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Experimental Agent May Stimulate Immune System in Multiple Myeloma Patients

Experimental Agent May Stimulate Immune System in Multiple Myeloma Patients

Researchers at the Mayo Clinic are reporting that they have identified a new therapy that shrinks tumors in patients with multiple myeloma (MM). They conducted a small study with 25 MM patients and found an experimental drug (LCL161), which is a small-molecule IAP (inhibitor of apoptosis proteins) antagonist, stimulates the immune system and shrinks tumors in patients affected by MM. The findings, which are published in Nature Medicine, suggest a potential new combination therapy for MM patients.

The results from this study are rather encouraging and so the team will now conduct a follow-up clinical trial of LCL161 in combination with an immune checkpoint inhibitor that has been widely used in many cancer treatments. The investigators are hoping that LCL161 could represent a potential new treatment approach that significantly improves survival rates.

“The drug, LCL161, was initially developed to promote tumor death,” said lead study author Marta Chesi, PhD, a biochemist at Mayo Clinic in Phoenix. “However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreigner invaders and eliminates them.”

Chesi and colleagues report that the cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers. Due to their role in the evasion of apoptosis, both are being eyed as potential therapeutic targets in multiple malignancies. Currently, small-molecule IAP antagonists similar to LCL161 are being evaluated for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells.

In this current study, Chesi et al. report that cIAP1 and cIAP2 are recurrently homozygously deleted in MM. Subsequently, this deletion results in the apparent constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. The researchers report they were surprised to observe robust in vivo antimyeloma activity of LCL161 in a transgenic myeloma mouse model. They also found robust activity in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival (PFS) of 10 months.

LCL161 appeared to result in the upregulation of tumor cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response. The effect was strong enough to activate macrophages and dendritic cells. This led to phagocytosis of tumor cells. In this current study, treatment of a MM mouse model with LCL161 established long-term antitumor protection. The agent was able to induce regression in a fraction of the mice. However, the combination of LCL161 with an immune checkpoint inhibitor anti-PD1 was curative in all of the treated mice.

The finding that LCL161 is active against multiple myeloma suggests that similar small-molecule IAP antagonists may have broader clinical activity than previously thought, according to the researchers.

                                                                       

 

 

 
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