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being used by a number of pharma and biotech companies.
Unum’s investors—Fidelity Biosciences, Atlas Venture, and Sanofi-Genzyme BioVentures led the $12 million A round—are backing a different business proposition than we’ve seen in this field so far. Instead of developing its own drugs, Unum’s goal is to partner with companies that want to enhance experimental antibody therapies that might need to be “armed” to be effective. Wilson says the goal is co-development and co-commercialization deals, with Unum supplying the T cells, and the partners supplying the antibodies.
Unum needs to boost the tumor-killing punch of these antibodies but avoid safety problems. While CAR-T approaches have shown significant response and remission rates, they can also cause cytokine release syndrome, a potentially serious condition that occurs when the immune system goes into overdrive.
The 18-person trial with ATTCK20 will mark the first human test of Unum’s T cells. Wilson says that given the safety unknowns (and the cytokine release problems of other therapies), Unum is trying a different way of modifying these cells. If it proves safer, it could have a big impact on the emerging field.
Here’s why: Most CAR-T progams use viruses to genetically reprogram the T cells. One problem, Wilson says, is that viral delivery “permanently modifie[s]” the cells it changes. That means cells will proliferate with their new receptors uncontrollably, which could be a potential reason for the cytokine storms.
So Unum is using messenger RNA (mRNA) to “transiently” or temporarily modify cells. Others are exploring this, too. For example, the University of Pennsylvania group led by Carl June published a study in Cellular Immunology Research last year using mRNA-based CAR-T therapy as a way to treat patients with solid tumors.
Unum is doing something similar, using a technique called electroporation to “zap” open T cells, get the mRNA in to deliver the instructions, and make the receptor. Wilson says with mRNA, the modified cell reverts back to its previous state in about a week because the mRNA essentially turns off.
“It gives you a very safe way of understanding what the effect is of expressing that receptor and creating this new biological activity,” Wilson says. “In some ways it is a more manageable approach that may able to address some of the limitations around cytokine release syndrome.”
It also has big questions. For example, will the temporary action create enough anti-tumor activity to bring about the potent effects that virus-based CAR-Ts have generated? Even if it were effective, it would likely require multiple doses, not the one-time CAR-T procedure that— in very small numbers so far—has produced cures.
In other words, there might be trade-offs: Less potency and convenience, but more control and safety.
Wilson expects the trial to run through 2015, but he hopes individual patients will provide insights as the year progresses.
“The hope would be that we can take patients who are either relapsed or refractory to rituximab treatment, and by effectively arming that antibody with the modified T cells, hopefully bring about cures,” he says. “But we’ll see how the clinical data play out.”