clicked.
“We’re exploring the idea of using the RNA editing technologies Josh has developed to create many, many neoantigens in the tumor, thus to increase mutational burden, which should increase the immune sensitivity of the tumor,” Hubbell says. They further hope this approach will trigger “epitope spreading” of immunity, such that tumor cells that aren’t directly treated by RNA editing will also be killed – even in distant tumors.
Their preliminary results are encouraging. In a mouse model for an aggressive melanoma, the tumors treated with RNA editing shrank substantially.
“The most promising aspect of this approach is the sheer number of changes we are making in the cancer cells, which activates immune cells and stunts tumor growth,” says Lisa Volpatti, a postdoctoral fellow in Hubbell’s lab who has been performing cancer studies in mice and characterizing the immune environment of the tumor.
The next step is to test the approach in a melanoma model engineered to develop human-like tumors, as well as in a mouse model for breast cancer, work being performed by Volpatti and research specialist Gustavo Borjas in Hubbell’s lab.
“The kind of data you need to translate [from academic to clinical development] is multiple mouse models. That’s the data everyone wants to see,” says Hubbell, who holds 77 patents and has founded three companies based on his research.
As an added dimension, Hubbell and Rosenthal expect their system will broaden the use of immune checkpoint inhibitors. While ICIs have shown great success in some cancers, they have low efficacy in cold tumors, such as breast and brain cancers. By introducing abundant neoantigens via RNA editing, cold tumors may not only become easier to detect by the immune system, but more responsive to ICI therapy.
This collaboration was seeded by funding from the Owens Family Foundation.