New project: CAR T cells for HIV cure?

Dr. Larry Corey wins $2.6M grant to investigate immunotherapy's potential to bring about long-term HIV remission
Dr. Larry Corey
Dr. Larry Corey Photo by Robert Hood / Fred Hutch News Service

Fred Hutch virologist and leading HIV researcher Dr. Larry Corey has received a $2.6 million grant from Gilead Sciences Inc. to investigate using CAR T cells — a type of immunotherapy — to bring about a cure or long-term remission for HIV.

“HIV creates such a persistent immune deficiency that one needs to improve the human immune response to develop an approach in which one’s own immune system can control the virus from replicating,” Corey said. “We think that we can bring the technology of genetically altering T cells, as is being used with cancer immunotherapy, to HIV.”

The grant will complement the CAR T-cell research that Corey is leading as part of the federally funded defeatHIV, a public-private research group based at Fred Hutch. The group in July received its second round of funding from the U.S. National Institutes of Health, allowing it to expand into exploring CAR T and other immunotherapies against HIV.

Fred Hutch already is known for its research into using CAR T cells to target cancer. Patients’ own T cells — a type of white blood cell that searches out and destroys pathogens — are genetically re-engineered with synthetic receptors called chimeric antigen receptors, or CARs, to kill cancer cells bearing a particular marker. There are now dozens of clinical trials underway at Fred Hutch and elsewhere of CAR T cells for treating leukemia and lymphoma, with promising early results.

The Gilead funding will enhance preclinical work to help determine whether current T-cell technologies can overcome the “significant challenges” that HIV poses, Corey said.

Working with him on the project, which is funded over three years, will be immunology and infectious disease experts Drs. David Rawlings and Thor Wagner of the University of Washington and Seattle Children’s; immunologist Dr. Louis Picker and his research group at Oregon Health & Science University; and Seattle-based biotech company Juno Therapeutics.

Corey is founder and head of the Hutch-based, global HIV Vaccine Trials Network and former president and director of Fred Hutch. Early in his career, his work on the first antiviral treatment for herpes paved the way for HIV therapies that in 1996 turned the virus from a certain death sentence to a chronic disease. But while antiretroviral drugs lower the level of HIV to undetectable levels, they are not a cure. The virus persists in a dormant state in “reservoirs” throughout the body. If therapy is stopped, HIV roars back.

The Gilead grant to Corey’s team was among a dozen totaling more than $22 million awarded by the pharmaceutical giant to HIV-cure researchers and nonprofit community groups.

— By Mary Engel / Fred Hutch News Service

Dr. Paul Nghiem
Dr. Paul Nghiem speaks during the Immunotherapy Symposium and Bezos Family Immunotherapy Clinic opening at Fred Hutch on Dec. 12, 2016. Photo by Robert Hood / Fred Hutch News Service

Immune responses against virus-related cancer may provide clues for improved immunotherapy

Researchers at Fred Hutchinson Cancer Research Center and the University of Washington say a new study suggests ways to improve immune therapy for certain cancers, including a virus-associated form of Merkel cell carcinoma, a rare, aggressive skin cancer.

Merkel cell carcinoma, or MCC, is 35 times less common than melanoma but, on average, it is about three times more likely to be deadly. Currently there are no therapies approved by the U.S. Food and Drug Administration for this cancer. About 80 percent of the 2,000 new cases diagnosed in the U.S. each year are caused in part by a virus — Merkel cell polyomavirus — which is often present on normal skin without consequence.

Previous studies have linked a weaker immune system with poorer survival in patients with the disease. In this study, researchers at UW and Fred Hutch conducted an unprecedented, in-depth analysis of the immune system’s “killer” (CD8) T cells that respond to a specific part of the Merkel cell polyomavirus.

The immune system’s effectiveness is determined by many factors, including how well T cells can infiltrate a tumor and bind to the “foreign” proteins, or antigens. More specifically, T cells seek out and attach to antigens using their highly diverse T-cell receptors. In this multicenter study, the researchers focused on T cells that target a piece of the virus referred to as “KLL.”

“We found that a surprisingly low number of patients — only about 20 percent — had T cells specific for the ‘KLL’ region of the virus. This suggests that about 80 percent of patients aren’t making T cells that recognize this very prominent target,” said Dr. Paul Nghiem, an affiliate investigator of the Clinical Research Division at Fred Hutch, and professor of medicine in the Division of Dermatology at the University of Washington School of Medicine.

