Terapia della leucemia mieloide acuta migliorata grazie al trapianto di cellule staminali CRISPR. / Acute Myeloid Leukemia Therapy Improved by CRISPR Stem Cell Transplant
Terapia della leucemia mieloide acuta migliorata grazie al trapianto di cellule staminali CRISPR. / Acute Myeloid Leukemia Therapy Improved by CRISPR Stem Cell Transplant
Un nuovo studio condotto dai ricercatori di WashU Medicine dimostra che, per i pazienti affetti da tumori del sangue, un trapianto di cellule staminali geneticamente modificate aiuta a prevenire gli effetti collaterali tossici e potenzialmente migliora l'efficacia delle terapie. / A new study led by WashU Medicine researchers shows that, for blood cancer patients, a genetically engineered stem cell transplant helps prevent toxic side effects and potentially improves the effectiveness of therapies.
Per le forme più aggressive di tumore del sangue, il trapianto di cellule staminali è spesso l'unica terapia potenzialmente risolutiva. Tuttavia, questi tumori possono spesso recidivare anche dopo il trapianto. In particolare, la terapia con cellule CAR-T non si è dimostrata efficace contro tutti i tumori del sangue, tra cui la leucemia mieloide acuta (LMA) e la sindrome mielodisplastica (SMD).
Un recente studio clinico multicentrico di fase I/II, condotto da ricercatori della Washington University School of Medicine di St. Louis, dimostra che un trapianto di cellule staminali, che rimuove il CD33 dalle cellule del donatore utilizzando la tecnologia CRISPR, può contribuire a prevenire la recidiva del cancro.
Lo studio è stato pubblicato su Nature Medicine con il titolo " Trapianto allogenico di cellule ematopoietiche con delezione di CD33 mediante CRISPR-Cas9 e terapia di mantenimento con gemtuzumab ozogamicin nella leucemia mieloide acuta: uno studio di fase I/II ". Lo studio è stato condotto presso il Siteman Cancer Center, con sede presso il Barnes-Jewish Hospital e WashU Medicine, ed in altri 14 centri negli Stati Uniti ed in Canada. Trenta pazienti adulti affetti da leucemia mieloide acuta o sindrome mielodisplastica ad alto rischio di recidiva hanno ricevuto il trapianto di cellule staminali.
I tumori mieloidi, come la leucemia mieloide acuta (LMA) e la sindrome mielodisplastica (SMD), sono difficili da trattare con le cellule CAR-T perché le stesse proteine bersaglio sono presenti sia sulle cellule tumorali che sulle cellule mieloidi sane, il che comporta rischi di tossicità.
"Siamo incoraggiati dai risultati di questo studio, che dimostrano come un trapianto di cellule staminali con delezione del CD33 sia molto simile ai risultati di un trapianto di cellule staminali standard", ha affermato John DiPersio, MD, PhD, professore di medicina presso WashU Medicine e autore corrispondente dello studio. "In futuro, speriamo di poter combinare questa tecnica con immunoterapie mirate al CD33, come le cellule CAR T, e migliorare le opzioni di trattamento per i pazienti affetti da questi tumori del sangue molto aggressivi".
Secondo DiPersio, i risultati dello studio gettano le basi per lo sviluppo di interventi combinati di trapianto di cellule staminali con delezione del CD33 e immunoterapia mirata al CD33, che evitano la distruzione delle cellule sane del donatore nel corso del trattamento del cancro.
ENGLISH
For highly aggressive types of blood cancer, stem cell transplantation is often the only potentially curative therapy. Yet, these cancers can often return even after a transplant. Notably, CAR T cell therapy has not been effective against all blood cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
A recent Phase I/II multicenter clinical trial, led by researchers at Washington University School of Medicine in St. Louis, shows that a stem cell transplant, that removes CD33 from donor cells using CRISPR, can help prevent cancer recurrence.
The work was published in Nature Medicine and titled, “CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a Phase I/II trial.” The study was conducted at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and 14 other sites in the U.S. and Canada. 30 adult patients with AML or MDS at high risk of relapse received the stem cell transplant.
Myeloid cancers, such as AML and MDS, are difficult to treat with CAR T cells because the same proteins targets are present on both cancer cells and healthy myeloid cells, leading to toxicity risks.
“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 John DiPersio, MD, PhD, professor of medicine at WashU Medicine and corresponding author of the study. “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.”
As proof of concept, patients also received a maintenance therapy that targets CD33, after completion of the stem cell transplant. While not a CD33-targeted CAR T cell, the maintenance therapy, called gemtuzumab ozogamicin, is an engineered antibody that targets CD33 and carries an anti-cancer drug. Gemtuzumab ozogamicin is approved by the Food and Drug Administration (FDA) to treat CD33-positive AML and is in clinical trials for CD33-positive MDS. While it helps prevent relapse, the drug’s use is limited because it can cause liver toxicity and damage to blood cells, including dangerously low counts of white blood cells, red blood cells, and platelets.
All patients from the trial achieved engraftment of their transplanted stem cells by day 28. Some patients met this goal sooner with platelet production returning by day 16 on average. These timeframes are comparable to those of standard transplanted stem cells.
Average survival was just over 14 months. Nineteen patients received at least one cycle of the antibody maintenance therapy as part of a dose-escalation protocol. The authors found that patients maintained blood cell counts across all doses, suggesting that the gene-edited stem cell transplant protected patients from low blood cell counts typically seen following a standard stem cell transplant.
DiPersio and colleagues published a single case study detailing a patient with high-risk AML who received a CD33-deleted stem cell transplant. Upon relapse after the transplant, the patient received a CD33-targeted CAR T cell therapy, which used T cells from the same donor who provided the stem cell transplant.
The treatment resulted in complete remission and the patient remains cancer free over one year after receiving the CAR T cell therapy. Normal blood cell production returned with all blood cells lacking CD33, providing evidence that the genetically engineered donor cells had established themselves in the bone marrow.
DiPersio said the results of the study lay the groundwork for developing paired CD33-deleted stem cell transplant and CD33-targeted immunotherapy interventions that avoid destruction of healthy donor cells in the course of cancer treatment.
Da:
https://www.genengnews.com/topics/cancer/acute-myeloid-leukemia-therapy-improved-by-crispr-stem-cell-transplant/?_hsenc=p2ANqtz-_Uk3l0X8RsIPUr5NrjfgwbF6hl0hN-86Vcy6x9i5upU_D-ur0AKDeEZmUtz7pOuiZquW5U-KqM35hwXbHMSlnxYnCfJh7fxi3sDfR2VKDl39AXS28&_hsmi=418588000
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