Leukemia Therapy Approach “Deletes” Affected Blood System While Transplanting Healthy Stem Cells

Researchers headed by a team at the University of Basel have developed an approach to treating leukemia that involves “deleting” the affected blood system by removing the leukemia patient’s blood cells in a targeted manner, while simultaneously building up a new, healthy system with donor hematopoietic stem cells (HSCs). The strategy involves harnessing an antibody-drug conjugate (ADC) targeting the pan-hematopoietic marker, CD45, to enable antigen-specific deletion of the entire affected hematopoietic system, including HSCs.

Reporting on their work in Nature (“Selective hematological cancer eradication with preserved hematopoiesis”) the team, led by Lukas Jeker, PhD, from the department of biomedicine at the University of Basel, described promising results from studies in animal models and in human cells in the laboratory. In their paper, the team concluded, “The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased hematopoietic system, irrespective of disease etiology or originating cell type. We propose that this approach could have broad implications beyond hematological malignancies.”

In aggressive cases of leukemia, the only chance for a cure is to replace the diseased blood system with a healthy one. Although the transplantation of donor blood stem cells—hematopoietic stem cell transplantation (HSCT)—is a well-established form of treatment, it is an onerous process for patients. First, chemotherapy is used to remove the body’s own blood stem cells as well as most of the blood cells. Only then do the attending physicians intravenously administer the stem cells from a suitable donor to the patient. This procedure is associated with side effects and potential complications.

As the authors explained, “Hematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of hematological malignancies, but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells.” The development of antigen-specific, cell-depleting drug modalities, such as ADCs or chimeric antigen receptor (CAR) T cells, “… holds the promise of depleting HSCs and cancer cells in a targeted manner and could therefore profoundly improve HSCT,” the team suggested. However, these approaches are not without challenges, including the risk of toxicity, and difficulties with target selection.

Jeker’s team developed an approach enabling them to remove all the blood cells from a leukemia patient in a targeted manner while a new blood system is built up at the same time. The new system, they suggested, can be likened to a mixing console, where a DJ gradually fades down the level of the first song while raising the volume of the second until the first track dies away completely and only the second is audible.

To enable the “fading down” process, specific antibodies coupled to a cytotoxic drug recognize all blood cells in the patient’s body based on a surface marker. The marker, CD45, is common to all the different types of blood cells (both healthy and diseased) but does not appear on other cells of the body. “… we hypothesized that an attractive target would be broadly expressed by all hematopoietic cells, including hematopoietic stem and progenitor cells (HSPCs), leukemic stem cells and differentiated cells, but not non-hematopoietic cells,” the investigators commented. “The receptor tyrosine phosphatase CD45 is expressed only by nucleated cells of hematopoietic origin and therefore represents a pan-hematopoietic marker.” Bit by bit, the antibody-drug conjugate recognizes and destroys all cells of the diseased blood system. While this is taking place, the patient receives a transplant of new, healthy blood cells from a suitable donor.

To prevent the antibody-drug conjugates from also attacking the new blood stem cells or the blood cells they produce, the researchers used genetic engineering techniques to modify the donor stem cells in a targeted manner. Specifically, they introduced a small change in the surface molecule so that the antibodies don’t recognize the new blood cells. The researchers referred to this targeted modification of the donor stem cells as “shielding,” because it acts like a protective shield against the cancer treatment. “… we have developed a highly potent CD45-targeting ADC and identified a combination of base editor (BE) and guide RNA that can install a molecular shield in HSPCs so they retain long-term reconstitution potential in vivo … Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukemic cells with preserved hematopoiesis,” they reported.

The two first authors of the study, Simon Garaudé, PhD, and Romina Matter-Marone, PhD, worked with an interdisciplinary team of bioinformaticians, biochemists, genetic engineering specialists, and clinicians from academia and industry to select the best-suited target structure—and the best protective modification for the fading-down process—from the multitude of surface molecules on blood cells.

“We needed a surface molecule that appeared with approximately the same frequency on all blood cells if possible, including the leukemia cells, but that wasn’t present on other cells in the body,” explained Jeker. CD45 met this requirement and, at the same time, was also suitable for “shielding”—in other words, it could be modified on the donor blood stem cells in such a way that these cells were protected from the cancer treatment but the function of CD45 remained completely normal.

Commented first author Romina Matter-Marone, PhD, “The new approach could pave the way for new treatment options for patients whose state of health is incompatible with the chemotherapy needed for stem cell transplantation.” Although further tests and optimization are needed, the aim is for initial clinical trials to begin in just a few years’ time.

The “mixing console for blood systems” also opens up further possibilities, as joint first author Simon Garaudé, PhD, further explained. “We show how cells that are ‘invisible’ to a blood cell remover can be used to swap out the entire blood system.” This, he says, is an important step toward a programmable blood system that could also assume functions on demand—for example, to correct a serious genetic defect or to impart resistance to specific viruses such as HIV.

Noting limitations of their study, the team nevertheless concluded, “… we have shown that CD45 constitutes an excellent target for antigen-specific therapy of hematological diseases,” the investigators wrote. “Because CD45 is expressed by most hematological cancers, including AML, the same drug could simultaneously condition for HSCT and target most cancer cells independent of their origin.” If successfully translated, they noted, their strategy also has the potential to be used for other diseases that benefit from depleting lymphocytes and replacing a diseased immune system, such as severe autoimmune diseases and possibly even HIV infection. “We predict that the approach presented here not only will enable cancer-selective therapy with preserved function of the hematopoietic system, but could more generally pave the way for synthetic hematopoiesis.”