image: A lab coat hangs in an MSK research lab.
Credit: Memorial Sloan Kettering Cancer Center
New research from Memorial Sloan Kettering Cancer Center (MSK) finds a potential therapeutic opportunity in regulatory T cells’ resilience to the loss of Foxp3; shows how cancer develops resistance to antibody-drug conjugates; develops a new system to help make gene editing safer and more reliable; and shows provider billing margin doesn’t drive cancer treatment selection.
Resilience of mature Tregs in the face of Foxp3 loss suggests therapeutic opportunity
Regulatory T cells (Tregs) serve as the immune system’s “brakes,” keeping damaging inflammation in check. And the transcription factor Foxp3 has been shown to be essential for establishing this role.
Now, using a novel mouse model that allows for the selective degradation of the Foxp3 protein, MSK researchers showed that Foxp3 is more context-dependent than previously understood. It’s critical for newborn mice — without it, they develop severe autoimmune disease. But in healthy adult mice, degrading Foxp3 in mature Tregs led to only minor changes. Further experiments showed this resilience in mature cells takes several weeks to develop.
In other words, context matters — and this could be especially helpful in the context of cancer, the researchers note.
Under stress, such as rapid cell division or severe inflammation, loss of Foxp3 has more profound effects. When the scientists degraded Foxp3 in adult mice with cancer, their tumors stopped growing and shrank. That’s because dampening Foxp3 impaired the function of Tregs inside tumors, releasing the brakes and allowing immune cells to better attack the cancer — while largely preserving Treg function outside of the tumor, therefore, avoiding severe adverse effects.
“This opens a potential path towards novel cancer immunotherapies employing Foxp3 degraders to inactivate highly activated regulatory T cells, which support tumor progression, while avoiding debilitating autoimmunity,” says senior study author Alexander Rudensky, PhD, who chairs the Immunology Program at MSK’s Sloan Kettering Institute.
The study was led by first author Wei Hu, PhD, a research fellow in the Rudensky Lab. She is now an assistant professor of immunobiology at Yale University.
Read more in Nature Immunology.
Learning how cancer develops resistance to antibody-drug conjugates (ADCs)
Antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd, also known as Enhertu®) have transformed cancer treatment in recent years, with 15 of these drugs now approved by the U.S. Food and Drug Administration (FDA). ADCs are thought to work by attaching to specific targets on cancer cells and releasing highly potent chemotherapies inside tumors. For example, T-DXd targets HER2, a protein found on the surface of many cancer cells. While ADCs can be significantly more effective than older treatments, many cancers still evolve to grow and survive despite these therapies. Furthermore, due to side effects similar to those from chemotherapy, many doctors and scientists have debated just how “targeted” ADCs really are.
In a new study led by MSK physician-scientists Sarat Chandarlapaty, MD, PhD, and Joshua Drago, MD, MS, researchers studied samples from more than 100 patients whose cancer stopped responding to T-DXd to find out what changed in their tumors. They found that in about half of patients’ tumors, HER2 levels went down, with HER2 disappearing completely in about half of those cases. In other patients, certain gene mutations changed the shape of the HER2 protein so that T-DXd could no longer bind to it.
To overcome this treatment resistance, the researchers tried combining T-DXd with dato-DXd, another ADC that hits a different cancer target, called TROP2. In cell and mouse models, this combination approach was more effective than either treatment alone, even when both treatments were given at very low doses. This approach could circumvent resistance due to target loss and reduce the side effects of ADCs, the researchers say, but the findings need to be confirmed in a clinical trial before they are adopted in practice.
This study is also significant because it helped confirm that T-DXd is, in fact, binding to HER2 on cancer cells. Because there are several other approved cancer therapies that also target HER2, the findings have implications for determining which treatments might be more effective when used after T-DXd.
Read more in Cancer Discovery.
New system could help make gene editing safer and more reliable
Researchers from MSK have developed a new system to help make gene editing — including the use of tools like CRISPR-Cas9 — safer and more reliable.
The system aims to detect a common problem called loss of heterozygosity (LOH), which occurs when a cell loses important information during the DNA editing process. LOH is a surprisingly common consequence of DNA double-strand breaks, the cuts made in both strands of DNA that are required for gene editing.
The system, which the team named Flo-LOH, employs a lab tool called flow cytometry to find and count cells with LOH. Flo-LOH was used to study mouse embryonic stem cells and human cell lines that had undergone gene editing. The researchers found that about 5% of cells experience LOH from a double-strand break. They also made several important discoveries about LOH, including revealing how extensive this damage can be, and pinpointing particular proteins and mechanisms that affect the degree to which LOH occurs. Importantly, they also discovered that when DNA repair pathways are inhibited, with the theoretical goal of making gene editing more efficient, it can backfire and lead to harmful genetic changes.
Interestingly, the group found that base editing, a newer CRISPR-based technique that does not require a DNA double-strand break, does not cause detectable LOH.
Cells with LOH grow more slowly than healthy cells, but they can still survive and multiply and eventually affect embryo growth or lead to cancer.
“We believe that by using Flo-LOH to study cells that have undergone the gene-editing process, it will help us to develop techniques that make this process safer and less likely to introduce errors,” says Sloan Kettering Institute developmental biologist Maria Jasin, PhD, who oversaw the research, which was led by graduate student Samantha Regan.
Read more in Molecular Cell.
Provider billing margin doesn’t drive cancer treatment selection
Does a fee-for-service model, such as the one we have in the United States, influence cancer doctors to prescribe drugs that are more profitable over drugs that work best? That was the question a team of researchers at MSK and their colleagues set out to answer.
The researchers, led by medical oncologist Aaron Mitchell, MD, MPH, found they did not. In a study of nearly 20,000 Medicare patients across 12 different types of cancer, they found clinical benefit rather than billing margin drove decision-making.
“The extent to which clinicians respond to billing incentives has direct relevance to healthcare policy,” Dr. Mitchell says. “It means, for example, that high drug fees do not appear to be necessary for the adoption of new, effective treatments.”
Further research is warranted to assess differences among different types of providers, such as comparing those working in private physician offices, where compensation is more directly tied to billed services, with those working in hospitals.
Read more in the BMJ.