Relapse of acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation remains a devastating clinical challenge. Patients who experience post-transplant relapse generally have limited therapeutic options and a poor prognosis when treated with conventional approaches. Although single-antigen chimeric antigen receptor (CAR) T-cell therapies targeting CD19 or CD22 have demonstrated high complete remission rates in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), durable remissions are difficult to maintain in most patients.

To address this unmet need, investigators explored a sequential CAR-T strategy combining CD19- and CD22-directed CAR T cells in patients with post-transplant relapsed B-ALL whose leukemic blasts retained expression of both antigens. The goal of this approach was to reduce antigen escape, enhance remission durability, and improve long-term survival outcomes after transplantation.

Patient-derived donor T cells were collected and engineered using lentiviral vectors encoding second-generation CAR constructs containing CD3ζ and 4–1BB costimulatory domains. Patients first received CD19 CAR-T cell therapy, followed by a second infusion of CD22 CAR-T cells at least one month later, and typically within six months, depending on disease status and treatment tolerance.

A total of 27 adult and pediatric patients were treated, including 11 patients with extramedullary disease. After the initial CD19 CAR-T infusion, 85% of patients achieved complete remission, confirming the strong antileukemic activity of CD19-targeted CAR-T therapy in this high-risk post-transplant population. Subsequently, 21 patients proceeded to receive CD22 CAR-T cell therapy and were followed for a median of nearly 20 months.

Long-term outcomes following sequential CAR-T treatment were encouraging. Fourteen of the 21 patients who received both infusions remained in continuous complete remission, while seven experienced relapse. Overall survival and event-free survival rates were both 88.5% at 12 and 18 months, with an event-free survival rate of 67.5% over the same period. These results represent a substantial improvement compared with historical outcomes for patients with B-ALL relapse after transplantation.

Safety analyses showed that CAR-T–associated graft-versus-host disease (GVHD) occurred in a subset of patients. New-onset acute GVHD was observed in a small proportion, while some patients experienced persistence or worsening of pre-existing chronic GVHD. Despite these events, the overall safety profile was considered manageable in the context of the significant survival benefit achieved.

Collectively, these findings demonstrate that sequential CD19 and CD22 CAR-T cell therapy can significantly improve long-term survival in patients with B-ALL who relapse after allogeneic transplantation. By targeting multiple antigens in a planned sequence, this strategy addresses key mechanisms of resistance and provides a durable treatment option for a patient population with historically poor outcomes.

This study highlights GoBroad Healthcare Group's leadership in advancing innovative CAR-T treatment paradigms and underscores the potential of sequential, multi-antigen cellular immunotherapy to transform outcomes for patients with high-risk hematologic malignancies.

Original publication: American Journal of Hematology, DOI: 10.1002/ajh.26160