Barcelona, July 27, 2020.– Primary central nervous system (CNS) lymphoma is a rare, highly aggressive tumor type whose biological characteristics unfortunately result in a poor prognosis and suboptimal response of patients to currently available therapies. The combination of Selinexor, an XPO1 protein inhibitor, plus Ibrutinib, a BTK protein inhibitor, has now merged as a promising new therapeutic avenue, as evidenced in PDX mouse models and recently reported in a VHIO-led study, first authored by Isabel Jiménez, Júlia Carabia, Francesc Bosch and Marta Crespo in collaboration with pathology and neurosurgery Vall d’Hebron departments and VHIO’s Translational Research Program, published in the Journal of Neuro-Oncology.
Findings show preclinical evidence supporting the combination of these two drugs as a much-needed therapeutic alternative. “This combinatorial therapeutic strategy not only showed a direct cytotoxic effect on malignant cells, but also favored an innate antitumor immune response. We have therefore have demonstrated that the combination of killing malignant cancer cells and boosting the antitumor activity of macrophages is a promising approach, warranting further exploration in future clinical trials,” observes Marta Crespo, Translational Research Coordinator of VHIO’s Experimental Hematology Group directed by Francesc Bosch, and coordinator of this present paper.
A tumor with a poor prognosis
Primary central nervous system (CNS) lymphoma is a rare, aggressive non-Hodgkin lymphoma that accounts for 4% of all brain tumors and between 4-6% of extranodal lymphomas. Due to the biological characteristics of the tumor, high doses of chemotherapy are required for treatment to cross the blood brain barrier, in combination with monoclonal antibodies and, occasionally, brain radiation. “However, patients generally respond poorly to therapy, with frequent disease relapse and a 5-year survival rate of only 30%,” adds Francesc Bosch, Principal Investigator of VHIO’s Experimental Hematology Group, and one of the authors of the study.
This type of lymphoma develops in a microenvironment that may contribute to the lack of response of the immune system in fighting tumor cells. In addition, a high proportion of these patients bear genetic mutations that prevent immune T-cells from identifying tumor cells. The inability of certain therapies to pass the blood brain barrier might also partially explain poor prognosis.
Mice models to assess response to treatment
Factoring in the specificities of lymphoma, Marta Crespo’s team hypothesized that the use of a small molecule that could cross the blood brain barrier, the XPO1 inhibitor, Selinexor, might prevent the proliferation of tumor cells. This drug was recently approved and is used to treat patients with multiple myeloma and patients with recurrent or refractory diffuse large B-cell lymphoma.
To provide a preclinical rationale for the design of new therapeutic strategies for patients with primary CNS lymphoma, the study was developed to assess inhibition induced by selinexor in PDX mouse models. “Our results show that this anti-cancer therapy blocks tumor growth and increases survival in PDX mouse models”, comments Isabel Jiménez, first co-author of the study and PhD student of the same group.
The combination of selinexor and ibrutinib was also tested while ibrutinib is already being used in this population of patients as monotherapy, it only induces a short-term response. “This combination further extended survival, with a direct cytotoxic effect on malignant cells, and also promoting an antitumor immune response by changing polarization in tumor-infiltrating macrophages to inflammatory M1″, concludes Marta Crespo.
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Reference:
Jiménez, I., Carabia, J., Bobillo, S. et al. Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition. J Neurooncol (2020). https://doi.org/10.1007/s11060-020-03580-y
