Tag: Claiborne

Daniel Claiborne, Ph.D., was recruited to The Wistar Institute through the Caspar Wistar Fellowship program, which fast-tracks promising early-career investigators to full faculty membership. Now an assistant professor in Wistar’s major research centers — the Vaccine & Immunotherapy Center as well as the Ellen and Ronald Caplan Cancer Center — his team focuses on understanding the immune system to develop new, more effective immunotherapies against cancer and other deadly diseases.

How do you explain your job to a non-scientist?

My lab works on immunotherapies, which are ways to enhance the immune system to do a better job fighting diseases, cancer, or any threat. We work on cell therapy and engineer immune cells to express proteins that redirect the cell and impart specific functions so that they can be injected into someone and attack whatever disease is marked by the surface proteins we’re targeting.

Every scientist has their own approach to a question; our approach uses the research area of immunotherapy as a springboard to understand the fundamentals of our immune system. All the incredible tools in this field give us a unique opportunity to get into the real nitty-gritty of what’s happening on the minute level of cell biology and how immune cells interact within our biological ecosystem.

I have this tongue-in-cheek sign that says, “DON’T DO EFFICACY STUDIES.” It’s a reminder to ensure our interventions are effective, generate novel understandings of how immunity works, and do not focus exclusively on clearing viruses and diseases as the endpoint for the experiment. Experiments directly testing efficacy can be important for gaining valuable insight too, but I want to take the science further as our primary focus.

We know how to run a test with a T cell that can kill a virus in a dish or clear the tumors in a model. Those results show that we’re moving in the right direction. We also know that moving an effective treatment from lab model to a person comes with many complications and differing results. The “why doesn’t this work?” question is what keeps my lab and I purpose-driven.

You want to know where the stumbling blocks are so you can build better, more predictive models?

I’d go further: I only want to use models where our cell therapies don’t work (initially). Years ago, I heard this at a conference, and it’s stayed with me: “models are lies that help you see the truth.”

No model system is perfect, they are contrived by their very nature because we designed them, but if we build models that are sufficiently advanced and most importantly stringent enough then we can say, “The treatment we’re testing has a relatively high probability of being potent in a human patient because this model system is so rigorous.” We’re getting better at accounting for what our model systems don’t do and being honest about the limitations, while prioritizing models that give us results that are more likely to be translational, rather than those that give us “good results” all the time.

What is it that you don’t know and what are you looking for?

We know more about how to get a T cell to express a given protein than we do about the ins and outs of how the T cells in your blood “know” when something is wrong, or when T cells decide to ignore those signals. We don’t even fully know why T cells stop working if they’re over-exposed to antigens, for example, though many in the field have contributed valuable insights into this process in the past several years. The intricate information exchanges between immune cells aren’t known to scientists so much as they are theorized, and that realm of the unknown naturally draws me in.

What’s your hope for your research?

I want our findings to become treatments and cures. But more importantly, I want our deep dives into the immune system to generalize to other areas of disease, cancer, and immune research. That is the key for sustaining progress: discoveries that empower even more discoveries.

My lab works on T cell therapy for HIV. It would be great if, in the near future, we discovered the right formulation of CAR T cell proteins to cure HIV once and for all — but that’s probably not going to be the sole solution to the very complex problem, but worthy endeavor, of an HIV cure. More likely, T cells will be part of the solution that, one day, produces an HIV cure. When we understand that, I believe we’ll understand T cells’ role in a wide variety of applications, too. Step one to that level of understanding is learning the cells inside and out.

Dr. Daniel Claiborne of The Wistar Institute was recently awarded two grants to support studying an approach to optimize CAR T cells, a type of engineered cell, for use against HIV. Claiborne, a Caspar Wistar Fellow in Wistar’s Vaccine & Immunotherapy Center, received a Target Grant for $120,000 from amfAR, The Foundation for AIDS Research, and was also awarded a $65,000 grant from The Campbell Foundation.

