Studies into the immune effects of a novel engineered tumour-specific Adenovirus in plasma cell neoplasms

Plasma cell neoplasms comprise multiple myeloma (MM) and plasmacytoma which are caused by the proliferation of malignant plasma cells in the bone marrow and extra-osseous tissue. Despite significant improvements in drug development, tumour recurrence remains a major challenge due to drug resistance. Therefore, novel treatment strategies are needed. Oncolytic virotherapy is an emerging treatment in several cancers, in addition to directly lysing tumour cells, some oncolytic viruses (OVs) can activate and amplify immune responses, increasing anti-tumour efficacy. Previously the Sheffield Myeloma Research Team genetically engineered an oncolytic adenovirus (Ad[SLAMF7 E1A]/CE1A) and demonstrated its efficacy against myeloma cells by direct lysis in vitro and reduced tumour burden in vivo. In this project we hypothesised Ad[CE1A] educates the immune system against MM, inducing beneficial anti-tumour immunity. Therefore, the aim of this PhD was to characterize the therapeutic effects and immune regulation of Ad[CE1A] in myeloma and the tumour microenvironments in vivo and ex vivo.

Our data revealed that Ad[CE1A] substantially reduced tumour burden in a syngeneic myeloma mouse model and induced an anti-tumour immune response in both primary patient cells and preclinical mouse models. In a 5TGM1 plasmacytoma model, Ad[CE1A] significantly enhanced Natural Killer (NK) cell degranulation in the tumour microenvironment and stimulated the redistribution of activated NK cells to the tumour site. These findings inspired further exploration of Ad[CE1A]'s efficacy in myeloma patient samples and in a systemic mouse model. Ad[CE1A] was observed to significantly increase the activation and degranulation of T and NK cells in bone marrow samples from both patients and mice. Moreover, impact on exhaustion markers were mixed, decreasing the expression of LAG-3 and CTLA-4 on lymphocytes, while increasing the expression of programmed death-1（PD-1） on T cells. Additionally, Ad[CE1A] reduced the number of Tregs throughout disease progression.

In summary, these results provide insight into the mechanisms of Ad[CE1A]'s immune regulatory effects in the tumour microenvironment, highlighting the potential of OVs as promising therapeutics for the treatment of patients with MM.