Leveraging doxorubicin immune-modulation, blood-brain barrier opening, and personalized medicine for effective immunotherapy in glioblastoma. A mechanistic approach and pharmacokinetic trial.

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ABSTRACT Despite preclinical promise and occasional long(er) term tumor growth control in subsets of patients, anti-PD1 checkpoint blockade (aPD1) has failed to improve outcome in glioblastoma (GBM). The failure to demonstrate a benefit to an anti-PD1 antibody (aPD1) may be due to 1) an immunosuppressive microenvironment with few immunogenic tumor cells; 2) insufficient aPD1 penetration across the blood-brain barrier (BBB), which fail to reach the infiltrating tumor cells in the peritumoral brain; and 3) molecular heterogeneity of GBM. Here we systematically address each of these challenges. We aim to elicit robust anti-tumoral response to Balstilimab (Agenus Bio), a novel aPD1 antibody by modulating the immune response by low doses of doxorubicin as has been shown previously. To allow for adequate drug tissue penetration, we will transiently disrupt the blood-brain barrier by a skull implantable ultrasound device (SonoCloud-9) in association with intravenous microbubbles (US/MB). In our ongoing research and clinical trials we have shown the feasibility of this approach including targeted biopsies of enhancing and non-enhancing tissue and measure drug tissue distribution. Lastly, we aim at identifying molecular characteristics that will allow to predict a benefit from aPD1 immunotherapy based on our prior work where we have identified MAPK activation (pERK staining) as a putative biomarker. We will firstly refine the sequence of DOX & aPD1 administration in preclinical models. Second, for verification and optimization we will treat a few pilot patients in the lead-in phase of our trial. Third, the optimized regimen will be tested in a multi-cohort study in patients with recurrent GBM who will be treated by DOX and the aPD1 Balstilimab (DOX+aPD1). Primary endpoints are tumor immune response in the resection specimen and/or peripheral immune response, drug concentrations in enhancing and non-enhancing brain tissue (targeted biopsies at the time of resection) and safety. Clinical outcome and biomarkers are secondary endpoints. Four cohorts of patient will be examined where DOX/aPD1 treatment starts at different time points: Induction (neoadjuvant, prior to resection); or intraoperatively upon resection, each with and without US/MB. A non-interventional standard of care cohort will serve as control. Our proposal has 3 specific aims: SA1: Characterize & optimize the effect of DOX + aPD1 on anti-tumoral immunity in GBM. SA2: Determine the effect of US/MB on the concentration of DOX + aPD1 in the human brain and anti-tumoral immune response in GBM. SA3: Investigate whether tumor pERK/MAPK activation predicts GBM response to DOX + aPD1. Successful completion will determine the i) value of immune modulation by DOX and aPD1; ii) the value of induction (pre-resection) treatment and in vivo evaluation of anti-tumor immune response; iii) the value (or absence thereof) of BBB-opening for aPD1 efficacy; and iv) whether pERK predicts response and identifies patients that will benefit from treatment.