A trial at the Clínica Universidad de Navarra, in northern Spain, with the participation of the Vall d’Hebron Institute of Oncology (VHIO) in Barcelona (northeastern Spain) has developed a next-generation antibody that could open a treatment for tumors that have been resistant to immunotherapy.
The study, its authors indicate in a statement, has initially demonstrated the ability of the GEN1046 antibody to trigger the antitumor activity in cancer patients, even in those with advanced refractory solid tumors. Some preliminary data that have already been published in the May issue of the scientific journal Cancer Discovery.
The drug GEN1046 has been tested for the first time in a phase I clinical trial in 61 patients with advanced refractory solid tumors and has demonstrated pharmacodynamic immunological effects in peripheral blood consistent with its mechanism of action, manageable toxicity, and early objective clinical activity in highly pretreated patients, including those with tumors resistant to prior anti-PD-(L)-1 immunotherapy.
“Thus, up to 65.6% of the patients experienced control of the disease. The high rate of control of the disease suggests a clinical importance for this population”, indicates Elena Garralda, head of the Group for Early Clinical Development of Drugs at the Vall d’Hebron Institute of Oncology (VHIO).
To verify the effect of GEN1046 on tumor cells, different tests were carried out both in vitro and in animal models that showed that this new drug was capable of achieving tumors insensitive to checkpoint inhibitors would have an answer thanks to its double specificity.
Thus, a powerful antitumor activity was achieved that also conferred protection against inocula of the same tumor in mice and significantly improved the arrival of CD8+ T cells capable of destroying cancer cells in the tumor tissue.
According to Ignacio Melero, co-director of the Immunology and Immunotherapy Service at the University Clinic of Navarra, senior researcher at Cima and senior author of the trial, the GEN1046 antibody “is designed to combine the blockade of the PD-L1 protein with conditional stimulation of the 4-1BB antigen. Therefore, it is capable of deactivating a crucial brake of the immune system (PD-L1) at the same time that it steps on a very important accelerator (4-1BB) capable of activating those cells of the immune system that may be capable of destroying tumor cells” .
And in this sense he adds that, although it has been known for almost two decades that the blockade of PD-L1 cooperates with the stimulation of 4-1BB, “until now we have not been able to do so in patients with a single bispecific drug” and therefore therefore this antibody “could fill a clinical gap for disease treatment refractory to treatment with anti-PD(L)1 checkpoint inhibitors”.
According to these results, the clinical development of the drug continues in a phase 2 study, which is already underway, to provide additional data on efficacy and safety, as well as help define the most appropriate treatment strategies and therefore, “although the results are promising, it is premature to draw conclusions,” warns Melero. (I)