The genetically modified immune cells known as CAR-T cells have cured thousands of people with blood cancers, but so far the treatments only work against a few types of the disease. Today in Science Translational Medicine (STM), a research team describes a provocative CAR-T strategy to tackle most blood cancers. Working in mice, the scientists sicced the immune cells on a protein common to nearly all cancerous blood cells. Because that protein is also found on normal blood-forming stem cells, the team also replaced those vital cells with ones genetically tweaked to be invisible to the cancer fighters, protecting them from the onslaught.
The team found that the two-pronged strategy spared the mice from acute myeloid leukemia (AML), a disease for which CAR-T cells aren’t currently used. They hope to have the approach ready for human trials within 2 years. And yesterday in Nature, a second team reported treating AML in mice with a similar, but narrower approach.
“It’s a very bold thing they have attempted and seem to have pulled off,” immunologist Jason Lohmueller of the University of Pittsburgh School of Medicine says of the STM study. “This is more than an incremental advance. This could work” to expand the targets of CAR-T therapies, says immunologist Marie Bleakley of the Fred Hutchinson Cancer Center, who like Lohmueller wasn’t connected to any of the studies. Still, they and other scientists agree the universal strategy needs more testing in animals, because replacing a person’s blood stem cells is risky.
CAR-T cells are engineered to carry a synthetic receptor on their surface that recognizes a specific protein, or antigen, on cancer cells. (CAR stands for chimeric antigen receptor.) Once CAR-T cells are infused into a patient’s bloodstream, they kill cancer cells sporting that antigen.
Researchers developing these treatments currently tailor the receptor for each cancer type. Patients with B-cell acute lymphoblastic leukemia, for example, receive T cells with receptors that zero in on CD19, a protein on their rapidly multiplying, cancerous B cells. CAR-T cells for treating multiple myeloma, in contrast, search out cells with a different antigen, BCMA. So far, five types of blood cancers have approved CAR-T therapies, all of which target one of these two proteins.
To help patients with other blood cancers, researchers are searching for additional antigens that CAR-T cells could aim for. One candidate is a protein called CD45. “It’s sort of a dream antigen,” Lohmueller says, because it occurs on most kinds of leukemia and lymphoma cells. But it is also present on vital normal blood cells, including T cells and blood-forming stem cells, making them vulnerable to the CAR-T cells.
A team led by immunologist Nils Wellhausen and hematologist and oncologist Saar Gill of the University of Pennsylvania came up with a clever way to avert these attacks. Their first step entailed creating CAR-T cells that pounce on cells with CD45. To keep those cells from attacking each other, the team used the CRISPR genome editor to make a small change in sequence of the T cell gene encoding CD45, altering the protein just enough to conceal it from the CAR-T receptor. To protect the normal blood cells that carry CD45, the group made the same change in a line of blood stem cells.
The researchers tested their approach in mice that had developed tumors after receiving injections of AML cells. In the control mice, which received the leukemia cells along with unmodified CD45-targeting CAR-T cells and blood stem cells, the tumors ballooned. All of these rodents died in less than 30 days. But nearly all of the mice infused with both kinds of modified cells were alive 40 days after the treatment, and their tumors remained small.
“I think it’s a very important paper” that will accelerate development of new treatments, says medical oncologist James Driscoll of Case Western Reserve University. The work shows that “there’s a way to specifically modify the CD45 protein to make it resistant [to CAR-T cells] that does not compromise its function,” says Miriam Kim, a CAR-T cell researcher at the Washington University School of Medicine in St. Louis. However, pediatric immunologist Waseem Qasim of the University College London Great Ormond Street Institute of Child Health thinks the two-pronged approach is not necessary. In a cancer such as AML, the CD45-targeting CAR-T cells could serve as a short-term treatment on their own, he says. In most cases patients could receive normal stem cells after, rather than the modified stem cells, because the preparatory treatment for a stem cell transplant would kill off the CD45-targeting T cells.
Nevertheless, other researchers are pursuing similar strategies that combine CAR-T cells and stem cells edited to evade them. In the Nature paper, a group led by Pietro Genovese of the Dana-Farber Cancer Institute treated AML in mice with CAR-T cells that targeted different antigens on the cancerous cells; they modified those same antigens on the animals’ stem cells to protect them. In addition, a clinical trial for AML is testing another cell-editing approach in which patients receive CAR-T cells that target yet another antigen, CD33, as well as stem cells modified to lack the protein.
But because CD45 occurs in a wider range of blood cancers than CD33, CAR-T cells targeting it could be a broad-spectrum treatment. “This is not going to be a panacea or a silver bullet,” Gill cautions, but the research suggests “it is practical and feasible.”
