The potential of adoptive transfer of γ9δ2 T cells to enhance blinatumomab’s antitumor activity against B-cell malignancy

Abstract

Blinatumomab, a bispecific T cell engager (BiTE) antibody targeting CD19 and CD3ε, can redirect T cells toward CD19-positive tumor cells and has been approved to treat relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, chemotherapeutic regimens can severely reduce T cells’ number and cytotoxic function, leading to an inadequate response to blinatumomab treatment in patients. In addition, it was reported that a substantial portion of R/R B-ALL patients failing blinatumomab treatment had the extramedullary disease, indicating the poor ability of blinatumomab in treating extramedullary disease. In this study, we investigated whether the adoptive transfer of ex vivo expanded γ9δ2 T cells could act as the effector of blinatumomab to enhance blinatumomab’s antitumor activity against B-cell malignancies in vivo. Repeated infusion of blinatumomab and human γ9δ2 T cells led to more prolonged survival than that of blinatumomab or human γ9δ2 T cells alone in the mice xenografted with Raji cells. Furthermore, adoptive transfer of γ9δ2 T cells reduced tumor mass outside the bone marrow, indicating the potential of γ9δ2 T cells to eradicate the extramedullary disease. Our results suggest that the addition of γ9δ2 T cells to the blinatumomab treatment regimens could be an effective approach to enhancing blinatumomab’s therapeutic efficacy. The concept of this strategy may also be applied to other antigen-specific BiTE therapies for other malignancies.

Exploiting adaptive immune receptor recombination read recoveries from exome files to identify subsets of ALL and to establish TCR features that correlate with better outcomes

“…Our results further indicated that a potential T‐cell response, keeping in mind the above limitations of the recovery of TRB and TRG IR recombination reads in the B‐cell ALL setting, 30–32 was associated with better survival probabilities, when BCR CDR3 AA sequence repetitions were detected in the WXS files and when those files represented the B‐cell ALL diagnosis, according to the TARGET protocols. Such results are consistent with prior reports that gamma‐delta T‐cells exhibited cytotoxicity of leukaemia blasts in vitro 36 and that gamma‐delta T‐cells not only potentiated the anti‐B‐cell ALL reactions but could do so in conjunction with the common ALL therapeutic, blinatumomab (anti‐CD19) 37 . However, given our results indicating little TRD clonotype expansion in B‐cell ALL, the question is raised, how prominent is the gamma‐delta T‐cell response to B‐cell ALL?…”

“…Such results are consistent with prior reports that gamma-delta T-cells exhibited cytotoxicity of leukaemia blasts in vitro 36 and that gamma-delta T-cells not only potentiated the anti-B-cell ALL reactions but could do so in conjunction with the common ALL therapeutic, blinatumomab (anti-CD19). 37 with an increased probability of OS. Thus, a possible conclusion from the chemical sequence motif approach is that, with a particular motif, there is a better chance of IR-tumour antigen interaction, and better chance of a T-cell reaction against the tumour.…”

Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers

“…There have been some studies investigating the combination of γδ T cells and bispecific T cell engagers, which have shown improvement in cytotoxicity against several types of cancer. 41 , 42 , 43 , 55 , 56 This study tested a novel technique of expressing sBites in this immune-competent cell, instead of co-administration. Having the cells secrete the sBites offers several advantages over co-infusing the cells with recombinant bispecific T cell engager protein.…”

Allogeneic gamma delta T cells as adoptive cellular therapy for hematologic malignancies

“…Concurrent binding of a BiTE combination results in forming a lytic immune synapse between the cytotoxic T cell and the cancerous target cell. A recent preclinical study by Chen et al [102] showed that combining the CD19-directed BiTE blinatumomab with γδ T-cells improved overall survival in a murine B-ALL model. Previously, Seidel et al [54] had tested both CD19-CD3 and CD19-CD16 using the CD19 antibody 4G7SDIE as its backbone, and showed that the dual antibody constructs could induce cytotoxic reactions from γδ T cells.…”