Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft- versus -host disease (G v HD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

RATIONALE:Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, there are no efficient methods to prevent relapse after allo-HSCT. Chimeric antigen receptor T (CAR-T) cells have achieved favorable outcomes in the treatment of refractory/relapsed acute lymphoblastic leukemia (ALL) because of their strong anti-leukemia activity. However, it is unclear whether the CAR-T cells constructed using viral systems can be used as preventive infusions to prevent relapse after haploidentical HSCT.PATIENT CONCERNS:Two patients with ALL with high risk received haploidentical HSCT.DIAGNOSES:Two patients were diagnosed with ALL with high risk.INTERVENTIONS:Patients received preventive infusion of donor-derived CAR-T cells constructed using viral systems on day 60 after haploidentical HSCT.OUTCOMES:The CAR-T cells were continually detected, and no graft versus host disease developed. The two patients survived with disease-free for 1 year and 6 months, respectively.LESSONS:Preventive infusion of donor-derived CAR-T cells after haploidentical HSCT may be safe and that immunosuppressors may not affect the proliferation of CAR-T cells.

BACKGROUND:Approximately 30% to 60% of patients with acute B-lymphocytic leukemia (B-ALL) show as refractory or relapsed, which is one of the major causes of death in patients with B-ALL, but the methods of the treatment for relapsed/refractory B-ALL (R/R B-ALL) are limited. The chimeric antigen receptors redirected T cells (CAR-T cells) have showed a strong anti-leukemia role for B-ALL. About 90% of patients with R/R B-ALL treated with CD19-CAR-T cells achieved complete remission. However, 60% to 70% of patients relapsed after CAR-T cells treatment, which may be related to target antigen reduction or escape. New products are urgently needed to prevent and treat antigenic escapes causing recurrence.PATIENTS AND METHODS:In this article, we retrospectively analyzed the immunophenotype of patients with B-ALL initially diagnosed in our center from January 2010 to December 2015 to determine whether aberrant antigen expression was associated with the prognosis of patients in order to find new targets for immunotherapy.RESULTS:The results show that disease-free and overall survival in patients without aberrant antigen expression were better than patients with aberrant antigen expression. The most common abnormal antigens were CD123, CD13, and CD56. Correlation analysis showed a negative correlation between aberrant CD123 expression and both disease-free and overall survival.CONCLUSION:Therefore, in the construction of CAR-T cells in patients with R/R B-ALL, conventional CD19 can be combined with aberrant antigens such as CD123 to form CARs with bi-specific antigens or multi-specific antigens may achieve the purpose of improving efficacy. However, more clinical trials are needed.

Background The Chimeric Antigen Receptor T (CAR-T) cells with strong anti-leukemia role can treat relapsed/refractory CD19-positive acute lymphoblastic leukemia (CD19+-ALL) with good outcome. The allogeneic CAR-T cells receives activation signals from both T cell receptor (TCR) and CAR, which may possess stronger activity in anti-leukemia cells. However, the infusion of allogeneic CAR-T cells may cause graft-versus-host disease, which could limit its application after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is still unclear that the role of the donor-derived CAR-T cells in treating relapsed patients after allo-HSCT. In this study, the prospective study was performed to investigate the role of donor-derived CAR-T cells on relapsed patients after allo-HSCT. Methods From April 2016 to March 2019, relapsed patients after allo-HSCT with CD19+-ALL and a Karnofsky score greater than or equal to 60 were enrolled in this study. The donor underwent apheresis for mononuclear cells to construct the CAR-T cells. The bone marrow aspiration every month after CART- cells infusion was carried out for the assessment of disease status by follow cytometry. The chimerism was detected every month after CAR-T cells treatment. Results Eighteen patients enrolled in this study. The median number of infused CAR-T cells was 1.825Í106/Kg. Thirteen patients (13/18=72.22%) reached complete remission (CR) after CAR-T cells treatment. Four patients (4/18=22.22%) had ineffectiveness. One patient died from b uncontrolled bleeding because of low platelet. The patients with blast cells <5% had higher CR. The full chimerism achieved after CART- cells treatment for all patients with the decrease of chimerism at the time of relapse. The median time of follow-up was seven months (ranged from three months to twenty-five months). Three patients with decreased CAR-T cells or chimerism was underwent allogeneic hematopoietic stem cell transplantation or relapsed within six months. The other eleven patients were complete remission with full chimerism or the continual proliferation of CAR-T cells without the second allo-HSCT during our follow-up period. Seventeen patients observed cytokine release syndrome in which six patients with degree III-IV. Two patients developed GVHD in skin and intestinal tract. All patients recovered after management. No other severe complications and death were observed. Conclusion Our results showed that the treatment by donor-derived CAR-T cells for relapsed patients after allo-HSCT is safe and effective. No second transplantation was needed for relapsed patients after allo-HSCT with the treatment of donor-derived CAR-T cells that with good chimerism and continual proliferation of CAR-T cells. However, further clinical trials should be performed to investigate this protocol with larger cases. Disclosures No relevant conflicts of interest to declare.

The chimeric antigen receptor T (CAR-T) cells play an antileukemia role, and can be used to treat or prevent relapse by targeting minimal residual disease for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the infusion of allogeneic CAR-T cells may also cause graft-versus-host disease, which limited their applications during and after allo-HSCT. In this review, we discuss the clinical trials that applying CAR-T cells before allo-HSCT and the use of donor-derived CAR-T cells as conditioning regimen during allo-HSCT. At last, we analyzed the effect of donor-derived CAR-T cells on preventive infusion after allo-HSCT.

Background: The chimeric antigen receptor T (CAR-T) cells have showed strong anti-leukemia role, which can treat or prevent relapse by targeting minimal residual disease for patients undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). The infusion of allogeneic CAR-T cells may cause the graft-versus-host disease, which could limit its use during and after allo-HSCT. It is still unclear whether CAR-T cells can be used during and after allo-HSCT. In this study, the use of CAR-T cells in these situation was explored.

Chimeric antigen receptor redirected T cells (CAR-T cells) have achieved inspiring outcomes in patients with B cell malignancies, and are now being investigated in other hematologic malignancies and solid tumors. CAR-T cells are generated by the T cells from patients' or donors' blood. After the T cells are expanded and genetically modified, they are reinfused into the patients. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. In this review, we first discuss the structure and evolution of chimeric antigen receptors. We then report on the tools used for production of CAR-T cells. Finally, we address the challenges posed by CAR-T cells.

BACKGROUND:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the cornerstone in treatment of hematological malignancies. However, relapse of the hematological disease after allo-HSCT remains a challenge and is associated with poor long-term survival. Chimeric antigen receptor redirected T cells (CAR-T cells) can lead to disease remission in patients with relapsed/refractory hematological malignancies. However, the therapeutic window for infusion of CAR-T cells post allo-HSCT and its efficacy are debatable.MAIN BODY:In this review, we first discuss the use of CAR-T cells for relapsed cases after allo-HSCT. We then review the toxicities and the occurrence of graft-versus-host disease in relapsed patients who received CAR-T cells post allo-HSCT. Finally, we review clinical trial registrations and the therapeutic time window for infusion of CAR-T cells post allo-HSCT.CONCLUSIONS:The treatment of allogeneic CAR-T cells is beneficial for patients with relapsed B cell malignancies after allo-HSCT with low toxicities and complications. However, multicenter clinical trials with larger sample sizes should be performed to select the optimal therapeutic window and confirm its efficacy.