The grants will enable Dr. Claiborne to engineer a panel of CAR T cells targeting non-traditional portions of the HIV viral envelope, or outer protein, and test them in a mouse model.

CAR T cells, or chimeric antigen receptor T cells, are patient-derived T cells that have been engineered to target and destroy a specific antigen on the surface of a cancer cell. They are considered “super charged” immune cells that act like a living drug, latching onto a tumor cell to terminate it. CAR T cells have been developed as an immunotherapy for cancer, but Dr. Claiborne explores their potential against HIV.

“My research has focused specifically on identifying the hurdles in repurposing CAR T cells for HIV, and how we can overcome those hurdles to develop an effective treatment,” explained Claiborne. “These grants will enable us to continue working toward that goal, test the approach, and uncover how we can use CAR T cells to develop a successful HIV therapy.”

Dr. Claiborne joined Wistar as a Caspar Wistar Fellow in 2021 from the Ragon Institute of MGH, MIT and Harvard, where he focused his work on better understanding T cells and CAR T cells for the treatment of HIV.

Launched in 2019, The Caspar Wistar Fellows Program is designed to offer exceptional autonomy and resources to recent Ph.D. or M.D. graduates with outstanding research records, who are prepared to take an accelerated path toward independence as principal investigators and join the next generation of scientific leaders.
Caspar Wistar Fellows are appointed for a three-year term with the possibility of extending or being considered for promotion. The Program enables scientists to quickly outfit their lab by offering start-up funds to purchase materials, hire laboratory staff, and access the state-of-the-art shared resources at the Institute.

About amfAR

amfAR, The Foundation for AIDS Research, is one of the world’s leading nonprofit organizations dedicated to the support of AIDS research, HIV prevention, treatment education, and advocacy. Since 1985, amfAR has invested more than $635 million in its programs and has awarded more than 3,500 grants to research teams worldwide.

About The Campbell Foundation

The Campbell Foundation was established in 1995 by the late Richard Campbell Zahn as a private, independent, nonprofit foundation dedicated to supporting clinical, laboratory-based research into the prevention and treatment of HIV/AIDS. It focuses its funding on supporting alternative, nontraditional avenues of research. The Campbell Foundation has given away more than $12 million since its inception.

With just over a year at The Wistar Institute under their respective scientific belts, innovator-scientists Amelia Escolano, Ph.D., and Daniel Claiborne, Ph.D., have been pushing the scientific envelope in Wistar laboratories using mouse models to pursue basic research and potential therapies for one of the toughest problems in medicine: HIV.

In line with the priorities of Wistar’s Bold Science // Global Impact Strategic Plan to advance the scientific enterprise at the Institute, they are making their mark as the newest members of The Vaccine & Immunotherapy Center (VIC) at The Wistar Institute.

Escolano joined Wistar from Rockefeller University, where she was a postdoctoral fellow. With a background in inflammatory diseases, Escolano began her postdoctoral work focusing on vaccine design. There, she was one of the first researchers to use a mouse model called immunoglobulin knock-in mice for HIV vaccine research. Escolano’s expertise with this mouse model, along with her experience developing sequential immunization protocols, make her a valuable addition to the VIC team.

A knock-in mouse is a mouse that has a specific DNA fragment inserted into a particular position on the mouse’s genome. In the case of immunoglobulin knock-in mice, genes that make antibodies are inserted into the genome. Escolano and her lab then use the mice to test whether their immunogen designs — proteins that induce an immune response, like in vaccines — activate the mouse’s B cells to produce those antibodies that fight disease.

“These mice are used to see how we can activate those B cells and how we can make them evolve to become broadly neutralizing antibodies,” said Escolano.

