NEWS IN BRIEF

MARCH 2017�CANCER DISCOVERY | 239

models that predict likelihood of remission, relapse, and mortality—could spare patients with AML a stem-cell transplant if they are unlikely to benefi t, which could improve quality of life and lower health care costs while maintain-ing overall survival rates (Nat Genet 2017 Jan 16 [Epub ahead of print]). Such “knowledge banks” could also be used to personalize treatment for patients with different types of cancer.

“It’s the only way forward in many senses,” says Peter Campbell, MD, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK, who co-led the study. “Drugs are not going to be a universal panacea across all patients with a par-ticular type of cancer, and there might be ways to use molecular data to predict which patients are going to benefi t.”

Campbell previously teamed up with Hartmut Dö hner, MD, of Ulm Univer-sity in Germany, to sequence the cod-ing regions of 111 cancer-related genes from 1,540 patients with AML from a trio of treatment trials. By combining mutational data with cytogenetic measures and clinical outcomes, they stratifi ed the disease into 11 subtypes, each with a distinctive constellation of clinical and genomic features (N Engl J Med 2016;374:2209–21).

Now, in one of the largest analyses of its kind, Campbell, Dö hner, and their colleagues have used that dataset to develop a model to predict survival odds associated with different treatments. They based their algorithm on 231 vari-ables in patients’ genetic and clinical records, including copy-number alter-ations, point mutations, and demo-graphic details. They then validated the model using data from an indepen-dent cohort of 186 patients from The Cancer Genome Atlas. The algorithm’s predictions closely matched patient outcomes in each cohort.

The team concluded that up to one third of individuals could have their treatment altered if a knowledge-bank approach was implemented. For example, in the United States, about 44% of young adult patients with AML undergo a stem-cell transplant. By using the tool to tailor treatment decisions, that could drop to 35% without affecting overall survival.

“This is a powerful study which addresses how we can begin to apply data from population studies to individual patients,” says Jeffery Klco, MD, PhD,

diffi cult to treat, with survival being 8 weeks on average,” says Behnam Badie, MD, chief of neurosurgery and the study’s co–senior author. Badie and his team resected several of the patient’s brain tumors before giving him multiple infu-sions of CAR T cells engineered to target IL13Rα2, which is frequently overex-pressed in glioblastoma.

“In a previous trial, we generated IL13Rα2-targeting CARs on cytotoxic CD8+ T cells, but the antitumor effi -cacy achieved wasn’t long-lasting,” says first author Christine Brown, PhD. “This time, we used central memory T cells and optimized our CAR design along with the manufacturing pro-cess. Preclinical studies indicated that these improvements resulted in more potent, persistent therapeutic cells.”

Rather than the standard route of intravenous infusion, the researchers used a catheter device to deliver the patient’s CAR T cells directly into his largest resected tumor cavity. After six treatment cycles, however, they observed that although there were no signs of local recurrence, his nonresected tumors were progressing, and additional lesions had developed, including new spinal metastases that caused leg numbness.

As such, the delivery route was tweaked: CAR T cells were injected directly into the patient’s cerebrospinal fl uid instead. “We hypothesized that the fl uid would carry the cells to different regions of the brain, improving control of tumor growth at distant sites,” Badie explains. Even so, the team was surprised to see complete elimination of the patient’s brain and spinal tumors. His robust response lasted 7.5 months, during which he returned to his normal activities.

Notably, the side effects were mild—low-grade headaches, fever, and fatigue—and cytokine release syndrome, which is poten-tially deadly, did not occur. Although the patient’s disease eventually recurred, the tumors were found in new locations, not at or near the initial sites. Preliminary research suggests the development of resistance through decreased IL13Rα2 expression on the tumor cells, Badie says.

To Michael Lim, MD, director of the Johns Hopkins Brain Tumor Immuno-therapy program in Baltimore, MD, “the fact that this patient had a 7.5-month response is pretty impressive,” given the nature of his cancer. He is encouraged by the unconventional delivery method,

noting that “this is such a diffi cult disease to tackle, it’s great to see people thinking out of the box.”

Overall, “we should be cautiously opti-mistic that CAR T-cell therapy will have a role in glioblastoma,” Lim says, “but it’s just one modality. Sustained antitumor responses will require incorporating mul-tiple components of the immune system.”

