Science fiction draws readers in by depicting wildly inventive and imaginative scientific, medical, or technological advances. In the early 20th century, replacing a person’s blood system with healthy donor cells to cure leukemia was a fantasy; however, by the 1970s, fiction became reality when the first successful allogeneic hematopoietic cell transplants (HCTs) were reported in patients with advanced leukemia. In the early 21st century, using cancer-antigen-targeted immune cells to cure refractory blood cancers was a pipedream, but by 2012, the first child with refractory acute lymphoblastic leukemia (ALL) was cured following a single infusion of CD19 chimeric antigen receptor (CAR) T cells. Combining these two powerful cellular therapies — CAR-T and HCT — to provide targeted, effective cancer-killing and immunologic replacement without the need for intensive chemotherapy or additional immunosuppression would be a huge medical achievement. And using this strategy to successfully treat the most lethal of all acute leukemias — refractory acute myeloid leukemia (AML) — is seemingly the stuff of science fiction.
Yet, in the April 25, 2024 issue of The New England Journal of Medicine, Yongxian Hu, MD, PhD, and colleagues from China’s Zhejiang University School of Medicine describe results among 10 patients with highly refractory CD7-expressing acute leukemias (seven with AML and three with T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma) who received allogeneic CD7-targeting CAR T cells directly followed by haploidentical HCT. Initially, the concept appears familiar: The allogeneic CD7 CAR T cells wipe out the CD7+ leukemia cells, and the haploidentical donor HCT is used as a hematopoietic rescue, providing immune reconstitution and long-term graft-versus leukemia effect. However, the approach’s ingenuity is far-reaching. In the absence of both HCT conditioning chemotherapy and pharmacologic graft-versus-host disease (GVHD) prophylaxis, the allogeneic CAR T cells can persist after haploidentical HCT. The persisting CD7 CAR T cells exert ongoing anti-leukemia effects, but also reduce GVHD occurrence through some degree of donor T cell and natural killer (NK) cell depletion (CD7 is expressed on T cells and NK cells), diminishing the need for traditional immunosuppression. Additionally, immune reconstitution occurs through the development of CD7-negative donor T cells. Impressively, at a median follow-up of 15 months, six patients continued in deep complete remission, two patients relapsed with CD7-negative leukemia, and one patient died from infectious complications. Donor-derived CAR T cells persisted in all patients with ongoing responses. Acute GVHD was limited to grades 1 and 2, and no patients developed chronic GVHD.
In Brief
This extremely elegant all-in-one platform extends cellular therapy in new and novel ways. Cellular HCT conditioning, adoptive post-HCT cellular therapies, and cellular GVHD prevention strategies are areas of burgeoning research. Yet while the approach described by Dr. Hu and her colleagues leaves open the optimal method for infection prevention, it does not adequately address post-CAR antigen loss or expansion of preexisting CD7-negative clonal populations, which appeared to occur in the two patients with post-HCT relapse. These are issues that must be improved upon in future iterations of this work. What is clear is that next-generation allogeneic HCT has evolved from the pages of science fiction to our cancer clinics, and many advanced leukemia patients will benefit from this new reality.
Competing Interests
Dr. Muffly indicated no relevant conflicts of interest.
