Back to the Bench

Three-and-half years ago, immunologist Larry Corey left his laboratory at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, Washington, and his post as director of the HIV Vaccine Trials Network (HVTN), to become the president and director of the FHCRC.

But as of June 1, Corey decided that at age 67 he was ready to trade the board room for the bench and return full-time to research focusing on cancer immunology, HIV vaccines, and herpes simplex virus.

During his tenure as director of the FHCRC, which many refer to simply as “the Hutch,” Corey raised over US$100 million and bolstered the research profile of the institution, particularly in the areas of genomics and immunotherapy. In April, the FHCRC secured its largest gift ever—a $20 million donation from the family of Amazon founder and billionaire Jeff Bezos to develop novel cancer therapies, following recent advances in the use of genetically modified human T-cell therapies to fight leukemia and lymphoma. Under Corey’s leadership, the FHCRC also collaborated with Memorial Sloan-Kettering Cancer Center in New York City to establish Juno Therapeutics Inc., a biotechnology company focused on bringing forward novel immunotherapies for cancer.

Corey’s roots in Seattle and his history at the Hutch go back much further. He trained in infectious diseases at the University of Washington School of Medicine and joined the faculty there in 1978. He moved his laboratory to the FHCRC in 1997, and since then has been involved in, and in some instances headed, groundbreaking studies that led to the development of more effective antiviral therapies for hepatitis B virus, HIV, and herpes. At the direction of Anthony Fauci, the longtime director of the US National Institute of Allergy and Infectious Diseases, Corey also helped establish the HVTN in 1998. He remains a principal investigator there.

Corey was also a major driver in the creation of the Global HIV Vaccine Enterprise in 2004 and founder of the FHCRC-based Washington Vaccine Alliance (WAVA), a virtual biotechnology coalition of nonprofit research institutions dedicated to developing novel vaccines for the prevention of human diseases ranging from typhoid to syphilis.

“The Hutch’s loss of Larry as president and director is a major gain for the field of HIV vaccine research,” said Fauci, reacting to Corey’s decision, which was announced in early May. “Dr. Corey is an extraordinary thought leader and practicing physician-scientist in this area and we welcome him back on a full-time basis to this critical area of biomedical research and global health.”

IAVI Report caught up with Corey right after he attended the annual HVTN meeting, held June 3-5 in Washington, DC. We asked him about the meeting, his return to research, his take on the current state of AIDS vaccine and cure research, including the follow-up trials to RV144—the only HIV vaccine trial to demonstrate protection against HIV—and what he considers to be his most significant accomplishments as director of the Hutch.

How did your colleagues react to your decision to return to research full time?

They gave me some smiles. And they didn’t say, ‘Gee, we don’t want him back’ (laughs). It was very gratifying to be able to have people say we have missed you and it’s nice that you are spending more time on this and you can make a difference here. Whether they were pandering or not, I don’t know.

What was it that you missed most about research?

I spent considerable energy looking at what I wanted to do for the next five to six years. I had done a lot at the Hutch but there’s a freedom with research and it came down to where I wanted to focus my energy and where can I make the most difference.

You have different research interests—HIV/AIDS, herpes, and cancer. What will be occupying most of your time now?

It’s going to be a little bit of all three, to be honest. My lab discovered a new T cell that I think has given us some insights about how to rationally design a genital herpes vaccine. That is really exciting. With regard to the HVTN, I can see myself being able to devote more time to this now. I can think more, I can create partnerships or relationships that have some scientific insights, and develop leadership skills that will help move this thing forward. And now that we have the reagents to explore how to define correlates of protection or drive the immune response to a more diverse set of neutralizing antibodies, that kind of leadership skill becomes useful. And there is no question I will be involved with cancer as I am a scientific advisor to Juno, the immunotherapy company we founded at the Hutch. I am an immunologist by training, so helping Juno is also very gratifying.

What do you consider your biggest accomplishments as head of the FHCRC?

We totally improved the translational program, brought in new leadership in the public health sciences division, and built better relationships with the University of Washington and Children’s Hospital. I raised more funds than any other Hutch president—there’s the $20 million Bezos gift and another large gift that I am responsible for that will be announced fairly soon.

