The potential of the CMB305 vaccine regimen to target NY-ESO-1 and improve outcomes for synovial sarcoma and myxoid/round cell liposarcoma patients

Abstract

Introduction: Synovial Sarcoma (SS) and Myxoid Round Cell Liposarcoma (MRCL) are devastating sarcoma subtypes with few treatment options and poor outcomes in the advanced setting. However, both these diseases may be ideal for novel immunotherapies targeting the cancer-testis antigen, NY-ESO-1.

Areas covered: In this review, we discuss the novel NY-ESO-1 targeted vaccine regimen, CMB305. This regimen uses a unique integration-deficient, dendritic-cell targeting lentiviral vector from the ZVex® platform, LV305, in order to prime NY-ESO-1 specific T cells. LV305 has single agent activity, and, in one case, caused a durable partial response in a refractory SS patient. CMB305 also includes a boost from a NY-ESO-1 protein vaccine given along with a potent toll-like-4 receptor agonist, glycopyranosyl lipid A. CMB305 induces NY-ESO-1 specific T cell responses in both SS and MRC patients and these patients had excellent overall survival (OS) outcomes in the initial phase I study.

Expert commentary: CMB305 is a therapeutic vaccine regimen targeting NY-ESO-1 based on the lentiviral vaccine vector, LV305. Phase I studies have proven this vaccine is active immunologically. Data suggesting this vaccine may improve OS for SS and MRCL patients is exciting but early, and on-going work is testing the impact of CMB305 on patient outcomes.

Keywords: CMB305; LV305; Myxoid; NY-ESO-1; Sarcoma; Synovial; dendritic cells; immunotherapy; therapeutic vaccine.

Figure 1.

LV305 mechanism of action. (a) LV305 (green octagon) enters dendritic cells (DC) via specific interaction with DC-SIGN/CD209 (triangle) on the DC surface as a result of the modified Sindbis virus envelope. (b) LV305 is replication incompetent and has only a low level of integration because of the D64V integrase mutation and deletion of the 3ʹ-poly purine tract. (c) NY-ESO-1 is expressed by the DC and processed in the immune-proteasome. Peptides are presented by class I and cross-presented by class II MHC molecules. (d) CD4+ and CD8+ T cells recognizing NY-ESO-1 peptides presented in the context of class I and class II MHC proliferate and produce cytokines. In murine models, these T cells are effective at killing tumors. Full color available online.

Figure 2.

CMB305 schedule. LV305 (blue arrows) is used as the priming agent given for 4 doses, starting day 1 then days 21, 49 and 77. The boosting regimen is called ‘G305’ (red arrows) and starts on day 35 every 4 weeks for three doses and then every 8 weeks for up to 1 year. The G305 regimen includes whole recombinantly expressed NY-ESO-1 protein and the synthetic toll like receptor 4 (TLR4) agonist GLA (Glucopyranosyl lipid A) formulate in a stable oil-in-water emulsion (GLA-SE). Full color available online.