Big Questions, Tough Answers

Norman E. Sharpless, MD
Dr. Sharpless is the director of the National Cancer Institute and is specialized in the care of patients with leukemia.

On October 17, 2017, Norman “Ned” Sharpless, MD, was sworn in as the 15th director of the National Cancer Institute (NCI), succeeding Harold E. Varmus, MD, who stepped down as director in March 2015, and Douglas R. Lowy, MD, who had served as acting director since April 2015.

Previously, Dr. Sharpless was director of the Lineberger Comprehensive Cancer Center at the University of North Carolina, where he was also the Wellcome Distinguished Professor in Cancer Research. As a practicing hematologist at the N.C. Cancer Hospital, the clinical arm of Lineberger, he specialized in the care of patients with leukemia.

As he begins his term as NCI director, ASH Clinical News spoke with Dr. Sharpless about transitioning from academia to government, the challenges facing investigators, and the exciting developments in precision oncology and translational research.

In Sound Bites, hear more from our interview with Dr. Sharpless.

What is the biggest difference between working in academia and at the NCI?

The move to Washington, DC, and severing ties with external companies as a federal employee were both big changes. The biggest change, though, is in the nature of the work. The NCI is an astoundingly big and wonderful organization. Running the Lineberger Comprehensive Cancer Center was fun; this job is unbelievably great. The problems are significant, but terribly interesting. Every day is different, and I’m really having a great time learning how federal government works.

It’s early in your term, but could you tell us about your general vision for your tenure as NCI director?

The NCI is a big, complicated organization, so I’m still in listening-and-learning mode to understand it better before I’m able to say, “Here are the top six priorities of the new NCI director.” However, the areas where we will be expending more effort during my tenure as director are already becoming clear.

One is big data. When I talk with patients and advocates, this is their No. 1 concern.  Mobile phones can tell people about every hotel in North America, yet we rely on 30-patient clinical trials to answer questions about treatment choice. Patients and advocates want more information and larger sample sets, so they know what to expect from an investigational drug.

How will we aggregate these massive amounts of information with the goals of preventing and treating patients with cancer? Issues of patient privacy make accessing the information difficult. Our next step is mining these data for insights about investigational treatments.

Also, as a working scientist who ran a basic science laboratory for my entire career, I want to ensure that the NCI remains committed to deepening the basic biologic understanding of cancer. At times, it feels like we’re making so much progress in treating certain diseases that perhaps we should stop funding basic science. That’s not the case. While we have made impressive achievements and progress in many malignancies, we still lack a fundamental understanding of cancer. To continue our forward march against cancer, we need to fill in these gaps.

The NCI is operating in a tight funding climate. How do you think that has affected progress in basic science?

Unfortunately, in every grant cycle, there will always be great science that goes unfunded due to budget constraints. That’s why organizations like the American Society of Hematology (ASH) are so important – particularly for early-career investigators. Grants from non-federal agencies support young scientists as they build up enough preliminary data to successfully apply for an NCI-funded grant.

The NCI has enjoyed broad congressional support for the last three years. However, the institute’s $5.7 million budget pales in comparison to the burden of cancer in our society – both in terms of the financial costs of treating cancer and the personal costs of living with cancer. How we deal with these budgetary challenges is the work of the NCI and its committed staff. We use tried-and-true techniques, like peer review, to identify the best science, and we pay close attention to emerging scientific areas that could translate rapidly into improved patient care.

Left to right: Dr. Sharpless (joined by his wife, Julie Lund Sharpless, MD), is sworn in as NCI director by Acting Secretary of Health and Human Services’ Eric D. Hargan.
Left to right: Dr. Sharpless (joined by his wife, Julie Lund Sharpless, MD), is sworn in as NCI director by Acting Secretary of Health and Human Services’ Eric D. Hargan.

What have been the greatest successes in translational research in the past few years?

The example I’ve been pointing to lately is the approval of chimeric antigen receptor (CAR) T-cell therapy in B-cell lymphoma in late 2017. This is a game-changing development for patients. When I describe it to patients, it sounds like science fiction: “We’re going to take your cells out, turn them into little cancer-fighting robots, and give them back to you. And it’s going to work.”

The work to get to this point goes back 40 years, as scientists learned how to use the body’s own immune system to treat cancer. It was a long time coming, and it was by no means a straight path. There were many fits and starts on the way, but where would we be if people hadn’t been doing that basic science for so many years?

The basic discovery that led to the creation of a new therapy and the therapy’s approval can be decades apart. That’s understandably frustrating. But when new agents gain approval, we must emphasize that they were developed from basic investigations that go back many years.

The best basic science doesn’t come from the top down. You can’t have a committee that tells assistant professors what to work on; the greatest ideas bubble up from the community through investigator-initiated research. I believe the NCI should continue to support basic science in a robust way.

