Towards Risk-Adapted Therapeutic Strategies in CNS Lymphoma
James Rubenstein
MD, PhDUniversity of California, San Francisco
Project Term: July 1, 2024 - June 30, 2027
This project will significantly advance the treatment and prevention of CNS lymphomas in two key areas. One, we will further develop and validate candidate genomic biomarkers that identify high risk disease and that are useful in risk stratification in future clinical investigations in primary CNS lymphoma. Two, we will evaluate novel pharmacologic interventions that we hypothesize will: a) potentiate both the anti-lymphoma immune response, including agonists of the toll like receptor 7 and 8 pathway, as well as the combination of the anti-CD19 monoclonal antibody tafasitamab plus lenalidomide; and b) antagonize the NFkB pathway, via the orally-administered BTK degrader, Nx-5948, that we have demonstrated to be active in preclinical models using patient-derived CNS lymphomas.
"In this research we will significantly advance the treatment and prevention of CNS lymphoma via four key investigations. First, we will address the unmet clinical need for genetic biomarkers that identify those patients with newly-diagnosed primary CNS lymphoma (PCNSL) at high risk of progression, both during standard induction with methotrexate as well as after dose-intensive consolidations including bone marrow transplantation. This approach will facilitate a precision-based approach to therapy in which high risk patients are treated early with interventions designed to prevent disease progression. We will build upon our discovery that identified high-risk genomic loci, chromosome 6p as well as tumor suppressors BTG1 and ETV6, and will evaluate these and other genomic biomarkers in diagnostic specimens of PCNSL using independent cohorts, including subjects that participated in clinical trials Alliance 51101 and A51901. Results of these studies will have immediate impact in the design of the next generation of clinical trials in PCNSL.
Second, based on our preliminary data, we will test the hypothesis that pharmacologic interventions increase the expression of antigen presentation molecules localized to 6p, including TAP-1 and HLA molecules, and test the hypothesis that novel agents that stimulate immune stimulatory molecules, toll like receptors 7 and 8, that we discovered to be expressed by tumor-associated macrophages in these tumors, potentiate anti-tumor immune responses and survival prolongation in CNS lymphoma. These studies will be performed using preclinical models with potential to translate to early phase investigations in CNS lymphoma.
Three, based on the recent discovery of the expression of the B-cell marker CD19 by mural cells within the blood-brain barrier, and our preliminary data demonstrating activity of the anti-CD19 monoclonal antibody tafasitamab in relapsed, lenalidomide-resistant CNS lymphomas, we have initiated a phase I/II multicenter trial of tafasitamab plus lenalidomide in relapsed CNS lymphoma, NCT05351593. Here we will test hypotheses that tafasitamab, via interactions with perivascular CD19, may potentiate blood-brain barrier disruption and thus enhance CNS penetration of lenalidomide, determine safety of tafasitamab plus lenalidomide, and evaluate activity in relapsed primary CNS lymphoma. We will investigate impact of tafasitamab plus lenalidomide on immune responses in patients in correlation with outcome. These studies will have significant implications for the treatment of PCNSL and the protection of patients at risk for secondary CNS lymphoma.
Four, based on our data demonstrating the efficacy and CNS penetration of the BTK degrader Nx-5948 in patient-derived xenografts of CNS lymphoma that contain high risk mutations involving ETV6 and BTG1 as preclinical models of CNS lymphoma, we will evaluate oral Nx-5948 in a cohort of patients with relapsed/refractory PCNSL.