“Making antibodies evolve” is Escolano’s area of research, specifically designing a sequential immunization protocol to induce neutralizing antibodies against HIV. Sequential immunization involves a first injection with one immunogen, then a subsequent injection with a slightly different immunogen, and so on. The purpose is to gradually introduce mutations on the antibodies which make them evolve to neutralize against HIV more effectively so that the result is a potent and broadly neutralizing antibody. This sophisticated form of antibody is necessary to combat HIV and other viruses that mutate quickly and form many different strains.

“Here at Wistar, I’m continuing my efforts to design these types of sequential immunization protocols and make them work in model systems and eventually in humans,” said Escolano. Ultimately, she and her lab hope to answer the question of why some vaccines induce protection for years, while others only offer protection for months. With this knowledge, scientists will be able to design vaccines that induce protection for a long time — potentially even a lifetime.

Claiborne came to the VIC as a Caspar Wistar Fellow. This fellowship is awarded to early-stage investigators with outstanding research records who, as Claiborne puts it, “have unique angles on things.” His distinct expertise is using humanized mouse models to research T-cell dysfunction, specifically in pursuit of therapies that could cure HIV. “At the same time Wistar was just starting a humanized mouse program, I came in with knowledge on how to use that model well,” Claiborne shares.

In the context of vaccinology and immunology research, a humanized mouse is a mouse that is engineered to have a human immune system. Claiborne is a proponent of this model because it can be more readily translated to clinical settings. “I’m a basic scientist, but it’s always important to think about how this is going to advance human health,” he said. “In humanized mice, you can use authentic strains of HIV, which facilitates the translatability of anything you’re doing that’s a therapeutic intervention.”

In his own research, Claiborne is using humanized mice to try to answer the question of how T cells, a type of white blood cell, become dysfunctional when they see their target over and over again, like in chronic HIV or cancer. “Functional exhaustion” turns off T cells and protects them from becoming overactivated — a state in which T cells could kill you. However, when it comes to certain therapies for HIV and cancer, such as CAR T-cell therapies, T cells that turn off ruin the efficacy of the treatment.

In CAR T-cell therapies, T cells are removed from a patient’s blood. Then, a specific receptor is added to the T cells that helps them find the target the patient’s body needs to fight. The T cells — now called “chimeric antigen receptor” or “CAR” T cells — are injected back into the patient. However, these cells are only effective as long as they continue to find and fight that target. Researchers found that when CAR T cells encounter the same antigen repeatedly and do not clear it, as with HIV, they self-regulate and turn off. Claiborne and his lab are investigating how this process begins.

“At the end of the day, we’re trying to figure out how T cells start to go down that path of functional exhaustion so we can stop that from happening,” said Claiborne. “That would have implications for all CAR T-cell therapies.”

On the eve of World AIDS Day, we chat with trailblazing scientist Dr. Luis Montaner, Herbert Kean, M.D., Family Professor, and leader of the HIV Research Program at Wistar. On Dec. 1, tune in to hear him in person as part of the NIH World AIDS Day 2021 Virtual Event.

Q: Tell me about the National Institute of Health’s (NIH) World AIDS Day virtual event. Is this the first time you’ve taken part?

A: Yes, it is, and it coincides with the release of the national HIV/AIDS strategy. We are discussing the research priorities moving into the future. I’m part of a panel to discuss recommendations, and community engagement.

Q: Have you taken stock of your most meaningful accomplishments over the last year? Have you reflected on the Wistar HIV Program you’re building, the type of researchers you’re recruiting, and what this means?

A: The last year has been transformational because we were able to successfully renew our Delaney grant with a larger coalition of investigators and a larger budget than the first award. Community engagement has also developed to a much greater extent than what we had before. We also were able to recruit additional investigators into the HIV program with Drs. Amelia Escolano and Dan Claiborne. Wistar efforts also developed the infrastructure for bringing humanized mouse models of disease into our HIV Program, identified novel predictors of HIV control, and completed recruitment of a human trial testing a novel strategy of immunotherapy against HIV in spite of COVID-19. Last year was critical to creating a great foundation for the impact Wistar will have on the search for an HIV cure in the coming years.

