Talking Cure? For Cancer Immunotherapy, Still Many Rivers to Cross

Xconomy National — 

Cancer is a humbling thing: Our own cells gone bad, killing us from the inside, and so often able to rebound from attack or avoid it entirely. There has been progress fighting some types of cancers, but in no way equal to the resources (or rhetoric) the human race has aimed at the problem.

On stage at Xconomy’s annual Seattle biotech forum last week, I asked veteran cancer researcher D. Gary Gilliland, the new president and director of Seattle’s Fred Hutchinson Cancer Research Center—which brandishes the tag line “Cures Start Here”—if now, more than a decade into the genomic era, we’re justified to talk about cures. “There’s a certain amount of hubris in that tag line, but the point is we can finally see this coming against the backdrop of decades of work,” Gilliland said.

What Gilliland sees coming is cancer immunotherapy, a specialty at Fred Hutch, as the famous research center is known. The red-hot buzzphrase refers to different kinds of treatments, but all have in common the goal of stimulating a cancer patient’s immune system to attack the disease from within.

Gilliland: Decades of work.

Gilliland: Decades of work.

He is no impartial observer. Gilliland has played a role in those “decades of work,” first more than 20 years at Harvard University that included running the leukemia program at the Dana-Farber Cancer Center. More recently, he spent four years as head of oncology R&D at Merck, where he oversaw part of the development of pembrolizumab (Keytruda), one of only a few cancer immunotherapies to win approval.

Gilliland sees “a tidal wave of immunotherapeutic approaches” on the horizon, but to be clear, the wave has not arrived yet.

Cancer immunotherapy has helped drive the biotech financial boom the past couple years, with the biotech indices hitting all-time highs in March. A bit of froth has come off the top of the markets in the past month, so perhaps it’s a good time for a pause, a breather, a reality check. What needs to happen for that wave to reach patients? (Let’s pretend for a moment that tidal waves bring lots of wonderful health benefits, not death and destruction.)

We’ll start with the kind of cancer immunotherapy that Gilliland oversaw at Merck. Pembrolizumab (approved in the U.S. last September) is a monoclonal antibody, a kind of drug the industry has been developing and manufacturing for two decades. Four for cancer immunotherapy have been approved; three are “checkpoint inhibitors,” which disrupt a protein that cancer cells use to put a brake on the immune system.

The only checkpoint inhibitor with more than a few months on the market is ipilumumab (Yervoy), approved in 2011 for the skin cancer melanoma that has spread to other parts of the body or can’t be removed by surgery. It’s an important medicine, but it can sometimes be too toxic for patients.

Ipilumumab causes skin problems in up to 25 percent of patients, according to Jennifer Nam Choi, director of the Yale School of Medicine’s oncodermatology clinic. There are other immune-related side effects, too, serious enough to merit a “black box” warning from the FDA. Choi and other doctors have told me the potentially deadly side effects deter some physicians, who don’t have access to the latest research and resources, away from the drug.

“The rash”—which sounds tame but can be quite severe—“does not discourage us from using the drug since we know how to deal with it,” Choi told me. “But I can see how in smaller clinics and practices, it could be a reason.” (Choi noted that the two other approved checkpoint inhibitors, nivolumab (Opdivo) and pembrolizumab, so far seem to provoke milder side effects.)

The risks are worth taking when patients are otherwise facing near-certain death, as with the melanoma ipilumumab treats. The 5-year survival rate is 15 percent with a median survival between 8 and 9 months, according to a coverage report from insurance giant Aetna.

But to apply to a broader cancer population, checkpoint inhibitors need to get better. Keith Flaherty, who runs the Termeer Targeted Cancer Center at Massachusetts General Hospital in Boston, calls them “a phenomenal discovery” but to date “no panacea.”

That’s why every pharma company in the space is scrambling to try combinations. That’s the next hurdle for cancer immunotherapy: finding the right combinations out of dozens of possibilities. Even with some of the richest companies on Earth in the drug business, the costs could become prohibitive. When I asked Gilliland about the problem, he said “thoughtful and clever trial designs” would be needed—a topic he has written about in the past.

Better diagnostics are necessary, too. Adaptive Biotechnologies of Seattle has reeled in nearly $400 million in private funding since the start of 2014, including $195 million last week, because its backers believe the company’s immune system sequencing technology is exactly what immuno-oncology companies need to make smarter, faster drug development decisions.

“We have the ability to be involved in these trials early” to catch adverse reactions to drugs or help find the right dose, Adaptive CEO Chad Robins told me last week. Adaptive’s tests show how a patient’s immune system is responding to a drug, “and how that correlates with their outcomes and clinical data,” Robins said.

The company is also involved in studies at academic institutions “to design trials to answer some of these questions and not wait for a readout from the drug companies,” Robins said.

There are other technologies that might help by injecting tiny combinations of experimental cancer drugs into patients’ tumors—just enough to see if it’s worth continuing with larger-scale experiments. I wrote last month about one device, from Seattle’s Presage Biosciences, here; another comes from the lab of MIT’s Robert Langer.

As many readers know already, the most stunning data in cancer immunotherapy have come from treatments that use a patient’s own immune-system T cells, extracted and genetically engineered outside the body to be ferocious tumor killers, then given back to the patient.

In small Phase 1 trials, so-called CAR-T (chimeric antigen receptor T cell) therapies from Juno Therapeutics (NASDAQ: JUNO), Novartis (NYSE: NVS, and Kite Pharma (NASDAQ: KITE have quickly knocked out deadly hematological cancers in a large majority of patients. The most recent data came last month from a pediatric acute lymphoblastic leukemia (ALL) trial run by Seattle Children’s; Juno is the licensee. Twenty of 22 kids in dire straits saw their cancer go into complete remission.