Importantly, we energized the faculty to think bigger and more collaboratively. The institution became less insular and more involved with our lay and scientific communities. We started an institute of health economics of cancer. We totally transformed the immunotherapy program and made that the signature program. We also raised the money to start Juno and spun it out of the Hutch in collaboration with Memorial Sloan Kettering Cancer Center. We raised $175 million for Juno and it is all going into cancer immunotherapy to fund the science and trials. I look at all the goals I set out to do in five years, and I did them in three and a half.

I read recently that you coined the phrase “Miracles start in the lab.” What was the genesis of this?

That phrase, to be honest, took a while to evolve. Part of the job of being an administrator is that you are brought to dinners with potential donors and you become the evening’s entertainment. You explain the science, what the Hutch is, what cancer is, and occasionally about HIV. It is a talent of mine that I can explain science to lay people. So referring to major discoveries, I think I said that making major cancer discoveries begins in the lab—that the lab is where cures start and where cures are developed. Later on, I was at a talk and Stuart Sloan, who is a donor and friend, turned it around and was talking to someone and said, ‘Yeah miracles start in the lab.’ That clicked and we started using it. Of course, when we started treating our first patients with immunotherapy, or when you see these cancer drugs that are cancer-specific and all of a sudden a person responds and their tumors melt away, it is a miracle. It’s very cool.

What was the big news at the HVTN meeting this year?

I think the story is that the vaccine field, from a development point of view, is sort of emerging from what was a four or five year funk. There is now renewed optimism that we have some novel approaches and there is acknowledgment and maybe some new efforts on how to solve some of the structural problems in bringing a vaccine to fruition.

We are finally moving forward both with the post-RV144 program as well as the design of new immunogens for neutralizing antibodies. We are really starting to look at potentially more innovative approaches to vaccine development like vectored immune prophylaxis using adeno-associated virus vectors that express broadly neutralizing antibodies like PG9. There is finally a sense of looking forward rather than bemoaning the present.

What’s happening now with the RV144 follow-up studies?

Well we are finally getting the timeline set. In January 2015, we will start the HVTN100 trial in South Africa [a Phase I trial of a canary pox prime (ALVAX), followed by a protein boost, with an MF59 adjuvant], which is a big one. We’ll also be starting the DNA protein program in February 2015 in South Africa [a DNA clade C vaccine with Novartis’ bivalent gp120 boost].

I think the hypothesis behind the post-RV144 work continues to be valid, and if anything continues to be strengthened. The data from the HVTN 505 trial show that the vaccine regimen [consisting of a DNA prime and an adenovirus serotype 5 vector that did not work] did not produce the same kind of antibody responses that were seen in RV144 vaccine recipients, and all the major correlates of protection issues associated with RV144 still hold up after HVTN505. The scientific underpinnings of RV144 actually are getting stronger over time. We have a hypothesis behind the post RV144 program that is stronger now than it was a year and a half ago. That’s all good.

There have been significant developments on both the AIDS vaccine and HIV cure fronts. From your vantage point, what looks more promising right now?

I’ll take vaccines. There are some things going on with cure, but to me, the best ideas for cure are the transplantations—making everybody CCR5-resistant through cord blood. But that technology is sort of a one-person-at-a-time approach.

I don’t see the drug technology or the small molecule technology leading to a cure. The things I see leading to a cure are cellular and gene therapies, and that is going to take a while. At Juno we are investigating the link between cellular and gene therapy in the cancer therapy realm. I think that is what is going to be required for a cure at the moment, but we are going to have to perfect it in cancer first.

Are you more optimistic that researchers will be able to design a vaccine candidate that induces broadly neutralizing antibodies against HIV?

I am more optimistic. But first we’ll need to show what the targets of neutralization are. I come from a field in which we developed a vaccine that induced neutralizing antibodies against herpes, yet it still failed. So what we measure in a standard neutralizing assay may not be the mechanistic basis of protection. Now, I’m hoping the nature of the antibodies against HIV are going to be better, but I think we are going to have to pursue vectored immune prophylaxis studies to tell us just how good the neutralization needs to be.

I think blocking HIV acquisition is an antibody-based phenomenon, or an interaction between T helper cells and antibodies. I think this is what is leading to the protection against acquisition seen in RV144. So, yes, I am optimistic, but it would be nice to also have a little luck.