P1362: DEVELOPMENT OF A NOVEL ONCOLYTIC VIRUS -THEO-310 - SPECIALISED FOR TARGETING THE BONE MARROW TUMOUR MICROENVIRONMENT OF MULTIPLE MYELOMA PATIENTS

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: The definition of standard-of-care is rapidly shifting in relapsed refractory multiple myeloma, with the development of new biologics targeting BCMA becoming mainstream. Despite such advances, antigen escape or T cell anergy/ exhaustion results in a significant patient population in need of treatments with differentiated mechanisms not tightly governed by cell surface marker expression. Oncolytic virus therapies can offer this mechanistically distinct approach for myeloma patients, addressing the heterogeneity of the cancer and its microenvironment. Aims: To develop a novel oncolytic virus - THEO-310 - specialised for tackling the bone marrow tumour microenvironment (TME) of advanced late stage myeloma patients. Methods: The efficacy, pharmacokinetics and safety of THEO-310 was assessed using myeloma patient samples, cancer cell lines and in vivo models. Efficacy studies: the cellular fraction of fresh bone marrow aspirates (>10 patients with heterogeneous multicellular TME representative of newly diagnosed and late stage clinical disease) were infected with THEO-310 at clinically relevant doses, and virus induced cell lysis and immune responses were characterised. Pharmacokinetics and safety studies: CD1 immune competent non-tumour bearing mice were injected with THEO-310 intravenously and cytokine responses, blood kinetics and biodistribution were evaluated. Results: THEO-310 demonstrates efficacy in >80% of bone marrow aspirates, across newly diagnosed, relapsed and refractory patients. Superiority to standard of care and ‘best-in-class’ oncolytic virus strains including measles virus was observed in the presence of blood components. The virus replicates, to self-amplify at the tumour site, showing selectivity for the malignant cells over T/ B cell components. THEO-310 alleviates immune suppression in the TME, induces immune stimulatory effects upon cancer cell infection including an upregulation of NK cell degranulation markers and effector T/DC cell responses, as evidenced by increased IFN-gamma levels. THEO-310 has a rare virus capsid composition enabling it to bypass recognition by antiviral antibodies and is stable in whole human blood. Furthermore, the candidate demonstrates systemic safety as shown by IL-6 and MCP-1 levels post IV injection in vivo, whilst exhibiting >40 fold better circulation compared to a clinically validated oncolytic virus strain, thus supporting effective intravenous delivery. Biodistribution shows homing to the major clearance organs within 6 hrs as expected in non-tumour bearing in vivo models. Summary/Conclusion: Taken together, THEO-310 represents a new therapeutic option, with a highly differentiated mechanism independent of BCMA, for myeloma patients with relapsed refractory disease. Keywords: Myeloma, Immunotherapy, Multiple myeloma