What Early Looks From ASH Tell Us About Cancer Immunotherapy

Xconomy National — 

[Note: Ben Fidler contributed to this report.] Immunotherapy is one of the most promising new ways to fight cancer, and we’ve followed it closely for some time. One of its main proving grounds is in blood-borne cancers, because some of the immunotherapy methods are, at least for now, easier to target in that direction.

That’s one reason why the upcoming American Society for Hematology conference—and the research abstracts, or previews, that were released this week—have garnered so much attention. An important caveat is that abstracts are often not representative of final data sets. What researchers report next month in San Francisco might be different than what the abstracts reveal.

More cancer immunotherapy news will certainly emerge from the massive volume of abstracts between now and December 6, the first day of ASH. For now, there are several interesting developments to note.

Cancer immunotherapy drugs that attack the PD-1 protein on tumor cell surfaces have made headlines for their effects on solid tumors like melanoma. But the ASH abstracts are providing some guidance how they might work against blood cancers.

The initial results seem encouraging: Some 87 percent of Hodgkin’s lymphoma patients who had failed at least three prior therapies responded to nivolumab (Opdivo) from Bristol-Myers Squibb (NYSE: BMY). Pembrolizumab (Keytruda) from Merck (NYSE: MRK) also showed early promise. (Pembrolizumab is approved to treat melanoma in the U.S., nivolumab is approved in Japan but not yet in the U.S.)

One hematological cancer that might not respond as well to PD-1 blockers is multiple myeloma. Bristol-Myers Squibb reported that none of the 27 patients with the disease responded to nivolumab. That’s a boon for Summit, NJ-based Celgene (NASDAQ: CELG), as PD-1 drugs represented a potential competitive threat to its multiple myeloma franchise.

Another kind of immunotherapy is based on a patient’s own immune cells, removed and genetically engineered to be efficient killers of a specific type of tumor, and re-introduced to the patient. It’s called chimeric antigen receptor T-cell, or CAR-T, therapy.

One of the leaders in the field is Seattle’s Juno Therapeutics, which is pushing forward into human trials with CAR-T therapy and another kind of immunotherapy developed at three institutions: Memorial Sloan-Kettering Cancer Center in New York, Fred Hutchinson Cancer Research Center in Seattle, and Seattle Children’s Hospital.

Juno has already made a splash, not just with its prodigious fundraising, but with results of a Phase 1 CAR-T trial in which 20 of 22 acute lymphoblastic leukemia (ALL) patients with a particularly intractable form of the disease—in other words, a very grim prognosis—showed complete remission of the disease.

At ASH, Memorial Sloan-Kettering researchers will present follow-up data from those patients. That’s important because some of the most promising medical technologies have seemed transformative at first—and CAR-T cell therapy, which Juno and others are pursuing, fits that description—only to run into the frustrating intricacies of biology.

From the abstract, here’s the latest on those 20 patients. As of July, 1, five had relapsed. Three of them were re-treated, and two of them “achieved a second CR”—or complete remission. That leaves three of the 20 with uncertain status, but the overall results remain impressive in a patient population with little hope of remedy. We contacted Juno officials for comment, but they did not respond in time for publication.

Another important follow-up with these patients are the data on a known side effect of CAR-T called “cytokine release syndrome,” sometimes called “cytokine storm,” which essentially is the immune system going into overdrive and causing system-wide inflammation. The condition can be quite serious, and everyone involved in the new CAR-T field is working on ways to alleviate it.

Of the 20 patients in Juno’s ALL study, nine developed cytokine release syndrome, or CRS. (They all began treatment with an acute presence of disease, not just residual effects from previous treatments.) Researchers measured the cytokine levels, in particular the protein interluekin-6 (IL-6), and are developing a strategy to “reduce the severity of CRS and improve safety” of the therapy. In all, researchers wrote in the abstract, both the relapse rate and the development of safety protocols to alleviate side effects “strongly support” the continued use of the therapy, although they underscore that it’s still early days: “These findings will need to be evaluated systematically and confirmed in a larger phase 2 trial.”

Novartis (NYSE: NVS), with a program called CTL019 licensed from the University of Pennsylvania, made big news at last year’s ASH in CAR-T right around the time Juno came out of stealth mode. This year, the Penn researchers are reporting follow-up data from a study of 30 children with acute lymphoblastic leukemia that didn’t respond to chemotherapy or stem-cell transplant. At first, the treatment provoked 27 complete remissions, but that number is now down to 16 for various reasons that are detailed in the abstract. As with the other CAR-T programs, the cytokine side effects are important, and the researchers write that treatment for CRS was required in 37 percent of patients “and was rapidly reversed in all cases with the IL-6 receptor antagonist tocilizumab, together with corticosteroids in 5 patients.”

Novartis, the only Big Pharma so far to invest heavily in a cell-based cancer immunology program, has moved CTL019 into Phase 2 trials, the abstract said.

In Los Angeles, Kite Pharma (NASDAQ: KITE) is working on CAR-T cell therapy that, like the Juno and Novartis programs described above, attacks tumors by honing in on a surface protein called CD19. (CD19 is found all over the surface of B cells, which, once gone awry, drive several blood-borne malignancies.) The University of California, Los Angeles spinout is working with the National Institutes of Health, and NIH researchers will present an update.

The abstract says 22 of 27 patients with B-cell lymphoma that hadn’t responded to chemotherapy showed either complete or partial remission, and 10 of them remain in complete remission over various lengths of time. The researchers were also interested in reducing the treatment’s side effects, so they tracked 9 patients who were given low doses of chemotherapy before CAR-T. (So far, CAR-T requires some amount of chemotherapy as a preparation.)

Compared to previous research in which anti-CD19 CAR-T was preceded by high-dose chemotherapy, the researchers said in the abstract, “toxicity was reduced when CAR-T cells were infused after low-dose chemotherapy. None of the 9 patients treated with low-dose chemotherapy and CAR-T cells required vasopressor drugs or mechanical ventilation, although some patients did have short-term neurological toxicity.”

In other words, this particular kind of cancer immunotherapy, from research groups related to Juno, Novartis, and Kite, is moving ahead into bigger trials and more patients. The spectacular early results of the treatments aren’t sustainable over time, it seems, and there are safety concerns, but so far nothing has forced anyone to slam on the brakes.