Fred Hutch researchers optimize a radioimmunotherapy drug, examine how regulatory T cells influence immune memory

“The thought was that, if we can direct the same or more radiation to the sites where the leukemia cells are and away from healthy tissues, then maybe we can tweak the therapeutic window and get more benefit (with regard to tumor control) with less organ toxicity and less non-relapse mortality,” Walter said.

Early tests of an antibody directed against CD45, a molecule on most white blood cells (including, in most cases, blood cancer cells), attached to a beta emitter, iodine-131, demonstrated that RIT held promise as a component of transplant preconditioning. Researchers at Fred Hutch and elsewhere are now testing antibodies attached to a different class of isotopes called alpha emitters, which release more radiation over shorter distances.

In the recent first-in-human Phase 1 trial, Walter’s Fred Hutch colleagues Brenda Sandmaier, MD, and Rainer Storb, MD, tested the anti-CD45 antibody attached to the alpha-emitter astatine-211, an isotope of the element astatine. While promising, the antibody, which Fred Hutch scientists had generated decades ago in a mouse, needs a refresh. 

“The goal of the new grant is to develop a second-generation immunotherapeutic that will build on this and optimize what one can accomplish with this therapeutic strategy,” Walter said.

Antibodies are Y-shaped molecules that use the tips of the Y’s outstretched arms to grab onto their targets. Walter and his team will optimize the anti-CD45 antibody by tackling it in three parts: By making the tips of the Y’s arms more selective, by swapping in a safer, more effective “trunk,” and by improving the process by which astatine is attached to the trunk.

They’ve already started the trunk improvement process by swapping a trunk (also known as a heavy chain) from a human antibody for the original mouse heavy chain. (Antibodies from other animals can trigger reactions in people, so “humanizing” antibodies makes them safer.) Preclinical tests of the humanized version of the original antibody are promising.

There are several varieties of human heavy chains, and Walter and his collaborators are also comparing these to find the most effective version to graft onto the arms of the Y.

And to improve those arms, which determine how well an antibody recognizes its target, Walter’s team has generated several new, fully human antibodies against CD45. To identify the most efficacious antibody clone, the researchers are using preclinical models of leukemia to compare these to the humanized original version. The team is also working to refine the process of attaching astatine-211 to the antibody to create the safest and most effective therapeutic.

But they don’t expect the updated antibody to stand alone.

“Even the most optimized therapeutic will not cure all relapses,” Walter said. “Our final aim is more forward thinking.”

He and his team are seeking cellular pathways that, when blocked, amplify the effect of radiation against blood cancer cells. These could become targets for rationally designed therapies that could synergize with the astatine-conjugated anti-CD45 antibody.

These improvements could open up more opportunities for this antibody and RIT in general, Walter said.

“Pre-transplant conditioning is still the primary focus of the RIT field, but it could potentially expand to other uses,” he said. This might one day include other treatments in which blood cells need to be depleted, such as CAR T-cell therapy or gene therapy for blood disorders, or as a stand-alone treatment for blood cancers. 

Understanding how regulatory T cells influence immune memory

Lund is the associate program head of the Vaccine and Infectious Disease Divion’s Immunology and Vaccine Development Program. She studies a type of immune cell called a regulatory T cell. T cells are specialized white blood cells that fend off disease, including fighting infection or defending against cancer. Regulatory T cells, or T-regs, are a type of T cell that serve as immune referees. Immune responses that are too robust can cause collateral damage to healthy tissues, and T-regs tamp them down to minimize damage.

Lund discovered that T-regs can also act a bit like immune coaches. While studying the early phases of herpes simplex virus-2 (HSV-2) infection in mucosal tissues, she found that T-regs are critical to generating a robust-enough response as well.

Much of the research on T-regs focuses on “primary” infections, or the first time the body sees a pathogen. But many microbes trigger immune memory. Memory immune cells aren’t raw recruits; they’re seasoned veterans primed to quickly detect and respond to the pathogen the next time we encounter it. While some memory cells circulate through our blood, others patrol tissues like mucosal membranes.

“Tissue-resident memory T cells are really fantastic at rapidly responding to infections, partly because they're in the tissue site of infection,” Lund said. “If you're trying to prevent a bank robbery, you're not going to have guards circulating throughout the building — you're going to have them at the door.”

Depending on what type of T cell they are, memory T cells can eliminate infected cells or coordinate antibody responses. They can use molecules called chemokines to call other immune cells to the site of infection.

“This is great in terms of trying to prevent pathogen invasion, but we hypothesize that this would need to be kept in check,” Lund said.

In the new grant, Lund will investigate the hypothesis that T-regs work to restrict the memory response within tissues to limit tissue damage and maintain immune balance after the viral threat has abated. She’ll use a mix of mouse models of chronic HSV-2 infection and human tissue samples to verify the biological mechanisms she uncovers in the preclinical models.

“We are going to be looking at the fate of T-regs after infection,” Lund said.

She and her team will explore whether T-regs themselves — particularly those residing in tissues — can acquire memory the way other T cell types do. They’ll examine whether there are differences, such as patterns of gene expression or alterations in how DNA is packaged, which suggest the T-regs have acquired immune memory. And they’ll compare T-regs in tissues like the mucosa to those from lymphoid organs like lymph nodes.

HSV-2 is a great model in which to study tissue-specific immunity and immune memory. Like other herpesviruses, HSV-2 sets up a long-term infection of neurons. The virus is mostly dormant — but not always.

“It’s not a constant infection — it reactivates,” Lund said. “At least in humans, we think there are quite a few of these tissue memory recall responses happening monthly.”

And because about two-thirds of adults worldwide have either HSV-1 or HSV-2, Lund’s discoveries will have plenty of relevance to human health. Though she focuses on foundational immune biology, what Lund discovers could help us move toward vaccines for HSV or point toward possible ways to prevent long-term health effects from other viral infections.

“Thinking ahead, it’s good to know how the memory response is kept in check for infections that happen frequently, like COVID or rhinovirus infections,” Lund said. “Lots of T cells are getting awakened, and we’re coming to appreciate that there are a lot of long-term sequelae of viral infections.”