Fitting tumors to a T

Registration statements for initial public offerings are the Eeyores of public documents, and the prospectus Juno Therapeutics released on Monday is no exception. It drones on for page after page about the very real and highly numerous risks in launching up a business to treat cancer by re-engineering T cells.

But I like the ambition of the opening statement: “We are building a fully-integrated biopharmaceutical company focused on revolutionizing medicine by re-engaging the body’s immune system to treat cancer.”

Most of Juno’s research and almost all of its early trials are centered on chimeric antigen receptor (CAR) T cells designed to treat B cell leukemias and lymphomas. This technique plucks out some of a patient’s own T cells and genetically modifies them to glom onto a certain receptor on the cancer cell and start a snowballing immune attack. The reengineered cells are replicated in large volume and put back into the patient, where the immune attack often can effectively wipe out the disease.

If the attack is too strong, though, it can kill the patient, which apparently happened several times in recent trials. Juno and its clinical partners took steps this spring to minimize that danger, mostly by selecting patients more rigorously. And they’re pursuing a technique to make the engineered T cells susceptible to certain chemotherapies, so that the reintroduced cells can be killed off if their onslaught threatens to overwhelm the recipient.

Juno also is investigating another adoptive T cell approach called high-affinity T cell receptor (TCR). These T cells are modified to better seek out fragments of protein brought to the surface of tumor cells by major histocompatibility complex (MHC) cell-surface molecules.

“TCRs recognize proteins that are presented to the immune system as a peptide bound to an MHC, and are therefore restricted to a certain MHC type,” the prospectus notes. “Approximately 80% of the U.S. population has one of the four most common MHC types. Due to this variability, multiple different TCR product candidates will be needed to address any given target protein for a broad population.”

That requirement further complicates drug development. But unlike CAR T cells, TCR T cells can go after cancer cells that are flagged by peptides presented from inside the cell, which might make them useful against a much broader group of cancers.

Juno is pursuing both technologies to treat not just blood cancers but difficult-to-treat solid tumors, with at least four product candidates scheduled for clinical testing by 2016. Among them is a TCR T cell agent that targets WT-1, an intracellular protein overexpressed in adult myeloid leukemia (AML) and breast, colorectal, non-small cell lung and pancreatic cancers. The company expects to give first results of an AML trial this year, and to begin another trial both for AML and solid tumors next year.

TCR

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