PF558 THE ANTI-BCMA ANTIBODY-DRUG CONJUGATE GSK2857916 DRIVES IMMUNOGENIC CELL DEATH AND IMMUNE-MEDIATED ANTI-TUMOR RESPONSES, AND IN COMBINATION WITH AN OX40 AGONIST POTENTIATES IN VIVO ACTIVITY

Abstract

Background: Multiple myeloma (MM) is the second most common hematological malignancy and remains an incurable disease. Therefore, novel targeted therapies are in need. Achieving a 60% overall response rate in a phase 1 clinical trial for relapsed and refractory multiple myeloma patients, GSK2857916 is a promising drug candidate that targets the B-cell Maturation Antigen (BCMA) protein, expressed almost exclusively in multiple myeloma cells. GSK2857916 is an antibody-drug conjugate (ADC) consisting of a humanized anti BCMA monoclonal antibody that is conjugated to monomethyl auristatin-F (MMAF). MMAF is a member of the dolastatin family of microtubule inhibitors, which are potent antitumor agents also linked to immunogenic cell death (ICD), a type of cell death that can stimulate host immune responses. Pre-clinically, GSK2857916 was shown to mediate anti-tumor activity through several mechanisms including (a) induction of apoptosis, following the intracellular release of active cytotoxic drug conjugate Cys-mcMMAF, and (b) enhanced antibody-dependent cellular cytotoxicity (ADCC) as a result of the ‘engineered’ afucosylation of the antibody. Aims: The goal of these studies was to explore potential GSK2857916 immune-modulatory activities as single agent and in combination with immune-modulators. Methods: We developed cell-based assays and a subcutaneous syngeneic tumor model engineered to express human BCMA (EL4-hBCMA lymphoma) to assess GSK2857916 immune-mediated anti-tumor activity. Results: We report that GSK2857916 induces hallmarks of ICD in vivo and in vitro, such as cell surface expression of calreticulin and other ER stress response proteins, and secretion of HMGB1. In the immune-competent EL4-hBCMA tumor model, we examined the contribution of MMAF, as part of the GSK2857916 molecule, in driving adaptive immune responses by comparing the non-conjugated antibody to the ADC. We show that GSK2857916 treatment inhibits tumor growth and induces durable complete responses in mice carrying EL4-hBCMA tumors. Responding animals are immune resistant to re-challenge with parental EL4 and EL4-hBCMA tumor cells, suggesting an engagement of the host immune system, immunologic memory and tumor antigen spreading. Indeed, in this model, durable anti-tumor activity by GSK2857916 is characterized by T, NK and dendritic cell infiltration and increased ICD markers, and is abrogated upon depletion of CD8+ T-cells. Given the potential of GSK2857916 to mediate anti-tumor activity through the immune system, there is rationale to evaluate combinations with immune-modulatory therapies. One of these immune-modulators, OX40, is a co-stimulatory molecule that can stimulate T-cells against cancer cells. We evaluated combinations of GSK2857916 with a murine anti-OX40 (OX86) agonist antibody and demonstrated increased infiltration and activation of intratumoral dendritic and T-cells, antigen presenting T-cells and hallmarks of ICD, leading to statistically significant superior anti-tumor activity and increased durable complete responses over single agents. Summary/Conclusion: Our in vitro and in vivo results support immunogenic cell death and/or immune-modulation as a novel mechanism of action for GSK2857916 and provide rationale for clinical combinations with various immune-modulatory therapies.