HLA‐matched allogeneic anti‐CD19 CAR‐T therapy in treating a relapsed/refractory acute lymphoblastic leukemia patient with high tumor burden

The genetically engineered chimeric antigen receptor T cell (CAR‐T) therapy has shown remarkable clinical efficacy in the treatment of hematological malignancies. Nonetheless, it is difficult to harvest adequate autologous T cells to manufacture potent CAR‐T cell products in patients with high tumor burden and prior tumor‐reductive treatment. Here we reported a relapsed/refractory acute lymphoblastic leukemia patient with high leukemia burden and central nervous system (CNS) involvement. The patient responded to donor‐derived HLA‐matched allogeneic CAR‐T treatment, with the achievement of quick complete remission. And for the first time, we revealed the development of a cerebral CRS in situ after allogeneic CAR‐T therapy.

Generally, the manufacturing process of CAR-T cells is rather tedious and challenging as it is much dependent on the quantity and quality of one's autologous T cells. 6 However, in some patients with high tumor burden and prior tumor-reductive treatment, they might experience prolonged and severe lymphopenia. This condition would complicate the CAR-T cell production as it is more difficult to harvest and obtain enough T cells to manufacture potent CAR-T cell products in these patients. 7 Furthermore, autologous CAR-T cell production is costly 8 and time-consuming. Lastly, CAR-T therapy is an individualized therapy for patients, and thus, it might not be a feasible treatment plan for some patients with advanced diseases.
'Off-the-shelf' allogeneic CAR-T therapy has the potential to overcome these limitations. [9][10][11] Moreover, CAR expression of allogeneic cell types like NK cells is also currently under exploration. 12 Nonetheless, this plan may take several years to be clinically and technologically mature. Concerning convenience and clinical practicability, HLAmatched allogeneic CAR-T cells might be the most appropriate strategy during this transition period.
To date, a small number of patients with B-cell malignancies, especially those who relapsed post-transplantation, were treated by donorderived CAR-T cells. 13,14 As a result, most of them have achieved CR or partial remission (PR) with a relatively low incidence of graft-versushost disease (GVHD) and toxicity. 15 With this, we report a case of an R/R ALL patient with high disease burden and central nervous system (CNS) infiltration, which had been successfully treated by donorderived HLA-matched allogeneic CAR-T treatment.

CASE PRESENTATION
A 53-year-old female patient was admitted to our hospital due to R/R B-ALL. The initial bone marrow (BM) smear revealed the diagnosis of the L2 subtype of acute lymphoblastic leukemia (ALL-L2  [16][17][18] Once the diagnosis was confirmed, she received a series of chemotherapies but all therapies failed to achieve persistent CR (shown in Figure 1). Since October 2018, she received a cycle of

DISSCUSSION
In this study, we reported an R/R ALL (L2 subtype) patient with CNSL. Throughout this treatment process, the adverse effect was manageable. We posted a concern that the donor-derived non-CART cell expansion was induced by the cytokines released during the CRS process and might act against host tissue to cause GVHD. However, no GVHD symptoms were observed in this patient after the infusion of allogeneic CAR-T cells, which was similar to that reported in the previous studies. 15,22 Generally, the occurrence of GVHD was associated with concurrent stimulation of alloreactive T cells via TCR in response to allogeneic B cells. Ghosh et al. 23  T cells. It is noteworthy that there was a considerate discrepancy in cytokine distributions between CSF and serum, which is consistent with our previous study. 24 Since CNS cells showed absence of CD19 expression, the reason for CNS symptoms is less likely attributable to direct interactions between CD19+ normal cells and anti-CD19 CART cells. A similar moderate cerebral CRS with inflammatory cytokines was presumely generated by blood-brain-barrier (BBB) penetrating CAR-T cells. One of the possible mechanisms is that BBB penetrating CAR-T cells may be activated by CNS-entering potent minimal residual CD19+ leukemia cells which are less than detection limits. donor-derived CAR-T cells be part of the conditioning regimen prior to HSCT. 25,26 Besides, some cases reported of successful sequential or combined allo-and auto-CAR-T therapy in chemo-refractory patients with high tumor burden. 27 In short, the short-term persistence of donor-derived CAR-T cells is a significant hurdle to the broader application of allogeneic CAR-T therapy in hematological malignancies. Therefore, timing of subsequent treatment options like HSCT should be considered as soon as possible worth further exploration.

OUR DATA FIRST REVEALED THE DEVELOPMENT OF A CEREBRAL CRS IN SITU BY ALLOGENIEC CAR-T THERAPY
In summary, apart from the autologous CAR-T therapy, allogeneic CAR-T treatment is one of the best treatment options for patients with hematological malignancies. This approach circumvents the difficulty of harvesting adequate and optimal T cells from patients with severe lymphopenia with a relatively low incidence rate of GVHD and mild CRS toxicity. Despite its advantages, the short maintenance period and the high relapse rate of allo-CART therapy should be improved in future studies. All in all, allogeneic CAR-T cell therapy is definitely worth further investigation and exploration.