Pioneer’s Lament: Lack of Checkpoint Immunotherapy For Blood Cancer

Xconomy National — 

It might be hard to tell these days, but cancer immunotherapy can be disappointing, too. In a lunchtime review Monday at the American Society of Hematology annual meeting in San Francisco, Ronald Levy, a Stanford University professor with a long, storied history in the field, reviewed the trickle of clinical research presented at the meeting that involved so-called checkpoint inhibitors.

These antibody treatments have seen success treating solid tumors by blocking proteins that put the brakes on the immune system. Some tumor cells produce these proteins to hide from the immune system and multiply. Ipilimumab (Yervoy) from Bristol-Myers Squibb (NYSE: BMY) was the first, approved in 2011, and it fights metastatic melanoma by blocking the protein CTLA-4. A more recent approval was pembrolizumab (Keytruda) from Merck (NYSE: MRK), which is also approved for melanoma and has received a “breakthrough” FDA designation for non-small cell lung cancer. It blocks the PD-1 protein.

But no checkpoint inhibitors have been approved to treat hematological cancers; only a few have just reached the clinic, including the two mentioned above. In contrast to the steady beat of data from cell-based therapy programs, only four clinical checkpoint inhibitor studies were submitted to ASH, the year’s biggest showcase in the field.

It’s a “paucity,” according to Levy, whose antibody work in the 1970s and ’80s led to the San Diego company IDEC Pharmaceuticals (which merged with Biogen in 2003, forming Biogen Idec) and its pioneering cancer treatment rituximab (Rituxan).

Levy went through the four abstracts, noting both concern and optimism. But what stood out both from his comments and from others in the room were the preliminary data from one Phase 1 study that showed one checkpoint inhibitor, nivolumab (Opdivo) from Bristol-Myers Squibb (NYSE: BMY), had absolutely no effect in 27 multiple myeloma patients.

There are several treatments available for multiple myeloma, but the disease, the second most common blood cancer, is far from managed. About the lack of immunotherapy programs to tackle the disease, Levy said, “The silence is deafening.”

Even a researcher from AbbVie (NYSE: ABBV) working on the experimental antibody elotuzumab for multiple myeloma said after the session that the nivolumab results were “disappointing.”

In response to a comment from the audience, Levy’s co-presenter Stephen Ansell of the Mayo Clinic said, “It’s certainly depressing, initially.” But he stressed that some of the interaction in the bone marrow of myeloma cells and tumor-killing T cells—which checkpoint inhibitors are meant to unleash—was a mystery that researchers were eager to explore and “get our heads around which patients to target.”

Multiple myeloma is also an outlier among hematological cancers, in that it comes from malignant B cells like several leukemias and lymphomas, but unlike those cancers, it does not continue to express a B cell protein called CD19, as the University of Pennsylvania’s Carl June pointed out in his talk Sunday.

Nivolumab had much better results in Hodgkin’s lymphoma, as did pembrolizumab.

These were very small sample sizes, as Levy cautioned. But the studies together confirm for Levy that Hodgkin’s is “extremely sensitive to PD-1 blockade. When the brakes were taken off, amazing things happened.”

That said, Hodgkin’s lymphoma is a relatively treatable disease. Many of those treated in the early anti-PD-1 programs had failed other treatments such as brentuximab vedotin (Adcetris) from Seattle Genetics (NASDAQ: SGEN), but if checkpoint inhibitors make it through to approval, there will still be a question of how to integrate them into current paradigms of treatment, Levy said.

Ansell spent much of his talk in a deep scientific dive into some potential factors holding back the effectiveness of checkpoint inhibitors in lymphoma—including, for example, why certain tumor microenvironments are “hostile” to T cells. Both Ansell and Levy pointed out that, as in other cancer research, there are many other proteins to target in a pathway, and checkpoint inhibition should be no different. In lymphoma research, we might soon be hearing about LAG-3 and TIM-3 as much as PD-1 and CTLA-4, said Ansell.

“And next year at ASH,” said Levy, “I anticipate more than four abstracts.”