Augmented immune targeting of a myeloma-specific tumour antigen.

  • Shortt, Jake (Primary Chief Investigator (PCI))
  • Spencer, Andrew (Chief Investigator (CI))
  • Reynolds, John (Chief Investigator (CI))
  • Johnstone, Ricky W (Chief Investigator (CI))
  • Quach, Hang, St Vincent's Hospital Melbourne, (Chief Investigator (CI))
  • Grigoriadis, George (Chief Investigator (CI))
  • Kalff, Anna, (Chief Investigator (CI))
  • Khong, Tiffany (Chief Investigator (CI))
  • Walker, Patricia Ann, (Associate Investigator (AI))
  • Powell, David (Associate Investigator (AI))

Project: Research

Project Description

Multiple myeloma (MM) is a common incurable plasma-cell (PC) malignancy. Current
treatment combines conventional cytotoxics with novel agents, including the thalidomide analogues (IMiDs). IMiDs modulate tumour immunogenicity while also stimulating host immunity. Evidence suggests a capacity for sustained periods of immune control of MM during the ‘plateau-phase’ of disease remissions. This equilibrium between host immunity and quiescent MM is prolonged by consolidation and/or maintenance IMiD therapy (Kalff et al, Lancet Haematol 2014). However, progressive immunoparesis and drug resistance ultimately lead to refractory relapse. Combinatorial strategies exploiting the capacity of IMiDs to augment anti-MM immunity are required. Immuno-oncology (IO) is rapidly advancing in MM, with the monoclonal antibodies (mAb)daratumumab (anti-CD38) and elotuzumab (anti-SLAMF7) showing efficacy in pivotal clinical trials (Lonial et al, NEJM 2015; Lokhorst et al, NEJM 2015). Whereas single-agent IO treatment has limited efficacy, immunomodulatory combinations dramatically augment activity. Thus there is a pressing requirement for biomarker studies to guide partnerships between IO agents in MM. We have developed MDX1097, a mAb directed against ‘kappa myeloma antigen’ (KMA), a tumour-specific cell surface conformational antigen that (unlike CD38, SLAMF7 or CD138) is exclusively expressed on MM cells, including ‘stem-like’ CD138-ve/CD45+ve populations. IMiDs up-regulate KMA, augmenting antibody dependent cell cytotoxicity (ADCC) vs. MDX1097-treated cells. Phase I/II evaluation demonstrated favorable tolerability and pharmacokinetics, with both paraprotein and FDG-PET responses observed following single infusions in patients with stable disease (SD). We propose to capitalize on early access to MDX1097, performing an investigator-initiated study in combination with lenalidomide (Revlimid, R; LEN) for patients in early relapse. Our study will be annotated by biomarker studies, including immunological readouts, genomic profiling and real-time disease monitoring utilizing cell-free (plasma) tumour DNA (ctDNA). This study will accelerate access for Victorian patients to a promising new IO therapy, while building the rationale for further MDX1097 combination studies.
Short titleMDX1097 in myeloma
StatusFinished
Effective start/end date15/12/1631/12/18