For individuals battling some of the most aggressive forms of blood cancer, a stem cell transplant often represents the single remaining treatment option with the potential to achieve a lasting cure. Yet, even this high-stakes medical intervention carries significant risks. Cancers frequently return after transplantation, plunging patients and their clinical teams into complex scenarios where available options narrow drastically. <\/p>\n
Now, a new clinical trial led by researchers at Washington University School of Medicine in St. Louis suggests that a pioneering approach\u2014genetically modifying donor stem cells prior to transplantation\u2014could render subsequent cancer treatments both significantly safer and potentially more effective. The innovative strategy revolves around removing a specific protein from donor cells, effectively rendering them invisible to targeted therapies. This allows advanced treatments designed to home in on that protein to aggressively attack lingering or returning cancer cells while simultaneously sparing the healthy transplanted cells responsible for rebuilding the patient’s blood system.<\/p>\n
The study was conducted collaboratively across the Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, alongside 14 clinical and academic research sites spread throughout the United States and Canada. The findings of this significant multi-center trial were recently published in the esteemed medical journal Nature Medicine<\/em>.<\/p>\n A Major Challenge for CAR-T Therapy<\/p>\n According to the study’s corresponding author, Dr. John F. DiPersio, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine, this gene editing approach could help surmount a major biological barrier that has historically limited the utility of CAR-T cell therapy in certain difficult-to-treat blood cancers. <\/p>\n While CAR-T cell therapy has achieved remarkable, highly effective results against several types of aggressive blood cancers, its success rate has lagged significantly when applied to diseases such as acute myeloid leukemia, commonly known as AML, and myelodysplastic syndrome, or MDS. <\/p>\n The core difficulty, DiPersio explained, lies in cellular overlap. Many of the specific surface proteins expressed by AML and MDS cancer cells are also routinely found on healthy myeloid cells. Critically, these shared proteins also appear on the healthy donor stem cells that are infused into the patient during a standard transplantation procedure. Consequently, if CAR-T cells are genetically programmed to hunt down and destroy cells bearing one of those shared target proteins, they are unable to distinguish between malignant cells and healthy ones. As a result, they may inadvertently obliterate the healthy blood stem cells vital to the patient\u2019s recovery alongside the cancer.<\/p>\n That unintended collateral damage can trigger a profoundly dangerous inflammatory response within the patient\u2019s body. Furthermore, it can actively weaken the efficacy of the cancer treatment itself. Because vast numbers of engineered CAR-T cells become heavily occupied attacking healthy targets throughout the body, fewer cells are left to concentrate their forces on tracking down and destroying malignant cells.<\/p>\n The foundational concept behind avoiding this biochemical trap was initially conceived and described by Dr. Miriam Y. Kim, now an assistant professor of medicine at WashU Medicine. Kim began investigating the strategy as a postdoctoral researcher at the University of Pennsylvania before continuing her pioneering work in the DiPersio lab. She subsequently transitioned to an independent investigator role within the WashU Medicine Division of Oncology, where she treats patients and serves as a research member at Siteman Cancer Center.<\/p>\n Removing CD33 From Healthy Stem Cells<\/p>\n In the newly reported clinical trial, patients diagnosed with AML and MDS received donor stem cells that had undergone specialized genetic modification to eliminate a specific surface protein known as CD33. The overarching objective of this genetic alteration was to engineer a fresh supply of healthy blood cells that would be entirely impervious to subsequent medical treatments specifically designed to target and destroy CD33.<\/p>\n "We are encouraged by the results of this study showing that a CD33-deleted stem cell transplant looks very similar to the outcomes of standard stem cell transplantation," said DiPersio, who also holds leadership responsibilities as the director of WashU Medicine’s Center for Gene and Cellular Immunotherapy. "In the future, we are hopeful we will be able to combine this with CD33-targeted immunotherapies, such as CAR-T cells, and improve treatment options for patients with these very aggressive blood cancers."<\/p>\n In addition to the clinical trial findings, DiPersio and his collaborative research team recently reported a detailed single-case study involving an individual with high-risk AML who received a CD33-deleted stem cell transplant. When the patient’s cancer unfortunately recurred at a later date, medical teams treated the disease using CD33-targeted CAR-T cells manufactured from T cells originally supplied by the very same donor who provided the initial stem cells.<\/p>\n That patient, facing one of the most aggressive and treatment-resistant variations of AML, achieved a complete clinical remission and remained entirely cancer-free more than a full year after receiving the specialized CAR-T treatment. Furthermore, normal blood cell production successfully resumed, and comprehensive testing revealed that all of the patient’s circulating blood cells lacked CD33. That crucial finding demonstrated that the genetically engineered donor cells had successfully and permanently established themselves within the patient’s bone marrow. DiPersio served as the senior author of that study, which was published in October 2025 in the journal JCO Precision Oncology<\/em>.<\/p>\n Shielding Healthy Blood Cells<\/p>\n CD33 represents an especially attractive target for this type of gene-editing strategy because the protein is expressed almost exclusively on blood-forming cells rather than on other vital organs or tissues throughout the body. Moreover, existing medical evidence strongly suggests that CD33 is not strictly necessary for normal, healthy blood stem cell function. This conclusion is supported by observations of rare individuals born naturally without the protein, who do not appear to suffer from related health complications or blood disorders.<\/p>\n Following a successful transplant utilizing CD33-deleted stem cells, the underlying medical theory posits that any lingering cells still carrying the CD33 protein should consist primarily or exclusively of cancer cells. A subsequent course of CAR-T therapy, or another form of immunotherapy directed explicitly at CD33, could then be deployed to aggressively hunt down and eliminate those cancer cells while leaving the healthy, donor-derived blood cell population completely unharmed.