1052 | CANCER DISCOVERY SEPTEMBER 2018 www.aacrjournals.org

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able to nail down a good biomarker,” he says. “What this paper is suggesting is that maybe we weren’t looking in the right place.” –Catherine Caruso n

Advice Offered for Sharing Research Results

Whether to provide research results to individual study participants—and, if so, how to do it—vexes scientists, ethi-cists, and regulators. A recent report from the U.S. National Academies of Sciences, Engineering, and Medicine provides 12 recommendations to help researchers weigh the pros and cons of disclosing results and make shar-ing research findings easier and more informative for participants (avail-able at http://nationalacademies.org/returnofresults).

Researchers can uncover data that could alert participants or their fami-lies to potential health problems. For example, genome sequencing con-ducted as part of a cancer study might reveal that a patient carries a gene mutation that boosts the risk of car-diovascular disease. However, several obstacles make sharing that informa-tion difficult. Among them:

• Regulations on what data researchers can share are contradictory.

• Many researchers don’t have the train-ing or the time to explain a finding’s implications to participants or to talk them through treatment or preven-tion options.

• Sharing findings could be harmful—if the results are wrong, for instance.

The new report, drafted by a commit-tee convened by the National Academies, aims to help researchers decide whether to share results and provides advice for simplifying the process. The key first step is harmonizing federal regulations outlining the circumstances under which information can be returned, says Suzanne Bakken, PhD, of Columbia University in New York, NY, one of the committee’s 15 members. Currently, the Centers for Medicare and Medic-aid Services (CMS) prohibits return of results from labs that aren’t Clinical Laboratory Improvement Amendments (CLIA) certified. Many research labs don’t have that designation, yet they

MHC Expression Predicts Checkpoint Blockade Response

The presence of MHC proteins may affect response to immune checkpoint inhibitors in patients with advanced melanoma: In a recent retrospective study, patients with low MHC class I expression responded to a PD-1 inhibi-tor but were less likely to respond to a CTLA4 inhibitor (Sci Transl Med 2018; 10:eaar3342). Additionally, patients who expressed MHC class II had better responses to a PD-1 inhibitor.

“T-cell recognition of cancer-specific mutant peptides, in the context of MHC, is generally what’s thought to be essential for antitumor immunity, and this activity is enhanced when you treat patients with agents that target immune checkpoints,” says Scott Rodig, MD, PhD, of Dana-Farber/Harvard Cancer Center in Boston, MA, the study’s lead author. However, “it all hinges upon the idea that the cancer cell is able to actually present these mutant proteins to the immune system, and for the immune system to recog-nize them.”

In a previous study of patients with classic Hodgkin lymphoma, Rodig and colleagues discovered a paradox: The disease is highly responsive to a PD-1 inhibitor, but most tumor cells do not express MHC class I (Cancer Immunol Res 2016;4:910–6). They concluded that an alternate mechanism must be triggering a response.

“Once we found this in Hodgkin lymphoma, it was sort of an open question of, ‘Could downregulation of MHC I be a mechanism at play in other tumor types?’ ” Rodig says.

To answer this question, the researchers conducted a retrospective study of 138 patients with advanced melanoma in the phase II CheckMate 064 trial who had received either 13 weeks of the CTLA4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) followed by 13 weeks of the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb), or vice versa. They performed immunohistochemi-cal staining on biopsy samples taken before treatment and looked at MHC

class I and class II expression. They then correlated the results with tran-scriptional and genomic profiles and clinical outcomes.

Patients responded to 13 weeks of nivolumab regardless of whether they expressed MHC class I, suggesting that “if MHC class I antigen presentation is compromised, there are alternative mechanisms for activating an antitu-mor response,” Rodig says. A possible mechanism is MHC class II: Patients first treated with nivolumab for 13 weeks who lacked MHC class I expression but expressed MHC class II in more than 1% of tumor cells had better responses and improved overall survival (OS) than patients with low MHC class II expression.

Patients first treated with ipili-mumab for 13 weeks who had MHC class I expression in 30% or fewer cells were more likely to have progressive disease after 13 weeks than patients with higher MHC class I expression, and patients with expression in 50% or fewer cells had worse OS than patients with higher MHC class I expression, an indication that “antitumor immunity that is unleashed by CTLA4 blockade is exquisitely sensitive to retained expres-sion of MHC class I by melanoma cells,” Rodig says.

For Douglas Johnson, MD, of Vanderbilt-Ingram Cancer Center in Nashville, TN, who was not involved in the research, it confirms a positive correlation between MHC class II expression and response to a PD-1 inhibitor established in previous research (Nat Commun 2016;7:10582). “MHC class II has now been validated in a few different studies as a poten-tial biomarker for PD-1 [inhibitor response], and I think that it does look promising, although it still has a long way to go,” he says.

Adil Daud, MD, of the University of California, San Francisco, who was also not connected to the research, is intrigued by the link between MHC class I expression and response to ipilimumab because it may indicate that the drug works via a different mechanism than has been thought.