Q: What does World AIDS Day mean to you?

A: World AIDS day is really a reminder that we still have a lot of unfinished business to address. Although therapy has made living with HIV a chronic disease, there is still global disparity in access to therapy.

In addition, the need to generate a cure remains. On one hand, World AIDS Day is a reminder that we still have added efforts to move forward to provide answers as to how best to reach a cure, but at the same time, it’s sort of a time to reflect and recognize our progress in moving cure-directed efforts forward.

Q: Tell me about this year’s theme Ending the HIV Epidemic: Equitable Access, Everyone’s Voice. How do you ensure community representation in the recruitment of your clinical trials? How do you equally include minorities in clinical trial representation?

A: Community engagement across all NIH efforts is a priority and is reflected in the focus of the NIH virtual discussion happening on 12/1.

We at Wistar have recognized that it’s an important feature of our efforts from the beginning. Community outreach in Philadelphia has been effective in bringing voices from all people living with HIV into the Wistar research fold. It is reflected in the Jonathan Lax lectures we’ve held for over 25 years, the Legacy Awards earlier this year in which we acknowledged our partners, and the development of a cure research-directed Community Advisory Board (CAB), which now directly convenes around our research. Bringing together Philadelphia FIGHT with our Community Advisory Board, we now have created a Community Engagement Group that we call the CEG. The perspective from community groups is different than the perspective of individual persons living with HIV (members of the CAB). But together, each bring a lot more voices into the research effort.

Q: Tell me a few of the successes you’ve had in the course of your career thus far and why they are important?

A: I think the biggest success is the development of coalition of researchers singularly focused towards a cure. Bringing together and growing a group that nurtures new investigators and advances seasoned investigators towards a common goal, is a great story.

Q: In latest news, a second person has been cured naturally by their own immune system. What does it mean for the HIV cure research that you’re doing, and future?

A: I think this case gives us all hope as it shows that our immune systems can overcome an established infection. We still have the open question as to how it happened – but the fact it did means we can reach towards that goal for all.

Q: You work closely with community partners to continue advancing research towards an HIV cure. Is there any person or people who taught you what community outreach means and how to do it? What did you learn from them? How did they teach you? What do you think you taught them?

A: A lot of times we get so invested in the research effort that we have to stand back to see it from the community perspective, from individuals living with HIV, and all affected populations. Persons living with HIV come from all walks of life including those with disparities in access to health care, economic challenges, class challenges that may include a whole series of life experiences including domestic violence, or other types of unique circumstances that has shaped how HIV affected their lives. The recent creation of a CAB bringing community input into our cure-directed efforts has taught me the power of individual experience when deciding how best to communicate with and/or work with community partners to advance research towards a cure.

Mice differ from people in many ways. But over the last decade, scientists have succeeded in engineering mice that are more humanlike in their ability to be infected with HIV, making it possible to study the disease, and develop vaccines and therapies, in these small animals.

As Daniel Claiborne, Ph.D., a Caspar Wistar Fellow who started in August, gets his lab off the ground, these so-called humanized mice, which he worked to optimize during his postdoctoral research, will be central to his research goals. Dan will take advantage of two other technologies that have recently come of age: CAR T-cell therapy, which is used to treat certain blood cancers, and transcriptomics — or the large-scale study of gene expression, to tease apart how T cells function in these mice and, like in people, stop functioning during HIV infection. It was truly a trifecta — “none of these technologies existed, even in isolation, until fairly recently,” Dan said.

Perfect Timing

Dan clearly remembers the thrill of reading the email from The Wistar Institute inviting him for a job interview. “It felt good because I had a shot to talk about what I’m passionate about and to explain to people my vision,” Dan said. As soon as the interview was over, he had no doubt that Wistar was where he wanted to be.

