Targeted immunotherapy hits cancer-driving cells, spares others
Phase 1 trial planned as experiments in cells, mice show promise
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CAR T-cell therapy works by genetically engineering a patient's immune cells.
An experimental form of immunotherapy could identify and eliminate cancer-driving blood cells harboring a specific mutation while sparing most healthy cells, making it a promising therapeutic strategy for myelofibrosis and related cancers, a study found.
The study, led by researchers at University College London (UCL) and the University of Oxford, involved blood cells collected from patients and a mouse model of leukemia, a type of blood cancer. While it is too early to determine whether the immunotherapy will be safe and effective in patients, the researchers said they plan to begin a Phase 1 clinical trial in the next one or two years.
“Our ambition is to turn this into a first-in-human trial and, ultimately, a treatment that can selectively eliminate the root of the disease,” Alex Rampotas, MD, PhD, a lecturer at UCL Cancer Institute and the study’s first author, said in a UCL press release. “If successful, it could offer patients a route beyond symptom control towards deeper, longer-lasting remissions, with the hope of restoring healthy blood production.”
The study, “CAR T cell therapy selectively depletes disease-driving mutant calreticulin cells in xenotransplants and human organoid models of myelofibrosis,” was published in Science Translational Medicine.
Genetic mutation leads to abnormal protein
Myelofibrosis develops when the bone marrow produces too many abnormal blood cells, leading to fibrosis (scarring) and making it difficult for the bone marrow to produce healthy blood cells. Myelofibrosis is caused most often by mutations in one of three genes: JAK2, CALR, or MPL.
About one-third of patients have mutations in the CALR gene, which provides instructions for producing calreticulin, a protein that helps other proteins fold correctly inside the endoplasmic reticulum, a structure within cells. The mutation results in an abnormal form of the protein called mutant calreticulin (mutCALR).
The mutCALR protein attaches to the thrombopoietin receptor, a protein on the surface of blood cells. Because the combination of these two proteins is found mainly on the surface of cancer-driving abnormal blood cells, scientists can see a clear way to target those cells while sparing healthy ones.
CAR T-cell therapy involves collecting a patient’s own T-cells and genetically engineering them to recognize specific targets, in this case, mutCALR. When these CAR T-cells encounter abnormal blood cells carrying mutCALR, they eliminate them. This is expected to reduce the growth of abnormal blood cells, easing myelofibrosis symptoms and possibly eliminating the disease’s root cause.
“What’s exciting about this approach is its precision: the CALR mutation creates an abnormal protein on the surface of these cells, giving us a clear target,” Rampotas said. “CAR [T-cell] therapy technology can exploit this vulnerability, turbo-boosting the immune system to eradicate those cells and allowing normal blood production to recover.”
In the lab, these engineered CAR T-cells selectively eliminated mutCALR-positive blood stem cells — cells that can continue to produce the cancer — while leaving healthy ones largely unaffected. This CAR T-cell therapy also improved survival in a mouse model of mutCALR-driven leukemia.
To better reflect what happens in patients, the researchers created an organoid, a three-dimensional miniature model, that mimicked the fibrotic bone marrow seen in myelofibrosis. They found that the CAR T-cells remained effective even in this difficult tumor microenvironment.
“Our model is designed to recreate the real conditions these cancers grow in, including the fibrosis and complex tissue structure that can make treatments fail in the lab-to-clinic gap,” said study co-leader Beth Psaila, PhD, a professor at the University of Oxford. “Seeing the CAR [T-cells] find and kill the cancer cells in fibrotic marrow organoids was a highly encouraging step.”
In samples from patients with advanced myelofibrosis, in which immature blood cells called blasts made up more than 10% of blood or bone marrow cells, CAR T-cells were initially less effective because cancer cells had lower levels of the target protein. The researchers found that eltrombopag, a drug already used to treat certain blood and platelet disorders, increased the expression of the target protein on cancer cells, making them easier for CAR T-cells to recognize and kill.
“Just as importantly, the model lets us test not only whether a therapy works, but how it works, cell by cell, in human tissue,” Psaila said. “We hope this platform will speed up the development of safer, more effective immunotherapies for myelofibrosis and other blood cancers.”
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