Case Report: Unedited allogeneic chimeric antigen receptor T cell bridging to conditioning-free hematopoietic stem cell transplantation for a child with refractory Burkitt lymphoma

Abstract

Purpose: Burkitt lymphoma (BL) is the most common tumor of non-Hodgkin's lymphoma (NHL) in children, accounting for about 40% of cases. Although different combined short-course chemotherapies have achieved a good effect, refractory/relapsed BL has a poor prognosis with cure rates less than 30%. Chimeric antigen receptor T cell (CAR-T) therapy has developed rapidly in recent years and achieved excellent results in acute lymphoblastic leukemia (ALL). However, in some cases, there is a failure to produce autologous CAR-T cells because of T-cell dysfunction. In such cases, allogeneic CAR-T therapy has to be considered.

Methods: A 17-year-old boy with stage II BL did not respond to extensive chemotherapy and sequential autologous CAR-T therapy. Lentiviral vectors containing anti-CD20-BB-ζ (20CAR) and anti-CD22-BB-ζ (22CAR) transgenes were used to modify the T cells from an HLA-identical matched unrelated donor. Flow cytometry was used to assess the cytokine analyses and CAR-T cell persistence in peripheral blood, enumerated by qPCR as copies per ug DNA. Informed consent for autologous/allogeneic CAR-T therapy was obtained from the patient and his legal guardian.

Results: Unedited HLA-matched allogeneic CD20 and CD22 CAR-T cells were infused after lymphodepletion chemotherapy with cyclophosphamide and fludarabine. The patient experienced Grade IV cytokine release syndrome (CRS) and went into complete remission (CR) after anti-inflammatory treatment including tocilizumab. Because of persistent pancytopenia and full donor chimerism, the same donor's conditioning-free peripheral blood stem cells were successfully transplanted 55 days post CAR-T. Neutrophils were engrafted at day +11 and platelets were rebuilt at day +47 without obvious acute graft-versus-host disease (GVHD), but there was mild chronic GVHD in the skin and eyes. Currently, active anti-rejection therapy is still underway.

Conclusion: Unedited HLA-matched allogeneic CAR-T cell therapy could be an innovative, effective, and safe treatment for children with refractory/relapse BL without obvious acute GVHD. Conditioning-free allogeneic hematopoietic stem cell transplantation (HSCT) from the same donor is feasible for a patient with full donor T-cell chimerism after allogeneic CAR-T. It cannot be ignored that close GVHD monitoring is needed post HSCT.

Keywords: Burkitt lymphoma; CAR T-Cell Therapy; allogeneic cells; graft-versus-host disease; hematopoietic stem cell transplantation.

Figure 1

The time line and key events of allogeneic CAR-T bridging HSCT treatment in children with disease progression. After a series of chemotherapy and autologous CAR-T treatments, the disease eventually progressed. On day 0, the patient was infused with allogeneic CD20/CD22 CAR-T cells after conditioning chemotherapy (FLU and CTX were used as pretreatment on day −4 to day −3). The tumor disappeared on day 53. After he had complete remission, he was bridged to allogeneic HSCT on day 55. The allogeneic CAR-T-cell preparation protocol is illustrated inside the dotted lines.

Figure 2

The allogeneic CAR-T treatment outcomes. (A) The changing trend of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-10 (IL-10), and interferon gamma (IFNγ) after allogeneic CAR-T cell therapy. Changes in blood cells before and after HSCT. (*Granulocyte Colony-Stimulating Factor (G-CSF) was infused from day 55 to day 80.). (B) Changes in the chimerism of donor cells after allogeneic CAR-T cell therapy. (C) Changes in the number of copies of CAR-T cells after allogeneic CAR-T cell therapy. (*The copies of CAR-T cells less than 30*10³/ug: CAR-T cells have almost disappeared in the patient.).