For hematologic malignancies, what do you see as the biggest obstacles to advancing research?

Most of the diseases in malignant hematology occur with rare frequency, so the one-drug-fits-all approach isn’t going to work. And as we look at cancer under a more focused lens, we no longer view these diseases as one large group; it’s not just lymphoma, there’s B- and T-cell lymphoma, and then there’s a hundred different subtypes of T-cell lymphoma.

At the beginning of my career, trials enrolled 500 patients with leukemia. We gave 250 patients one drug and 250 the other drug. If the analyses of the results found that the Kaplan-Meier curve diverged by just 2 percent, that abstract could have been presented in the plenary session at the ASH annual meeting. Those days are over. Now we’re trying to find the acute myeloid leukemia (AML) with an NPM1 mutation that’s FLT3-wild type.

That’s precision oncology: figuring out the right therapy for your cancer and how your cancer is different from everybody else’s cancer. It’s already changing how we practice oncology, and it’s going to lead to better care for patients.

The fragmentation of diseases and clinical trials caused by precision oncology is a good problem, but it is still a problem. If every single patient requires a different treatment regimen, that makes direct discovery and conducting efficient, and cost-efficient, clinical trials challenging.

Conducting trials is getting more expensive, as are the regimens they’re evaluating.

The NCI doesn’t play a role in setting drug prices, but like everyone, we are concerned about financial toxicity for our patients. The good news about CAR T-cell therapies is when they work, they work great, and an expensive effective therapy is better than an expensive ineffective therapy, which is what we had for many years. The bad news is that we haven’t yet figured out how to manufacture CAR T-cells more efficiently or how to make them less toxic.

Once we answer those questions, we hope the costs will come down. We believe research can help perfect these types of therapies for patients with blood cancers.

Tell us how the NCI has invested in precision medicine.

We are excited about the NCI-MATCH (Molecular Analysis for Therapy Choice) trial, in which patients with cancer undergo genomic sequencing and are assigned in real time to a treatment based on the genetic changes found in their tumors. This type of trial is known as a “basket trial,” and MATCH is the mother of all basket trials. It’s a huge trial, enrolling more than 6,000 adult patients at 1,100 different sites.

Some results from MATCH have been presented at meetings, and already, a few things are becoming clear. First, machinery works. We can set up real-time sequencing, make clinical decision-making based on those results, and identify patients with rare mutation populations to go into clinical trials.

Second, drugs in certain arms of the trial are showing better-than-expected activity, meaning that, for patients with certain mutations who are allocated to a certain drug, the drug works.

Third, as we gain more experience with conducting these types of precision oncology trials, we’re also figuring out how to export this sequencing paradigm to the real world. We’re collecting all the data and learning from the successes and the failures. Some patients are clear responders and some aren’t. In some instances, we’re identifying patients who wouldn’t have benefited from sequencing. But we’ve also seen that the sequencing-based treatment options are better than what they would have likely received otherwise.

“The greatest ideas bubble up from
the community through investigatorinitiated
research. I believe the NCI
should continue to support basic
science in a robust way.”

Full results are planned for publication later this year, and the NCI-Children’s Oncology Group Pediatric MATCH trial is just starting in earnest. The design is similar to the adult MATCH trial, with a few differences: The agents and the arms are different because the mutations in pediatric cancers are different from all cancers. The pediatric trial includes some germline sequencing because germline mutations are more common in pediatric populations. It also incorporates some family counseling, where appropriate, for newly identified germline genetic events.

It’s an exciting trial that I think is going to inform the field of pediatric oncology.

How do you see the field of cancer immunotherapy evolving over the next five to 10 years?

CAR T-cells have proven their worth in a few specific hematologic malignancies; whether that paradigm is expandable to solid tumors isn’t clear yet. On the other hand, checkpoint inhibitors have had more success in solid tumors, but will they work in hematologic malignancies? Or is there some combination therapy of a tumor vaccine plus a PD-1 antibody, or multiple agents, that can stimulate the immune system and be active in certain hematologic malignancies? There is also considerable interest in how to translate the off-the-shelf checkpoint inhibitor–type agents to diseases like AML. We’re looking forward to seeing where that is going.

Personalized tumor-infiltrating lymphocytes, another autologous cellular immunotherapy in development, are beginning to show some activity in solid tumors. The approach is similar to CAR T-cell therapy, so we’re looking to clinical trials to help us decide which of these approaches to move forward with.

Also, as cellular immunotherapies take greater hold in hematologic malignancies, the infrastructure to manufacture them must keep pace. The NCI is interested in helping the community increase production capacity to support early-phase clinical trials.

With the rise of these therapies, we’re also facing an interesting issue: For some diseases, like Hodgkin lymphoma, we have curative options, but could we cure diseases with a less-toxic therapy? Could we switch out some of the more cytotoxic drugs for checkpoint inhibitors? Again, it’s a good problem to have.