Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses

Abstract

Purpose: Malignant gliomas have a highly immune-suppressive tumor microenvironment (TME) which renders them largely unresponsive to conventional therapeutics. Therefore, the current study evaluated a therapeutic protocol designed to overcome the immune barrier by combining myeloid cell–targeted immunotherapy with tumor vaccination. Experimental Design: We utilized a spontaneously occurring canine glioma model to investigate an oral TME modifying immunotherapy in conjunction with cancer stem cell (CSC) vaccination. Dogs were treated daily with losartan (monocyte migration inhibitor) and propranolol (myeloid-derived suppressor cell depleting agent) plus anti-CSC vaccination on a biweekly then monthly schedule. Tumor volume was monitored by MRI and correlated with patient immune responses. Results: Ten dogs with histologically confirmed gliomas were enrolled into a prospective, open-label clinical trial to evaluate the immunotherapy protocol. Partial tumor regression was observed in 2 dogs, while 6 dogs experienced stable disease, for an overall clinical benefit rate of 80%. Overall survival times (median = 351 days) and progression-free intervals (median = 163 days) were comparable with prior studies evaluating surgical debulking followed by immunotherapy. Dogs with detectable anti-CSC antibody responses had an increased overall survival time relative to dogs that did not generate antibody responses (vaccine responder MST = 500 days; vaccine nonresponder MST = 218 days; P = 0.02). Conclusions: These findings suggest that combining myeloid cell–targeted oral immunotherapy with tumor vaccination can generate objective tumor responses, even in the absence of conventional therapy. Overall, this approach has promise as a readily implemented therapeutic strategy for use in patients with brain cancer. Significance: In a pilot study of 10 dogs with glioma, we found that orally administered losartan and propranolol plus vaccination induced durable tumor responses in 8 of 10 treated dogs. The immunotherapy protocol was well tolerated, without systemic or local toxicities. These findings indicate that continuous oral immunotherapy plus tumor vaccination is a promising new strategy for glioma management that can be readily applied in clinical trials.