Badie agrees; he and his team would like to evaluate their therapy alongside checkpoint inhibition for this patient, who is still alive. They also plan to see if simul-taneous infusions into resected tumor cavities and cerebrospinal fl uid improve effi cacy. Developing multitargeted CAR T cells against other glioblastoma anti-gens, including HER2 and EGFRvIII, may be another option. –Alissa Poh ■

Precision Medicine Promising for AML

After achieving initial remission, many patients with acute myeloid leukemia (AML) opt to receive an allogeneic stem-cell transplant to rid their bone marrow of any lurking cancer cells. This inten-sive treatment decreases the risk of disease recurrence compared with stan-dard chemotherapy, but it also raises the risk of serious complications, such as graft-versus-host disease and death. Balancing the pros and cons can be challenging, but large collections of genomic data matched to clinical vari-ables could aid in decision-making.

According to a new study, databases of this kind—coupled with statistical

Contact between an IL13Rα2-targeting CAR T cell (blue) with a glioblastoma cell (green) triggers formation of an immunologic synapse (red) and tumor cell destruction.

Don

grui

Wan

g, C

ity

of H

ope

on July 6, 2021. © 2017 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from

Published OnlineFirst January 31, 2017; DOI: 10.1158/2159-8290.CD-NB2017-015

http://cancerdiscovery.aacrjournals.org/

NEWS IN BRIEF

240 | CANCER DISCOVERY�MARCH 2017 www.aacrjournals.org

“and put together a fi ve-element signa-ture that is prognostic for disease recur-rence, with greater than 85% accuracy.”

Epigenetic changes are key in this signature, notably hypomethylation of TCERGL1 and hypermethylation of ACTL6B. Point mutations in ATM, chro-mosome 7 rearrangements, and MYC amplifi cation comprise the remaining three elements. The researchers are now investigating the functional consequences of these molecular alterations.

For men whose intermediate-risk prostate cancer contains these adverse genomic features, more intensive treat-ment up front is warranted, Bristow says. “There are much better hormone thera-pies now that really shut down androgen signaling, which we could incorporate earlier than the metastatic setting. For some cases, we could utilize PARP inhi-bition, exploiting mutant ATM-induced defi ciencies in DNA repair.”

Whole-genome sequencing “is about as deep as you can go, and hadn’t been done to this extent in prostate cancer,” observes Peter Nelson, MD, of Fred Hutchinson Cancer Research Center in Seattle, WA. He considers this study an “expansive, powerful analysis,” not-ing that ATM mutations, in particu-lar, had been “a suspected feature of recurrence, but not really nailed down” until now.

“A key question that remains is deter-mining this signature’s frequency across a large patient population, which would give some indication of its utility,” Nel-son says. “It also remains to be seen if, besides recurrence, this constellation of bad genomic hallmarks is consistently associated with mortality.”

Bristow, Boutros, and their team are collecting more information, includ-ing RNA-sequencing data, to further refi ne their signature. “Our goal is to develop an assay that simultaneously measures each individual element, then commercialize this platform once its prognostic utility has been validated in a new cohort of approxi-mately 500 patients,” Bristow says.

Overall, “within 5 years, I think many more men diagnosed with prostate can-cer will undergo genomic screening,” he adds. “To be more precise in our care of this disease, the lexicon needs to evolve so it’s not only about Gleason scores and PSA levels, but also which molecular risk group a patient is in.” –Alissa Poh ■

NCI Launches Drug Formulary

Through its Cancer Therapy Evalu-ation Program (CTEP), the NCI has launched a public–private partnership with the pharmaceutical industry. Called the NCI Formulary, it aims to speed access to drugs for preclinical and clinical studies to investigators at NCI-designated cancer centers (https://nciformulary.cancer.gov).

“One of the key things with this part-nership is that it will expedite the process by which investigators studying combi-nations of drugs from different com-panies acquire those agents,” says James Doroshow, MD, the NCI’s deputy direc-tor for clinical and translational research. Instead of spending considerable time negotiating with separate companies, researchers can use the formulary as a go-between: CTEP will forward study proposals to the relevant companies, who then decide within 60 days if they will supply the drugs requested.

