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

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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 … Next Page »

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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!