A striking improvement in patient survival

Nghiem, senior and corresponding author of an article published online Jan. 16 in Cancer Immunology Research, said the study is important because an increase in the KLL-specific T cells infiltrating the tumor is associated with a striking improvement in patient survival.

First author Natalie Miller, an M.D./Ph.D. student in Nghiem’s research lab, performed an in-depth analysis on blood and tumors from 12 patients who had T cells that could recognize KLL.

“T cells that recognize this part of the virus are incredibly diverse. In fact, among these 12 patients, there were 397 unique ways for the T cells to recognize this single short piece of the virus; only one T-cell receptor was shared between two patients,” Miller said. “In addition, T cells from patients with better outcomes tended to stick to the viral target more tightly. This suggests that while nature has created many ways for the immune system to fight this cancer, some ways are better than others. Our hope is that these ‘better’ T-cell receptors can be turned into a therapy for patients who do not have them.”

At diagnosis, virus-associated MCC is typically treated with surgery and radiation, and although 95 percent of patients appear to be cancer-free, the disease returns in about half of cases, Nghiem said. The cancer often responds to chemotherapy, but the response is short-lived, with most tumors progressing about three months after treatment begins.

Last April, Nghiem’s group published findings of a phase 2 clinical trial of the immunotherapy drug pembrolizumab, reporting that the “checkpoint inhibitor” helped to revive “exhausted” T cells, providing significant and lasting responses in more than half of patients.

New findings may lead to clinical trial

With their new findings, the research team expects to propose the launch of a clinical trial in which T cells engineered with the most effective tumor tracking and attacking receptors would be transferred to patients who are unable to mount an effective immune response of their own.

“Like Merkel cell carcinoma, cancers that have a viral component provide a variety of potential targets for immunotherapy. We’re eager to find out if transgenic T-cell therapy can ‘reprogram’ lymphocytes to eliminate tumors in combination with checkpoint inhibition,” Nghiem said.

The study was supported by grants from the National Institutes of Health and other sources, including the Adaptive Biotechnologies Young Investigator Award, Kelsey Dickson Team Science Courage Research Team Award, Prostate Cancer Foundation Award, ARCS Fellowship, the David & Rosalind Bloom Endowment for MCC Research, the Michael Piepkorn Endowment Fund, the UW MCC Patient Gift Fund and the Deutsche Forschungsgemeinschaft (SFB TR36).

— Sandy Van / Fred Hutch News Service

Dr. Jonathan Golob
Dr. Jonathan Golob Photo by Bo Jungmayer / Fred Hutch News Service

Hutch/UW symposium underscores Seattle’s reputation as ‘infectious disease central’

A day-long symposium sponsored by Fred Hutch’s Infectious Disease Sciences Program and the University of Washington’s Virology Division drew about 130 physicians, scientists, postdoctoral fellows, and graduate students to the Pan Pacific Hotel on Tuesday to hear the latest on the Zika virus, the role of the microbiome in bone marrow transplant outcomes and other ongoing research. The breadth of topics presented underscored Seattle’s reputation as “infectious disease central.”

That reputation is why Dr. Michael Gale Jr. moved his lab of 15 researchers a decade ago from Texas to UW, where he is a professor of immunology, microbiology, and global health. The symposium’s opening keynote speaker, Gale started out studying the West Nile virus, then changed his focus after another mosquito-borne virus — Zika — suddenly appeared in the Americas in 2015.

Zika and West Nile: related but very different in how they are transmitted

Although from the same family, Zika virus operates in a very different way. With West Nile, Gale said, people don’t have enough virus in their blood for mosquitoes to pick it up and spread it to another human. Instead, mosquitoes pick the virus up from birds, which have higher viral loads. But Zika can be transmitted from person to person by mosquitoes. Additionally, it persists in sperm and other fluids, including vaginal mucosal tissues, and it can be sexually transmitted.

Gale and his colleagues were the first to show direct evidence, using animal models, that Zika virus can cross the placenta in pregnancy and cause brain damage; the paper was published online in Nature Medicine in September 2016. The link had been suspected after Zika suddenly turned up in Brazil, and thousands of children were born with abnormally small heads and brains after their mothers were infected.

