Interview Norman Sharpless , MD
that goes unfunded due to budget constraints . That ’ s why organizations like the American Society of Hematology ( ASH ) are so important – particularly for earlycareer 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 .
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 investigatorinitiated 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 decisions 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 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 sequencingbased treatment options are better than what they would have likely received otherwise .
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
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 .
“ 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 .”
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 . ●
70 ASH Clinical News February 2018