Earlier studies in leukemia and other blood cancers have had similar results. Some of those patients have since relapsed, and some have been hit with serious side effects, as Xconomy wrote about in December, but not enough to staunch the progress toward larger trials.

With the companies moving into Phase 2 for hematological cancers—with more patients, more scrutiny, and more time to work on countermeasures to the side effects—those results will be crucial to determine the eventual impact of CAR-T therapies on the field.

There’s a lot to hope for. The checkpoint inhibitors have a natural limitation: They only work in patients whose immune systems are already responding, even just a little, to a cancer. “But for a vast majority of cancers, that recognition isn’t happening,” says Flaherty.

Flaherty: No panacea.

Flaherty: No panacea.

For those patients, should we just “skip the intermediate steps and just give them the damn T cells,” as Flaherty asks? His answer: We’re not there yet. T cells, the hunting dogs of the immune system have to be used very carefully.

Juno has seen them propagate quickly, once back inside the patient, and almost work too well. CEO Hans Bishop said at our Seattle forum last week that one lesson from his company’s early trials is the need to “control the rate of expansion” of the cells, especially when a patient has widespread cancer that puts the cells into overdrive. “We believe the more cancer that’s accessible to the T cells,” said Bishop, “the faster they grow.”

That frenzy can produce serious side effects, such as systemic inflammation called cytokine release syndrome (CRS). (Two of 18 patients in an adult ALL program run by Memorial Sloan Kettering Cancer Center in New York and licensed by Juno died from CRS, although the company says they had health problems in addition to their leukemia.)

Drug developers also have to be careful where they point engineered T cells. Directed at cancerous B cells, a different type of immune-system cell in the blood, they’re extremely effective. But these engineered killers also wipe out non-cancerous B cells, which carry the same marker the T cells have been trained to seek out. That causes aplasia, a type of anemia. It’s not a life threatening condition, but drug makers will have to proceed with extreme caution when aiming T cells at other tumors that share molecular similarities with healthy cells. As two University of Pennsylvania researchers working with Novartis wrote in a report last year, “Targeting normal tissues is probably the largest hurdle in expanding CAR T cells to [solid] tumors.”

Or, in Flaherty’s words: “God help you if you try to target HER2 with T cells,” referring to the protein on certain breast cancer cells that’s also present in healthy tissue.

So in the coming months, also watch for CAR-T clinical data or trial news in solid tumors, which pose a tougher challenge for engineered T cells than hematological cancers. (The Penn group recently began a 12-person study in glioblastoma, a form of brain cancer.)

(Beyond CAR-T cells and checkpoint inhibitors, another kind of immunotherapy should produce data this year. Carlos Paya, CEO of Seattle’s Immune Design (NASDAQ: IMDZ), said he expects Phase 1 data by end of year for his company’s vaccine-like treatment that essentially presents a piece of solid tumor to a certain immune cell that serves as a sentry, thereby provoking a response against that tumor.)

To help CAR-T cells attack solid tumors, Juno, Bellicum Pharmaceuticals (NASDAQ: BLCM), and others are adding bells and whistles to their experimental products. One example is safety switches—methods to disable the cells if they go awry once in the body. Another is extra stimulation to help T cells overcome some of the tricks solid tumors use to suppress immune response. (There are a host of other start-ups, many of which Xconomy has written about, working on improvements to T cells, checkpoint inhibitors, and other kinds of immunotherapy. You can read about some of them here, here, here, and here.)

There’s one other hurdle the T-cell based immunotherapy companies will have to surmount: manufacturing. The companies tell us they’ve learned lessons from Dendreon, whose pioneering cell-based immunotherapy for prostate cancer came to market but failed to catch on—at least not enough to dig the company out from its massive debt load. (Juno CEO Bishop ran Dendreon’s operations.)

But so many things can go wrong making biologically active products. Just ask Genzyme, which was weakened and ultimately acquired less than two years after manufacturing glitches shut down a key Boston-area plant.

One investor, whose exchange-traded fund of 70 biotech companies includes nine clinical-stage immuno-oncology companies, says manufacturing worries him more than side effects. “It’s not a sexy topic, but it’s extremely important,” says Andrew McDonald, who helps manage the BioShares Biotechnology Clinical Trials Fund. “These will be challenging therapies to manufacture in a reproducible fashion.”

Manufacturing isn’t a problem the checkpoint inhibitors face, but those drugs have had no traction in treating blood cancers. It’s a good example how each type of cancer immunotherapy has its own set of challenges and trade-offs. “The impact of the entire swath of immunotherapy strategies leaves a lot on the table,” says Flaherty of Mass General. “I’m an optimist, but there’s a long way to go.”

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One response to “Talking Cure? For Cancer Immunotherapy, Still Many Rivers to Cross”

  1. Dieter Hovekamp says:

    Your article leaves out another type of T-Cell therapies that have been pioneered by the mTCR spin-outs from German Medigene AG and are silently in the focus of all big Pharma now: TCR based therapies.

    Beside Medigene and its UK pioneers Adaptimmune and Immunocore – Eli Lilly and Juno recently bought into other German companies BioNTech and Stage Cell. Kite and Bellicum try to catch up in TCRs as well with new collaborations this spring – also these are all often wrongly assigned as CAR-T play.

    The reason for this stealth can best be seen in this picture from the Immunocore Website (see ) – its all about new targets!