GEN1046 is a bispecific antibody – a molecule that can join two different antigens at the same time – which is being developed to offer an alternative for patients with advanced solid immune checkpoint inhibitor-refractory or relapsed tumours. A recent study published in the journal Cancer Discovery gives the results of the Phase 1 GCT 1046-01 clinical trial, conducted by the Clínica Universidad de Navarra (CUN) with the participation of the Vall d’Hebron Institute of Oncology (VHIO) – which is part of the Vall d’Hebron Campus, which show promising results encouraging the view that this new drug may fill a clinical gap and succeed in meeting the challenge to using 1-4BB therapeutic targeting.
Dr Elena Garralda, the head of the Early Clinical Drug Development Group at the Vall d’Hebron Institute of Oncology (VHIO), which is part of the Vall d’Hebron Campus, and the Director of the Cancer Molecular Therapy Research Unit (UTIM)-CaixaResearch, and Dr Guzmán Alonso, who is also at the UITM-CaixaResearch, took part in this research work. “GEN1046’s capacity for conferring a clinical benefit in patients with tumours that are typically less sensitive to immunotherapy may offer an alternative for the disease”, Dr Elena Garralda herself points out. She played a notable part in this research, as it was the Cancer Molecular Therapy Research Unit (UTIM)-CaixaResearch that included the most patients in the trial while, at the same time, contributing to the design of the study.
Dr Ignacio Melero, the co-director of the Immunology and Immunotherapy Department at the Clínica Universidad de Navarra and a senior researcher at the CIMA was the person who led this first clinical trial. According to him, “GEN1046 has a manageable safety profile and is very promising from the point of view of observed efficacy in some patients treated in this Phase 1 clinical trial. This new agent may fill a clinical gap for treating refractory or relapsed disease following treatment with anti-PD(L)1 checkpoint inhibitors”.
To verify the effect of GEN1046 on tumour cells, several tests, both in vitro and on animal models, were conducted. These showed that this new drug was capable of getting tumours that were not sensitive to checkpoint inhibitors to respond, thanks to its double specificity. Potent anti-tumour activity was achieved which would confer protection against inoculations of the same tumour in mice and significantly improved the number of T CD8+ cells reaching tumour tissue capable of destroying cancerous cells. “This may be attributed to the combination of the PD-L1 blockade, together with agonistic activity on 4-1BB, in other words, an activity stimulating the immune system, as the PD-L1 blockade alone with a durvalumab analogue, an anti-PD-L1 monoclonal antibody, did not achieve this effect”, notes Dr Elena Garralda herself points out.
The drug GEN1046 was also tested for the first time in the Phase 1 clinical trial on 61 patients with advanced solid refractory tumours. Here the drug demonstrated immunological-pharmacodynamic effects on peripheral blood consistent with its action mechanism, manageable toxicity and early objective clinical activity in heavily pre-treated patients, including patients with tumours resistant to prior PD-(L)1 immunotherapy. “Therefore, up to 65.6% of patients experienced disease control. The high disease control rate suggests clinical significance for this population of heavily pre-treated patients with limited response to their last line of treatment”, adds Dr Elena Garralda herself points out.
Immune checkpoint inhibitors are a normal part of the immune system, tasked with preventing the latter’s response from being so strong that it destroys healthy cells in the body. The mechanism is exploited by tumour cells to escape the immune system, by sending an “off” signal to T-cells, a type of white blood cell that helps to protect the body from infections and fight off cancer. Checkpoint inhibitors operate by blocking the proteins used by tumour cells to emit this “off” signal, so that T-cells are then capable of destroying them.
One of the proteins with the most results for developing targeted treatments is PD-1, a programmed cell-death receptor, and its ligand PD-L1. The inhibitors that have it as their target have transformed cancer treatment and become the standard of care in various solid tumours. Not all patients, however, respond to this treatment; and of those who respond, some do so only transiently. Hence the need to develop new regimes targeting complementary immuno-regulatory pathways capable of improving effective immune responses against tumours.
On the other hand, some immunotherapy treatments with initially promising results were the ones developed using 4-1BB targeting agents, which obtained good results in pre-clinical and clinical studies. This is a differentiation antigen selectively expressed on the surface of activated T lymphocytes and natural killer (NK) and on dendritic cells. The monoclonal antibodies acting as artificial ligands stimulating this receptor demonstrated that they boosted anti-tumour and anti-viral immunity in animal models. If we go back to the checkpoint-brake analogy, 4-1BB would be the accelerator pedal.
“Its clinical development, however, was hampered by several problems. Some of them, used in monotherapy, showed a dose-limiting hepato-toxicity, while others with a better toxicity profile demonstrated limited anti-tumour activity. It is a targeting agent in great demand in oncology because of its capacity for accelerating the immune system, but no one had succeeded in using it properly”, explains Dr Guzmán Alonso.
One of the main new developments that GEN1046 presents is that, as a bispecific drug, it combines these two distinct mechanisms, making it a dual inhibitor. It removes the immune system’s brakes on the one hand and on the other helps to boost its activity. “But this acceleration only occurs when there is PD-L1 present in cells, which helps to reduce toxicity, a big obstacle that had been facing us with drugs using 4-1BB as their targeting agent”, comments Dr Elena Garralda herself points out.
In summary, GEN1046 appears to have a better hepato-toxicity profile than the profile associated with 4-1BB targeted therapies, besides showing a clinical benefit in patients with several types of tumours, including those less sensitive to immune checkpoint inhibitors. All these results have justified a Phase II trial, which is currently in progress, which will provide additional efficacy and safety data, as well as exploratory analyses of possible response biomarkers that will help to define the most appropriate treatment strategies in those using this new drug.
In accordance with these observed results, the clinical development of the drug is continuing in a Phase 2 study, which is now in progress, to provide additional efficacy and safety data, as well as define the most appropriate treatment strategies. Dr Melero, the trial’s senior author, highlights how “although the results are promising, it would be premature to draw conclusions on efficacy until we have the results of the Phase 2 clinical trials currently in progress”.
References:
Alexander Muik, Elena Garralda, Isil Altintas, Friederike Gieseke, Ravit Geva, Eytan Ben-Ami, Corinne Maurice-Dror, Emiliano, Patricia M. LoRusso, Guzman Alonso, Maria E. Rodriguez-Ruiz, Kristina B. Schoedel, Jordan M. Blum, Bianca Sänger, Theodora W. Salcedo, Saskia M. Burm, Eliana Stanganello, Dennis Verzijl, Fulvia Vascotto, Angelica Sette, Juliane Quinkhardt, Theo S. Plantinga, Aras Toker, Edward N. van den Brink, Mark Fereshteh, Mustafa Diken, David Satijn, Sebastian Kreiter, Esther C.W. Breij, Gaurav Bajaj, Eleni Lagkadinou, Kate Sasser, Özlem Türeci, Ulf Forssmann, Tahamtan Ahmadi, Uğur Şahin, Maria Jure-Kunkel, Ignacio Melero. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors. Cancer Discov OF1–OF18. https://doi.org/10.1158/2159-8290.CD-21-1345
Image: Dr Elena Garralda
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