In a later talk, Dr. Keith Jerome, head of UW Virology as well as a member of the Hutch’s Vaccine and Infectious Disease Division, noted other UW contributions to the Zika effort, including substantial work on so-called “next-generation” sequencing of the Zika genome. His lab is working on a diagnostic test to better distinguish the Zika virus from another cousin in the Flavivirus family, dengue.

“The Zika epidemic illustrates the value of academic laboratories in rapid response to emerging infections,” Jerome said. “Challenges like Zika will continue to arise and will require the best effort from all of us. We need to be at the top of our game.”

Looking at the bugs within us

If Zika poses a threat from outside, Dr. Jonathan Golob, a past Joel Meyer Endowment scholar at Fred Hutch and the inaugural fellow of the Infectious Disease Sciences Program’s new training grant, is looking at the bugs within us — our gut microbiome. Studying weekly stool swabs from blood stem cell transplant patients from before transplant to 100 days after, he’s finding that antibiotics can lead to or worsen graft-vs.-host disease — a serious and sometimes fatal transplant complication — by killing off “good” bacteria that may have had a protective effect.

Golob is now looking at ways to determine whether these effects may be exacerbated by overlapping antibiotic exposures or antibiotic duration as a means of limiting the disruption in a patient population that depends on antibiotics for protection while their new immune systems take root.

UW’s Dr. Jane Kuypers, an affiliate researcher with Fred Hutch, talked about something that affects all of us: the common cold. Adults average two to three colds a year, and children, five to six. And with more than 160 gentotypes of rhinoviruses — one of the common culprits behind the common cold — we are not likely to run out of colds to catch.

A nuisance for most, rhinoviruses can be deadly to people with asthma or other lung disorders and to people with weak or undeveloped immune systems, including the young.

More than 50 percent of patients will develop at least one respiratory virus during the first 100 days after a blood stem cell transplant, added Fred Hutch’s Dr. Steve Pergam, director of infection control at Seattle Cancer Care Alliance, in a talk on preventing infections and containing outbreaks.

“Every time I give a talk like this, someone in the audience will cough or sneeze,” he said. “For our patients, this is terrifying to hear.”

Infectious Disease Sciences head and symposium co-host Dr. Michael Boeckh didn’t let an opportunity for research pass by.

“If you or anyone you know are sick and want to give us a few swabs, let us know,” he said.

— Mary Engel / Fred Hutch News Service

Dr. Matthew Trunnell
Dr. Matthew Trunnell Photo by Robert Hood / Fred Hutch News Service

Big ideas on big data

At the SLU Collaborative seminar Jan. 11, speakers from Fred Hutch, the Allen Institute for Brain Science, and University of Washington discussed how big data brings opportunities for collaboration, potential for new insights —and challenges. 

“We have entered the age of data,” Fred Hutch’s Chief Information Officer Matthew Trunnell said during a previous summit panel session on new technologies and the new economy. “We have gone from an era of being limited by how quickly we can hire qualified laboratory technicians to push research forward to an era where we are really limited by how we can bring in data-analytical capabilities.”

Trunnell joined UW computer scientist Dr. Su-In Lee and Dr. Michael Hawrylycz, who directs data analysis and annotation efforts at the Allen Institute, to share their perspectives and engage with the audience about big data’s future in South Lake Union.

“SLU is rapidly becoming a hub for big data analytics with applications in health care, basic research, and commerce,” wrote Hawrylycz in an email prior to the event. “The Allen Institute for Brain Science believes strongly in application of data analytics and modeling as an important part of the scientific process.”

While this wealth of new information brings wonderful potential, it also brings challenges that must be addressed before researchers can realize its potential.

“People tend to see only the bright side of big data,” Lee wrote in an email prior to the seminar. She develops artificial intelligence and machine learning techniques to pull relevant information from enormous, varied datasets so that researchers can make new biological insights that can be translated into improved, more personalized therapies. In other words, she works to “make big data smaller.”

“I want to focus on what we need to be careful about. Big data increases the number of biological hypotheses made from data and the opportunity to discover complex biological mechanisms. However, it also increases the overall number of hypotheses and the chance of making false positive discoveries,” Lee wrote.

The seminar was the second SLU Collaborative event and first of several planned for 2017. The quarterly seminars are designed to strengthen connections among research and tech partners in the SLU neighborhood by fostering networking and idea sharing. 

— Sabrina Richards, Fred Hutch News Service

Read more about Fred Hutch achievements and accolades.

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