July 2014 Edition Vol.11, Issue 7

The Complexities of Immunotherapies: CARs, TILs, and TCRs

The Complexities of Immunotherapies: CARs, TILs, and TCRs

By Neil Canavan

“It’s complicated.” 
– Cassian Yee, MD, Professor, Department of Immunology, University of Texas, MD Anderson Cancer Center

This is the second of two articles highlighting the burgeoning field of cancer immunotherapies, featuring expert commentary from stakeholders in the immunotherapy space: interviews were conducted by OBR prior to, during, and immediately following ASCO 2014.

Yes, immunotherapies are complicated, even the language to describe the field can be needlessly complex. “Actually, we’ve all got our separate lingos so that we can keep the club secret,” says Walter Urba, MD, PhD, Director of Cancer Research, Providence Medical Group, Portland. “It’s payback for all the molecular biologists and their signaling cascades.” I mean: MAP kinase-kinase-kinase, or MAP3K, or MEKK? Really?

That said, once a few basic concepts are in hand – such as thymic selection (whereby T-cells are culled for self-reactivity) to how selected T-cells are recruited and stimulated to attack at the site of tissue invasion (be it raging infection, or proliferating tumor) the imagination can run wild. Which is very much part of the appeal of immunotherapy; there’s plenty of room to be creative, innovative, and, in press release parlance: “forward-looking”.

Will it Fly?

Big Pharma and Wall Street, as evidenced by a recent flurry of activity, seems to think so with the announcements below:

• June 18, 2014 – Pharmaceutical giant, Pfizer, signs a deal with French biotech company, Cellectis, for the development of Chimeric Antigen Receptor T-cells (CAR-Ts). Unlike other approaches, these CAR-Ts will be allogeneic
• June 19, 2014 – MD Anderson Cancer Center issues a rebuke to Northwest Biotherapeutics for premature statements regarding its cancer vaccine, DCVax. Aman Buzdar, MD, vice president of clinical research at MD Anderson, speaking to one financial analyst stated that, in his opinion, “The company is trying to create a tremendous hype about this product,” suggesting that this was done to entice investors
• June 20, 2014 – Kite Pharma, involved in autologous T-cell therapy launches a successful IPO. Initially priced at $17, Kite shares are selling at $32.30 at the time of this writing    

CAR Wars

CAR-Ts are T-cells where the endogenous T-cell receptor has been modified with the addition of a targeting moiety – a monoclonal antibody.

In April of this year the immunotherapy company, Juno, reported on a small trial of an anti-CD19 CAR, an antigen relevant in leukemia. While the results of the therapy were impressive overall, two patients died on trial, leading to a great deal of discussion about how to make CARs safer.

The scientific consensus is now that such constructs require a “suicide switch” to be flipped should a patient experience potentially life-threatening, CAR-related adverse events.

Numerous candidates for a molecular suicide switch have been suggested; more than 10 years ago it was proposed that adenovirus-mediated, herpes simplex virus thymidine kinase, activated by acyclovir would work. A more elegant approach involving caspase-9, plus a small molecule activator has been recently put forth by Houston-based, Bellicum Pharmaceuticals.

“It works in minutes,” says Nabil Ahmed, MD, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston. “It’s a caspase monomer that has a binding domain to a small (proprietary) molecule.” At the first sign of trouble, a patient is given the small molecule and, via caspase-9, the CARs undergo apoptosis. “We’ve had patients who’ve had a graft versus host response whose cells were eliminated.”

This capability has taken much of the worry out of a technique fraught with uncertainties. “The toxicities associated with these therapies can be divided into two major categories,” says Crystal Mackall, MD, head of the immunology section of the National Cancer Institute. The first is autoimmune; this is where the tumor antigen targeted by the (therapeutic) T-cells is also expressed on normal tissues.