“Previously, this could take as long as 18 months because of the need to hammer out the terms, such as data rights, in indi-vidual agreements with each company,” Doroshow says. With the new for mulary, participating companies have agreed to use standard terms negotiated over many years with CTEP, he explains. Approved clinical trials will be conducted using the NCI’s established infrastructure, includ-ing its systems for reporting clinical data and serious adverse events.

Currently, the formulary comprises 16 drugs from six companies: Bristol-Myers Squibb, Eli Lilly, Genentech, Kyowa Hakko Kirin, Loxo Oncology, and Xcovery. These include not only approved drugs—the PD-1 inhibitor nivo lumab (Opdivo; Bristol-Myers Squibb), for instance, and the PD-L1 inhibitor atezolizumab (Tecen-triq; Genentech)—but also experimental agents such as prexasertib (Eli Lilly), which blocks CHK1, and ensartinib (Xcovery), a next-generation ALK inhibitor. (See table on the next page for a full list.)

Doroshow notes that approved stud-ies will be entirely investigator-funded; companies are not required to provide fi nancial support. In terms of expedit-ing agent access, “I don’t think this is inconsequential [to companies],” he says. “There’s quite a difference between being asked to supply a drug, versus that plus substantial funding.”

of St. Jude Children’s Research Hospital in Memphis, TN, who was not involved in the research. Klco notes, however, that the fi ndings rely on retrospective modeling. “Ultimately,” he says, “this algorithm is going to have to be evaluated appropriately in a prospective clinical study.”

According to co–fi rst author Elli Papaemmanuil, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, the team is adding 3,000 more patient records to the database to refi ne the algo-rithm before prospectively testing it.

Papaemmanuil and her colleagues are also implementing the approach for other cancers, starting with myelodysplastic syn-drome. The key, she says, will be building, maintaining, continuously updating, and properly analyzing large clinical–genomic databases for any given disease. “The data exist,” she says. “It’s more of an organiza-tional challenge.” –Elie Dolgin ■

Prostate Cancer Recurrence: Genomic Clues

In the largest genomic analysis of intermediate-risk prostate cancer samples to date, Canadian researchers have uncovered a molecular signature that could help pinpoint patients whose disease is likely to recur and metasta-size even after precision surgery or radi-otherapy (Nature 2017;541:359–64).

“I can have 100 men come through the door with what appears to be the same stage of cancer—localized and potentially curable—yet just by prob-ability, I know roughly 30% will relapse after surgery or radiotherapy,” says co–senior author Robert Bristow, MD, PhD, of Princess Margaret Cancer Centre in Toronto. “We need to improve our ability to predict which patients fall in this higher-risk category.”

With Paul Boutros, PhD, of Toronto’s Ontario Institute for Cancer Research, the team carried out whole-genome sequ encing on 200 intermediate-risk prostate tumors, and whole-exome se-quencing on another 277. They assessed the tumor samples for various markers of genomic instability, including point mutations, copy-number alterations, and DNA methylation status. Aided by avail-able outcomes data from 130 pa ti ents, “we ranked the relative importance of these different indices,” Bristow explains,

on July 6, 2021. © 2017 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from

Published OnlineFirst January 31, 2017; DOI: 10.1158/2159-8290.CD-NB2017-015

http://cancerdiscovery.aacrjournals.org/

2017;7:239-240. Published OnlineFirst January 31, 2017.Cancer Discov Precision Medicine Promising for AML

Updated version

10.1158/2159-8290.CD-NB2017-015doi:

Access the most recent version of this article at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

.pubs@aacr.org

To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerdiscovery.aacrjournals.org/content/7/3/239To request permission to re-use all or part of this article, use this link

on July 6, 2021. © 2017 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from

Published OnlineFirst January 31, 2017; DOI: 10.1158/2159-8290.CD-NB2017-015

http://cancerdiscovery.aacrjournals.org/lookup/doi/10.1158/2159-8290.CD-NB2017-015http://cancerdiscovery.aacrjournals.org/cgi/alertsmailto:pubs@aacr.orghttp://cancerdiscovery.aacrjournals.org/content/7/3/239http://cancerdiscovery.aacrjournals.org/