07/08/2024 | Press release | Archived content
Combining CAR-T cell therapy and stem cell transplantation could help patients with difficult-to-treat blood cancers.
A new 'all-in-one' treatment that integrates CAR-T cell therapy with more established stem cell transplantation therapy might improve outcomes for patients with blood cancers, according to a study led by researchers at Zhejiang University in China.
The treatment exploits the way CAR-T cell therapy kills cancer cells and also depletes the donor T cells that cause severe adverse effects, so that fewer toxic drugs are required for a successful stem cell transplant. The study was published in the New England Journal of Medicine.1
"This approach might be particularly beneficial for patients with relapsed or refractory haematological cancers who are not eligible for conventional stem cell transplantation," says HUANG He, director of the Bone Marrow Transplantation Center at the First Affiliated Hospital, Zhejiang University School of Medicine.
Seek and destroy
In the trial, 17 patients with relapsed or treatment-resistant CD7-positive leukaemia or lymphoma, aggressive blood cancers, characterised by CD7 antigens on the cancer cells - first received CAR-T cell therapy. This is a new type of immunotherapy where T cells from patients or donors are genetically modified to recognize a specific antigen - in this case CD7 - and then infused back into the patient, where they seek out and destroy cancer cells.
Ten patients were selected for the next stage in which they received a haematopoietic stem cell transplantation (HSCT) from a donor - in this case, a close family member whose tissue type is half-matched to the patient. The new stem cells move to the bone marrow and produce healthy blood cells to replace the ones with cancer.
In the 10 selected patients, the CAR-T cell therapy had completely destroyed the cancer cells, which can be detected in the patients' blood. In addition, their bone marrow was not fully recovered, but they had no severe graft-versus-host disease (GvHD), in which transplanted cells attack the patient's tissues and cells. These conditions indicated that these patients' bone marrow can allow for stem cell engraftment. Critically, this meant that, unlike with conventional HSCT, the 10 patients didn't have to receive the aggressive chemotherapy - namely myeloablative conditioning - to destroy the bone marrow before HSCT and the immunosuppressive agents to reduce GvHD. Those treatments are so toxic that they prevent many patients from using HSCT to treat their cancer. The approach also allowed the cancer-destroying CAR-T cells to remain in the body after the transplant.
Underlying mechanisms
For the majority of patients, the all-in-one treatment appeared to cause long-term remission, with manageable side-effects - such as very low blood cell counts or moderate symptoms of GvHD. During a median follow-up period of around 15 months, six patients had no detectable disease. Most notably, the research team analysed the recovered T cells after HSCT, and revealed their intrinsic characteristics to reduce the severity of GvHD without immunosuppressive agents. However, two patients experienced a relapse with CD7-negative leukaemia and two died from treatment-related complications.
Larger clinical studies are needed to validate the findings, say the researchers. "Further research will probably focus on larger, more homogeneous cohorts to validate these findings and optimize the therapeutic strategy," says HU Yongxian, vice director of the Bone Marrow Transplantation Center. "Additional studies may also explore the mechanisms underlying leukaemia relapse and long-term effects of persisting CAR T-cells."
The researchers also need to find ways to manage the toxicities associated with both treatments, says Hu. "Another major challenge is the relapse of CD7-negative leukaemia. This occurs when the cancer cells lose the CD7 antigen, making them invisible to CD7-targeted CAR-T cells, leading to disease relapse after initial remission."
Note: The study was led by HUANG He, director of the Bone Marrow Transplantation Center at the First Affiliated Hospital, Zhejiang University School of Medicine. HU Yongxian and WANG Dongrui from Zhejiang University, and Alex. H Chang from Fudan University, co-supervised this study.
Reference
1. Hu, Y. et al., N. Engl. J. Med.390, 1467 (2024).