Researchers from the Cima and the Clínica Universidad de Navarrain partnership with the Hospital General Universitario Gregorio Marañón, have completed phase I of the clinical essay of the first immunotherapy developed in Spain. Promoted by the biotech business Highlight Therapeutics, this essay investigates the combination of BO-112 and two anti PD-1 antibodies (nivolumab or pembrolizumab) and has demonstrated its safety and potential to reverse resistance to immunotherapy in cancer patients.

The formulation of BO-112 is based on double-stranded RNA molecules and achieves a direct antitumor response that is in turn enhanced by the activation of innate immunity mechanisms. This immunotherapy treatment is injected directly into the tumor or its metastases.

Patients with melanoma, lung cancer, and renal cancer.

The research with BO-112 was initiated in 16 patients with advanced cancer. It was shown to be safe and changes were observed in biopsies of injected tumors indicating potent activation of the immune system.

In this second phase, BO-112 and anti-PD-1, which are protein inhibitors that increase the ability of T cells to kill cancer cells, were combined. The essay was performed on a group of 28 patients with melanoma, lung cancer and renal cancer for whom previous immunotherapy based on anti PD-1 (nivolumab or pembrolizumab) did not work.

The combination produced a stabilization of the disease in 10 of them and an objective decrease in the size of their tumors in another 3. Of the patients who obtained this benefit, 2 diagnosed with advanced melanoma remain in remission of their disease to date, two years after the start of treatment. In the patients with the greatest benefit, a greater activation of the immune system was demonstrated by molecular analysis than in those patients in whom the combination did not work.

According to Dr. Ignacio Melero, researcher senior at the Immunotherapy Service of Cima and Clínica Universidad de Navarra and co-director of project, "we have shown that the best way to use this compound is to inject it into the tumors, because inside the lesions it mimics a viral infection very well and makes the immune system believe that it has to fight against a virus infection in the tumor tissue".

"If the results at programs of study are confirmed, this intratumoral treatment strategy with BO-112 could help to reverse primary resistance to immunotherapy, a problem faced by between a third and half of the patients who are treated with anti PD-1-based immunotherapy and for which we need therapeutic alternatives. The next step is to advance in defining the profile of the patient who can benefit most and in the study of biomarkers that help in this selection", points out Dr. Iván Márquez Rodas, of the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón and co-director of project.

This work has also counted with the participation of 5 other Spanish hospitals (Ramón y Cajal, 12 de Octubre, QuirónSalud Madrid, ICO Barcelona and Virgen de la Victoria in Málaga).  

Launching of new clinical trials

As a result of these results, several clinical trials have been launched, both in Spain and abroad, which will continue to study the role of BO-112 in combination with immunotherapy in the treatment of cancer. "Specifically, Dr. Melero points out, in Spain we are developing new clinical trials that focus on the treatment of liver metastases of various types of tumors. There are also advanced plans to begin treatment of patients with melanoma who have shown resistance to treatment with anti-PD 1 antibodies, which is the standard immunotherapy for this disease."

These results are really important since they would pave the way for the commercialization of the product, should it prove to be effective. "This is a very promising approach in the field of cancer immunotherapy, which is included in the use of intratumoral immunostimulatory agents. At least twenty agents are being tested in patients by this novel route, making this a highly competitive research field ." association The Spanish Agency Against Cancer (AECC) is collaborating in the further development of this therapeutic strategy.

The results have been published in the journal Science Translational Medicine¹. In the same journal issue , the group of research led by Dr. Antoni Ribas, at the University of California Los Angeles (UCLA), has published research conducted by Dr. Anusha Kalbasi and collaborators that delves into new mechanisms of action of BO-112 in animal ^models2. According to Dr. Antoni Ribas "BO-112 is like lighting a fire with a match that works on wet wood", since BO-112 has the ability to initiate antitumor responses in models of resistance to other immunotherapies.
 

REFERENCES:

^1. I. Marquez-Rodas, F. Longo, M. E. Rodriguez-Ruiz, A. Calles, S. Ponce, M. Jove, B. Rubio-Viqueira, J. L. Perez-Gracia, A. Gomez-Rueda, S. Lopez-Tarruella, M. Ponz-Sarvise, R. Alvarez, A. Soria-Rivas, E. de Miguel, R. Ramos-Medina, E. Castanon, P. Gajate, C. Sempere-Ortega, E. Jimenez-Aguilar, M. A. Aznar, A. Calvo, P. P. Lopez-Casas, S. Martin-Algarra, M. Martin, D. Tersago, M. Quintero, I. Melero, Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci. Transl. Med. 12, eabb0391 (2020).

^2. A. Kalbasi, M. Tariveranmoshabad, K. Hakimi, S. Kremer, K. M. Campbell, J. M. Funes, A. Vega-Crespo, G. Parisi, A. Champekar, C. Nguyen, D. Torrejon, D. Shin, J. M. Zaretsky, R. D. D. Damoiseaux, D. E. Speiser, P. P. Lopez-Casas, M. Quintero, A. Ribas, Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma. Sci. Transl. Med. (2020) doi:10.1126/scitranslmed.abb0152.