With Souped-Up Rituxan, Unum Plots First Foray Into T-Cell Therapy

Xconomy Boston — 

Unum Therapeutics emerged from stealth a few weeks ago with its own twist on the increasingly crowded field of cellular immunotherapy. Today the Cambridge, MA-based company is disclosing more details, not the least of which is that the technology is ready to be tested in patients.

Any cell-based immunotherapy effort is bound to attract attention these days, but Unum will be closely watched for a few scientific and strategic reasons. Unum has begun recruiting patients for the first clinical trial of what it’s calling ATTCK20. The experimental therapy is for patients with various B-cell malignancies such as chronic lymphocytic leukemia (CLL) and non Hodgkin lymphoma. ATTCK20 combines Unum’s T-cell technology with the antibody therapy rituximab (Rituxan), one of the early monoclonal antibodies to be approved and one of the most widely used in biotech history.

The trial is Unum’s first chance to prove the worth of its version of cellular immunotherapy, in which a patient’s own T cells are extracted, genetically engineered to be efficient killers of certain types of tumors, and infused back into the body. To date, most cellular immunotherapies use only the patient’s souped-up immune cells as the treatment. Adding an antibody as a therapeutic ingredient is a novel approach.

“In many ways, the trial that we’re doing right now is to provide proof of concept for what our T cells can do,” says CEO and former Novartis executive Charles Wilson.

Several companies are working on chimeric antigen receptor therapy, or CAR-T for short, which reprograms T cells to seek out and kill tumor cells that have a protein called CD19 on their surface. Paired with institutional collaborators, Novartis, Juno Therapeutics of Seattle, Santa Monica, CA-based Kite Pharma (NASDAQ: KITE), and others are testing CAR-T methods in blood cancers like acute lymphoblastic leukemia with impressive but early results so far.
But with that field increasingly crowded, some companies are eyeing next-generation approaches aimed at making the process quicker, cheaper, and safer.

One of those approaches was the center of a deal last week, when Johnson & Johnson teamed with Lexington, KY-based Transposagen Biopharmaceuticals, which is developing an “off the shelf” type of CAR-T. Pfizer is doing something similar through a deal with France’s Cellectis.

Unum CEO Charles Wilson

Unum CEO Charles Wilson

Unum is trying to be more universal. Rather than fixate on a specific cancer type or antigen—a substance that sparks an immune response, as CD19 is in the case of many of these other CAR-T approaches—Unum wants to engineer T cells with a surface protein that helps them latch onto antibodies.

The idea is to let antibodies like rituximab, which are proven to hone in on certain tumors, act as beacons. Rituximab finds tumor cells with CD20 on their surface; the Unum T cell would follow a bit later (or travel together after being infused at the same time) and bind to the rituximab, which helps form a molecular bridge to the tumor cells so the T cell can kill them.

Rituximab by itself does a pretty good job of fighting CD20-related diseases such as CLL and Non Hodgkin lymphoma. But not all patients respond to rituximab, and almost all end up taking something else after the drug stops working. Unum will first test its approach, in a variety of dose levels, in patients with chronic lymphocytic leukemia or Non Hodgkin lymphoma who either haven’t responded to rituximab or relapsed after treatment. Patients will be dosed a day or so after they get rituximab, according to Wilson.

By using this type of approach, the thinking goes, you can not only effectively supercharge a targeted antibody, but also apply a CAR-T approach to any type of cancer to which antibody therapies are being applied. Unum calls this “antibody-coupled T-cell receptor” technology, or ACTR; the name Unum, as in e pluribus unum (“out of many, one”) reflects that universal approach.

ACTR was developed by Dario Campana, who created the platform at the National University of Singapore and St. Jude Children’s Research Hospital. Campana also developed a CAR-T approach that’s 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.”