A new type of immune cell therapy has wiped out cancer in mice without damaging the rest of the immune system, a long-standing problem with today’s CAR-T treatments, and may also open the door to safer therapies for autoimmune diseases such as lupus.
The research, published in Science Translational Medicine, describes a next-generation CAR-T therapy that precisely targets cancerous and disease-causing immune cells while sparing healthy ones. The approach could overcome two major drawbacks of existing CAR-T treatments: long-term immune suppression and cancer relapse.
CAR-T therapy works by re-engineering a patient’s own T cells, key fighters of the immune system, to recognise and destroy cancer cells. At present, all US Food and Drug Administration–approved CAR-T therapies for B-cell cancers target a molecule called CD19. However, CD19 is found on almost all B cells, including those of healthy individuals.
As the study explains, this creates a serious problem. Current CAR-T therapies “often [lead] to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients.” The result is that even patients cured of cancer can become dangerously vulnerable to infections.
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“The nonrelapse mortality of CART19 is up to 10 per cent 1 year after infusion, with the most common cause being infections,” the writer writes.
A more precise target
To solve this, the research team turned to a much narrower target: a gene called IGHV4-34, found on the surface of certain B-cell receptors. Unlike CD19, this gene is rarely seen in healthy B cells but appears frequently in cancerous ones.
“Whereas the IGHV4-34 gene is expressed in ~5% of normal B cells, it is the dominant clonotype in a high percentage (10 to 60%) of patients with lymphoid malignancies,” the study notes.
The team developed a new therapy called CART4-34, which targets only B cells carrying this gene. In mouse models of diffuse large B-cell lymphoma, the results were striking.
The study found that “CART4-34 showed robust expansion and antitumor activity comparable to those of CART19,” meaning it was just as effective at destroying cancer — but without wiping out healthy B cells.
Crucially, the study found that cancer cells treated with conventional CAR-T therapy can escape by switching off CD19. But this did not happen with the new treatment. “Although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34+ BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape,” the authors write.
Implications for lupus and autoimmune disease
The findings may be just as important for autoimmune diseases, especially systemic lupus erythematosus (SLE). In lupus, the immune system mistakenly attacks the body’s own tissues, driven by harmful antibodies.
The study explains that in lupus patients, “IGHV4-34+ IgG antibodies represent up to 45 per cent of the serum IgGs and are associated with SLE severity and lupus nephritis.”
When researchers tested CART4-34 on immune cells from people with lupus, the results were highly selective. The therapy “could target human IGHV4-34+ SLE B cells and deplete IGHV4-34+ autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers.”
In simple terms, it removed the harmful antibodies while leaving the rest of the immune system intact — something current treatments cannot do.
A step toward precision immune therapy
The researchers describe their work as a move toward precision medicine. “We developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications,” they conclude.
Experts caution that the therapy still needs to be tested in humans, and it will not work for everyone. Not all cancers or autoimmune diseases involve IGHV4-34. But the concept is powerful.
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As the authors suggest, this approach could lead to a future where doctors choose from “a portfolio of different CARs” depending on the exact molecular fingerprint of a patient’s disease, destroying the illness without destroying the immune system along with it.