<\/p>\n To explore this hypothesis in a clinical setting, the phase 1\/2 multicenter trial enrolled a total of 30 adult patients diagnosed with either AML or MDS who were categorized as facing a high risk of disease relapse. Prior to the transplantation procedure, the donor stem cells were processed using CRISPR gene-editing technology specifically to delete the CD33 protein.<\/p>\n The resulting gene-edited cellular product is known clinically as tremtelectogene empogeditemcel, or trem-cel for short. The product was developed by Vor Biopharma, a biotechnology company that also provided financial support for the clinical study.<\/p>\n Testing a CD33-Targeted Cancer Treatment<\/p>\n To rigorously test whether these newly engineered stem cells possessed the resilience to withstand a therapy directed against CD33, trial participants were administered a specific maintenance treatment following their transplantation procedure.<\/p>\n The therapeutic agent utilized, a drug called gemtuzumab ozogamicin, functions differently from a CD33-targeted CAR-T therapy. Instead, it operates as an engineered monoclonal antibody that specifically recognizes the CD33 protein and delivers a potent anti-cancer pharmaceutical directly inside any cell bearing that surface marker.<\/p>\n Gemtuzumab ozogamicin is already approved by the U.S. Food and Drug Administration for the management of CD33-positive AML and is currently being evaluated in clinical trials for CD33-positive forms of MDS. Although this treatment can play a valuable role in helping to prevent cancer relapse, its clinical usefulness has traditionally been severely constrained by profound side effects. These adverse reactions frequently include dangerous levels of liver toxicity and severe damage to healthy blood-producing cells, leaving patients vulnerable to critically depleted counts of white blood cells, red blood cells, and platelets.<\/p>\n Gene-Edited Cells Successfully Engrafted<\/p>\n Despite the complexities of the protocol, clinical outcomes regarding engraftment were highly encouraging. All 30 patients enrolled in the trial achieved successful engraftment by day 28 following the procedure, marking the point at which the transplanted stem cells successfully migrated to the bone marrow environment and initiated the production of new blood cells. Several patients reached this vital recovery milestone even earlier, with platelet production returning by day 16, on average.<\/p>\n Significantly, these recovery timeframes closely mirrored the timelines typically observed following a standard, conventional stem cell transplantation procedure.<\/p>\n Across the entire cohort, the average overall survival rate recorded in the trial stood at just over 14 months. A subset of 19 patients received at least one cycle of gemtuzumab ozogamicin as part of a structured dose-escalation protocol, a design that enabled researchers to identify an optimal recommended dose for future investigations.<\/p>\n Across the various administered doses, patients were able to maintain their blood cell counts effectively. This observation strongly suggests that the gene-edited transplant successfully shielded patients from the precipitous and often dangerous drops in blood cell counts that typically plague patients when this type of maintenance therapy is administered following a conventional stem cell transplant.<\/p>\n Side Effects Remained Similar to Standard Transplants<\/p>\n The broader spectrum of side effects observed throughout the course of the treatment period was generally consistent with the complications traditionally associated with standard stem cell transplantation. Documented adverse events included anemia, low platelet counts, fevers, various infections, and graft-versus-host disease\u2014a complex condition wherein the newly introduced donor immune cells react against the patient’s own healthy tissues.<\/p>\n During the course of the study, seven patients passed away. Of those fatalities, four were attributed directly to the continued progression of the underlying cancer, while three were linked to complications arising from the transplantation process itself, including kidney failure, liver toxicity, and sepsis.<\/p>\n Reflecting on the broader implications of the trial, DiPersio emphasized that these findings establish a solid scientific and clinical foundation for future therapeutic strategies. By successfully pairing CD33-deleted stem cell transplantation with subsequent CD33-targeted immunotherapies, researchers hope to provide clinicians with a powerful new paradigm: the ability to attack aggressive blood cancers with unprecedented force without simultaneously destroying the healthy donor cells required to rebuild and sustain the patient’s vital blood and immune systems.<\/p>\n","protected":false},"excerpt":{"rendered":" For individuals battling some of the most aggressive forms of blood cancer, a stem cell transplant often represents the single remaining treatment option with the potential to achieve a lasting cure. Yet, even this high-stakes medical intervention carries significant risks. Cancers frequently return after transplantation, plunging patients and their clinical teams into complex scenarios where […]<\/p>\n","protected":false},"author":6,"featured_media":1697,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[455],"tags":[756,1611,2733,457,2731,2729,2735,464,2730,2734,2646,2702,84,456,2528,458,2732],"class_list":["post-1698","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","tag-blood","tag-cancer","tag-cells","tag-discovery","tag-donor","tag-genetically","tag-immunotherapies","tag-major","tag-modified","tag-obstacle","tag-overcoming","tag-promise","tag-research","tag-science","tag-show","tag-space","tag-stem"],"_links":{"self":[{"href":"https:\/\/tcjsj.com\/index.php?rest_route=\/wp\/v2\/posts\/1698","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/tcjsj.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/tcjsj.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/tcjsj.com\/index.php?rest_route=\/wp\/v2\/users\/6"}],"replies":[{"embeddable":true,"href":"https:\/\/tcjsj.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=1698"}],"version-history":[{"count":0,"href":"https:\/\/tcjsj.com\/index.php?rest_route=\/wp\/v2\/posts\/1698\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/tcjsj.com\/index.php?rest_route=\/wp\/v2\/media\/1697"}],"wp:attachment":[{"href":"https:\/\/tcjsj.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=1698"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/tcjsj.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=1698"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/tcjsj.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=1698"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}