Immunomodulatory Therapy With Second Mitochondrial Activator of Caspaces Mimetics

Immunomodulatory drugs (IMiDs) are the backbone of conventional therapies for multiple myeloma. This project, Immunomodulatory Therapy With Second Mitochondrial Activator of Caspaces (SMAC) Mimetics, identifies an entirely new and unrelated class of immunomodulator with marked preclinical activity in multiple myeloma.

Inhibitor of apoptosis proteins (IAPs) antagonists have been studied in cancer because of their ability to induce caspase 9 release from XIAP, resulting in apoptosis. The SPORE research team previously identified homozygous deletion of cIAP1 and cIAP2 in multiple myeloma as a mutation that activates the alternative NFkB pathway. This finding provided the first clue about the role of IAPs in the NFkB pathway. The IAP antagonist LCL161 has more than 10 times greater affinity for cIAP1/2 than XIAP.

As expected, this drug has no direct anti-multiple myeloma activity in vitro against multiple myeloma cell lines or primary multiple myeloma samples. However, in the project team's immunocompetent mouse model of multiple myeloma, the drug has marked activity. The in vivo activity is due to activation of the alternative NFkB pathway in tumor-infiltrating innate immune cells (likely macrophages), which together with signaling from IFNβ leads to activation of a cytotoxic program.

Objectives of the immunomodulatory therapy project include:

  • Identifying a new role for SMAC mimetics in cancer therapy as immunomodulators
  • Identifying a new immunomodulator active in an immunocompetent model of multiple myeloma
  • Using an innovative, immunocompetent, genetically engineered mouse model of multiple myeloma (GEMMMM) to dissect out the contribution of host immune cells to drug response
  • Characterizing a tumor-instructed immune cell population that uniquely mediates the anti-tumor activity of LCL161
  • Identifying induced changes in immune activation in patients treated in a phase II clinical trial of LCL161 in multiple myeloma

Anticipated outcomes include:

  • Introducing a new class of immunomodulator into cancer therapy
  • Validating the use of the Vk*MYC GEMMMM for preclinical modeling of immunotherapy
  • Characterizing a unique interaction between multiple myeloma cells and their immune environment