In fact, the timing seemed perfect because, although the humanized mouse model has not been widely embraced, the Institute believes so strongly in its potential, as Dan does, that it is launching a research program around it. Since he has joined, Dan and his new colleagues have wasted no time discussing how they can collaborate together and capitalize on Dan’s deep experience working with the mice during his postdoc at the Ragon Institute of MGH, MIT and Harvard, and his understanding of which aspects of the immune system they recapitulate well and which they don’t. For example, Dan can help another lab take a small molecule they found has interesting properties in cells in a Petri dish and study it in these small animals.

Dan also looks forward to what he can learn and share with just the other new recruits, three assistant professors, who are also joining Wistar this fall. “You always have peers, but to have true peers that are just starting out is kind of amazing,” he said.

Mining the Data

Going into his interview, Dan already knew the Philadelphia area well. As a postdoc, he had been collaborating with James Riley at the University of Pennsylvania, combining his expertise with HIV-susceptible humanized mice and the Riley lab expertise making CAR T cells specifically designed to recognize and kill HIV-infected cells.

This collaboration will continue now that Dan is at Wistar. While the Riley lab is focused on developing CAR T cells as a potential cure for HIV, Dan sets himself apart by making use of these engineered T cells, which he calls an “untapped resource,” to tease apart how they become exhausted and lose their ability to fight off HIV, just like natural T cells do, during infection. Dan plans to use a host of molecular tools to try to prevent CAR T-cell exhaustion and then probe what the precise pathways and gene expression profiles are within these cells that allow them to retain anti-HIV activity. The experimental system is in place, Dan said, and now “we just need to mine it.” What they find could ultimately help his collaborators who are working toward a CAR T-cell HIV cure figure out ways to make the therapy more effective.

For Dan, collaborations are not just really fun but absolutely necessary. “I tend to take on more ambitious and risky projects that take a lot of labs working together. I think biomedical science has evolved into that, where the questions we are asking really involve a lot of expertise that rarely is contained in one lab.” He thinks Wistar is fertile ground for these relationships because the small private institution really embodies the spirit of partnership.

Inspired by Immunology

For Dan, being easily bored has served him well. It made the idea of science, and constantly learning something new, seem very appealing to him as he was growing up. As much as Dan always knew he wanted to be a scientist — and counts himself in the lucky minority for figuring it out early, he recharted his course as an undergraduate at Florida State University. He started off focusing on organic chemistry, but soon decided the lab work was far too dull. Then Dan took an immunology course about halfway through his degree and he was hooked. He promptly started a project in the professor’s lab and never looked back. “I was so fascinated with immunology because it was so clear that we didn’t know anything, but the things that we did know were awesome,” Dan recalled. For the first time, he was motivated to go for his Ph.D., which he got at Emory University, instead of getting a job after college.

While being easily bored turned Dan on to science, being stubborn made him stick with it. Through what he calls the “fourth year grad school slump” and the ups and downs of his postdoc, he refused to quit. “It’s just part of how I’m wired, I keep after it until I get somewhere,” Dan said. “I have been lucky that I have not suffered from a lack of conviction.”

Happy Homemaker

In addition to brainstorming about collaborations with his new colleagues, Dan’s first few weeks at Wistar have involved a lot of ordering lab supplies. Even though he oversaw a small team of scientists during his postdoc, it never really occurred to him that many of the reagents they used for experiments didn’t just come with the lab space. Nevertheless, he is enjoying the experience. “It is like Christmas, you get to go on a shopping spree.”

There is plenty for Dan to set up at in his new home, too. He and his wife moved to the Philadelphia area with their three-year-old son and their infant son, who was born about the same time that Dan started his own lab. He jokes that he will get back to his old hobbies such as lifting weights one day, once he gets a handle on some kind of work-life balance. “It is all good things, just smashed into a really small timescale,” Dan said.

Written by Carina Storrs, Ph.D.