Experimental LCL161 Combo Therapy Boosts Immunity and Shrinks Tumors in Myeloma Patients
By activating the immune system, the experimental drug LCL161 has the potential to fight myeloma in both mice and humans, according to a new study by researchers at the Mayo Clinic.
The study, “IAP antagonists induce anti-tumor immunity in multiple myeloma,” appeared in Nature Medicine.
The cellular inhibitors of apoptosis (cIAPs), proteins that allow cells to evade death, are amplified in about 3 percent of cancers and have been identified as possible therapeutic targets to treat cancer patients. But previous studies have suggested that cIAPs play a dual role in cancer, with some cancers like myeloma, rendering these proteins inactive.
Researchers hypothesized that inactivating cIAPs in myeloma patients would enable tumor growth by promoting uncontrolled proliferation of B-cells. But their results showed otherwise. While treating myeloma cells with LCL161, an experimental cIAP inhibitor, didn’t kill cells, treating myeloma-diseased mice with LCL161 did reduce the tumor burden when compared to that observed in response to standard-of-care myeloma therapies.
The animal model researchers used had been previously validated as a model for predicting drug activity in myeloma. That underscored LCL161’s value as a promising anti-myeloma agent.
“The model for preclinical studies to predict with great accuracy which drugs would work in the clinic was developed a decade ago,” Mayo Clinic biochemist Marta Chesi, PhD, said in a news release. “And it has been instrumental in the prioritization of which experimental therapeutics should be tested in patients with multiple myeloma.”
The team conducted a Phase 2 clinical trial (NCT01955434), designed to evaluate the efficacy of LCL161 in relapsed or refractory myeloma patients. Among the 25 patients enrolled in the study, 44 percent had high-risk features and 72 percent had refractory disease that had progressed during their last line of therapy.
The study was designed to add cyclophosphamide if patients had disease progression, or lacked a response after eight weeks of LCL161 monotherapy.
While no patients responded to single-agent LCL161, five patients responded following the addition of cyclophosphamide. The median progression-free survival was 10 months.
Further experiments in mice revealed that LCL161’s anti-tumor activity was not a result of direct induction of tumor cell death, but rather induced a strong inflammatory response that activated the body’s first line of defense — macrophages and dendritic cells which engulfed tumor cells.
The findings suggested that combining LCL161 with immune checkpoint inhibitors that boost the immune system could potentially treat myeloma, as it induced tumor regression in a fraction of treated mice. Mayo Clinic researchers now plan a follow-up trial of LCL161 with immune checkpoint inhibitors in myeloma patients.