Direct Visualisation of BCMA Bispecific Antibody and the Myeloma Immune Microenvironment

Introduction: Multiple myeloma is haematological malignancy that remains difficult to cure despite recent therapeutic advances. Novel T cell redirecting therapies such as CAR-T cells and bispecific antibodies have shown promising efficacy in the relapse setting However, durable responses have yet to be achieved. Mechanisms of resistance and the dynamics of immune cell interactions within the bone marrow remain poorly defined. Here, we used in situ imaging of the bone marrow in living mice (intravital imaging) to characterise immune cell interactions with myeloma in the context of murine BCMA bispecific antibody therapy.

Methods: We used a traceable myeloma cell line derived from the spontaneous Vk*MYC mouse model (Vk14451-GFP) that recapitulates human disease. To visualise the cytotoxic immune response, Vk14451 cells were transplanted into recipient mice where CD8 T cells were labelled with fluorescent tomato protein (E8I-Cre tomato). >Five weeks post-transplant, multi-day intravital imaging of the calvarium bone marrow was performed using 2-photon microscopy. This imaging approach was performed in the absence or presence of murine BCMA bispecific antibody. Mice were treated with 1 to 4 doses of the bispecifc antibody to visualise immune and myeloma responses.

Results: Direct visualisation of T cells in situ in the absence of therapeutic intervention revealed CD8 T cells were excluded from areas of myeloma infiltration. Furthermore, CD8 T cells that gained entry to tumour had significantly altered cell interactions compared to T cells in healthy bone marrow. Following administration of a dose of bispecific antibody, we observed drastic changes in the biology and spatial distribution of CD8 T cells within the bone marrow. Surprisingly, following activation the immunosuppressive myeloma microenvironment had no effect on the ability of CD8 T cells to engage with myeloma cells within tumour foci and undergo rapid expansion. However, we observed significant changes in the persistence of T cells within the myeloma foci. In addition, in cohorts of mice that received repeated dosing of bispecific antibody, we observed loss of tumour control. In these mice, we still observed access of T cells to the tumour foci and active proliferation. However, we did not observe sustained interactions and active killing of MM cells suggesting development of a tumour agnostic state of T cells.

Conclusion: This dynamic analysis of immune cell interactions with myeloma within the bone marrow microenvironment suggests that targeting persistence of activated T cells may play a key role in the therapeutic efficacy of T cell redirecting therapies.

Declaration: This research was supported by Bristol Myers Squibb. The company had no role in analysing the data or preparing the abstract