“The mystery of how ipilimumab works, in my mind, has just grown over the years, because people have not been

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NEWS IN BRIEF

SEPTEMBER 2018 CANCER DISCOVERY | 1053

it, and trying to get at the answers in a group of men that experience the highest burden from this disease,” Martin says. –Catherine Caruso n

Modified Poliovirus Tested in Glioblastoma

A modified poliovirus may improve overall survival in patients with glioblas-toma, an aggressive, usually fatal brain cancer, according to preliminary results from a phase I clinical trial (N Engl J Med 2018;379:150–61).

“Poliovirus is very interesting for this cancer-targeting idea because of its recep-tor,” says Matthias Gromeier, MD, of Duke University in Durham, NC, a lead author of the study. He explains that the virus binds to the surface receptor CD155, which is expressed in cells in the spinal cord, as well as in almost all neo-plastic solid-tumor cells and in antigen-presenting cells such as macrophages, dendritic cells, and B cells.

Previously, Gromeier and his team created their modified poliovirus—the recombinant nonpathogenic polio–rhi-novirus chimera (PVSRIPO)—by replac-ing a portion of the poliovirus genome with the corresponding section of the common-cold virus genome. In a 2017 study, they established a possible mecha-nism for how PVSRIPO fights cancer: It enters CD155-expressing tumor cells and destroys or damages them, prompting a proinflammatory immune response from antigen-presenting cells in the tumor (Sci Transl Med 2017;9:eaan4220). This immune response elicits a sustained antitumor response.

Now, the team is testing PVSRIPO in patients with glioblastoma. “Recur-rent glioblastoma is an untreatable cancer—therapies invariably fail,” Gromeier says. Senior author Darell Bigner, MD, also of Duke, adds that virtually all glioblastomas recur after standard-of-care treatment with sur-gery, radiation, and chemotherapy.

For the phase I trial, researchers infused PVSRIPO into brain tumors in 61 patients with recurrent, grade IV glioblastoma. In a preliminary analysis, patients had a median overall survival of 12.5 months, compared with 11.3 months in 104 matched historical controls. Addi-tionally, 21% of patients were alive at 24 and 36 months, compared with 14% and 4%, respectively, in the controls.

may have to divulge test results because the Health Insurance Portability and Accountability Act (HIPAA) gives indi-viduals the right to obtain their health information in certain situations.

To ensure that research labs com-municate sound information, the report suggests that the NIH create an alternate quality-management system. Under this system, labs that meet cer-tain standards for generating accurate and reliable results, as well as CLIA-certified facilities, could pass on their findings, removing the conflict between CMS and HIPAA.

The report also suggests steps that researchers, institutional review boards (IRB), and other organizations can take after the regulatory changes are complete. For example, investiga-tors should address their strategy for returning results in research proposals and grant applications. IRBs should set up procedures and identify experts to review these plans.

“We are moving into an era of more open science, and part of that includes sharing data with research participants who generated the data. We need to be getting prepared for that,” says Bakken.

“I think they have done a wonderful job of reviewing the multiple issues around returning research results,” says Susanne Haga, PhD, of Duke University School of Medicine in Durham, NC, who wasn’t involved in drafting the report. How much impact the report will have remains unclear, she says.

Haga estimates that changing the regulations that cover information shar-ing will take “easily 5 years.” By then, the rapid development of genomic tech-nologies may have rendered moot some of the problems the report considers, she adds. In a few years, for instance, many people may have copies of their full genome sequence, so sharing the results of genomic studies may not be an issue. –Mitch Leslie n

Studying Prostate Cancer in African-Americans

The NIH recently launched a large-scale research effort on aggressive prostate cancer in African-American men. The $26.5 million study, dubbed RESPOND, will enroll 10,000 African-American men with the disease, and analyze existing data from another group of 10,000 men.

RESPOND will be funded by the NIH through the NCI and the National Institute on Minority Health and Health Disparities, as well as by the Prostate Cancer Foundation.

“In the U.S., [African-American] men have about a 15% chance of developing prostate cancer, compared to a 10% chance in white men, and they’re more likely to be diagnosed with aggressive prostate cancer” and have twice the risk of dying from the disease, says Damali Martin, PhD, MPH, a program director at the NCI. “We want to learn more about why these disparities exist, and to learn more about the risk factors for these disparities, so we can start to address this issue.”

Tamara Lotan, MD, of Johns Hopkins University School of Medicine in Balti-more, MD, a RESPOND investigator, says it is the first prospective, large-scale study on prostate cancer in African-American men that will integrate biological data, including genomic data from germline and tumor sequencing, with lifestyle and social risk factors such as discrimination.

Martin thinks the genomic findings could eventually help researchers iden-tify men with aggressive forms of pros-tate cancer, thus informing screening and treatment. Additionally, informa-tion on lifestyle and social risk factors could be incorporated into interventions designed to help prevent the disease.

“What really excites me about this study is the multifactorial nature of

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