Engineered TNF in primary CNS lymphoma: the results of a pilot clinical trial
A new study, published today in Blood, demonstrates the safety – and shows the first signs of efficacy – of an engineered antitumor drug in the treatment of primary central nervous system lymphomas (PCNSL), a type of blood cancer confined within the CNS and still lacking an effective therapy. The pilot trial was conducted on 12 patients at the IRCCS Ospedale San Raffaele and it was coordinated by Andrés José María Ferreri, head of the Lymphoma Unit. The antitumor drug, a molecule called NGR-hTNF, was developed in over 15 years of research by the laboratory of Angelo Corti, director of the Division of Experimental Oncology of Ospedale San Raffaele and full professor at the Università Vita-Salute San Raffaele. The molecule was then optioned by the biotech Molmed, which supported the study by making it available for free. The results obtained pave the way for further studies that will test the protocol on a larger number of patients.
NGR-hTNF is a genetically modified version of Tumor Necrosis Factor (TNF). TNF is a human protein known for its antitumor activity, but very difficult to use in clinic due to its high toxicity. The intuition of Angelo Corti and his group was to engineer the TNF sequence in order to allow the delivery of extremely low, yet pharmacologically active, doses of the drug to the tumor vasculature, thereby avoiding toxic reaction. To do this, researchers genetically modified the TNF molecule to enable recognition of receptors expressed on tumor blood vessels. «Experimental studies show that NGR-hTNF is able to reach the tumor vessels, to enhance their permeability and, thus, to promote the penetration of anti-tumor drugs and the infiltration of immune cells» explains Angelo Corti.
The efficacy of NGR-hTNF in the treatment of solid tumors was addressed in a number of clinical studies, as the one recently concluded on mesothelioma, which also involved Ospedale San Raffaele. The idea of Ferreri’s group was to use the same molecule to target tumor vessels in patients with PCNSL. This is the first use of the NGR-hTNF in the field of blood cancer and the results are very promising.
12 patients with relapsed/refractory PCNSL were treated by combining NGR-hTNF with the R-CHOP immuno-chemotherapeutic combination, normally used for aggressive lymphomas that occur in other parts of the body, but ineffective in PCNSL due to the blood-brain barrier. In fact, this barrier acts as a filter, preventing drugs from reaching the tumor cells in sufficient amount. Thanks to advanced brain imaging techniques, researchers at San Raffaele showed that NGR-hTNF enhances the barrier permeability in the tumor, thus, allowing for the passage of active amounts of antitumor drugs. As a consequence of this effect, 9 out of 12 treated patients presented a rapid and substantial regression of the lymphoma, without significant toxicity.
«The results obtained exceeds by far our expectations» says Andrés José María Ferreri. «Although this is just a pilot study, which primary aim is to address safety and tolerability of the treatment, it suggests a synergistic effect between NGR-hTNF and immune-chemotherapy, paving the way for further research on a larger population of patients».
The INGRID trial has been supported by a grant of the Leukemia and Lymphoma Society (USA). Registered patients were treated with NGR-hTNF that was kindly provided by Molmed SpA. The original discovery of the NGR-hTNF has been possible thanks to the support of AIRC, the Italian Association for Cancer Research.
Ferreri A.J.M., Calimeri T., Conte GM, Cattaneo D, Fallanca F, Ponzoni M, Scarano E, Curnis F, Nonis A, Lopedote P, Citterio G, Politi L, Foppoli M, Girlanda S, Sassone M, Perrone S, Cecchetti C, Ciceri F, Bordignon C, Corti A, Anzalone N R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor- α in primary CNS lymphoma, Blood, 22 giugno 2019