A Phase 1 trial to treat advanced solid tumors has dosed its first patient with a combination of AGEN1181, a next generation CTLA-4 inhibitor, and the PD-1 inhibitor balstilimab — two immune checkpoint inhibitors developed by Agenus.
The dose escalation trial (NCT03860272) is testing a AGEN1181 as a stand-alone treatment, and in combination with balstilimab, in people whose cancer has spread to nearby lymph nodes or to distant regions of the body. Another enrolled patient was the first to be treated with AGEN1181 alone.
Both were dosed at the John Wayne Cancer Institute and Cancer Clinic, one of the five US clinical sites where the trial is taking place. Additional sites include the HonorHealth Research Institute, the University of Southern California Norris Comprehensive Cancer Center, the Beth Israel Deaconess Medical Center, and The University of Texas Health Science Center.
These treatments are designed to harness the body’s immune response by blocking proteins involved in mechanisms used by cancer cells to evade immune system attack. Balstilimab and AGEN1181 both target proteins found on T-cells (immune cells involved in fighting cancer), but while PD-1 inhibitors are meant to remove the ‘brakes’ from these cells, CTLA-4 inhibitors work to increase their expansion.
AGEN1181 has additional benefits compared to traditional, first-generation CTLA-4 inhibitors, Agenus states. By binding with stronger affinity to a specific receptor, its therapy aims to improve the cross-talk between T-cells and other immune system cells needed for a robust anti-cancer response, enabling the optimal activation of T-cells and the formation of memory immune responses.
The treatment is designed to deplete immunosuppressive cells in tumors, potentially further increasing immune system responses. AGEN1181 may also help an additional 40% of these cancer patients because of a binding ability that’s superior to earlier versions of this molecule, the company reports.
“AGEN1181, with its potential for enhanced immune activation and tumor fighting abilities, may bring superior benefit to a broader group of patients compared to first generation anti-CTLA-4 antibodies,” Steve O’Day, executive director of the John Wayne Cancer Institute & Cancer Clinic, said in a press release. “The pre-clinical data suggest the superiority of this molecule as a monotherapy and in combination with anti-PD-1, like balstilimab.”
The ongoing Phase 1 trial aims to enroll up to 86 people with locally advanced or metastatic solid cancer, and is currently recruiting at each of its five sites.
Patients will be given ascending doses of AGEN1181 — between 0.1 mg/kg and 4 mg/kg by intravenous injection — alone or in combination with a fixed dose of balstilimab.
Those in the monotherapy group will receive AGEN1181 injections every three or every six weeks. Those in the combination group will be given AGEN1181 every six weeks, and balstilimab every two weeks.
The trial’s primary goal is to determine treatment safety — measured via reported adverse events and dose-limiting toxicities — and to establish an optimal AGEN1181 dose for additional testing. Secondary measures include the proportion of patients responding to treatment, duration of response, time to disease progression or death, and overall survival.
“Expanding the important immune priming benefit of CTLA-4 to a broad group of patients would be outstanding. I am thrilled to be working with this compound,” O’Day said.