EXTH-40. SPECIFIC DENDRIMER-MEDIATED DELIVERY OF IMMUNOTHERAPY BLZ945 TO TUMOR-ASSOCIATED MACROPHAGES IMPROVES THERAPEUTIC EFFICACY IN GLIOBLASTOMA

Abstract

Abstract Patients with glioblastoma have failed to see improved outcomes despite the discovery of powerful anti-cancer drugs because such therapies do not adequately cross the blood-brain barrier and penetrate into solid tumors to access pathological cells. In addition to these delivery challenges, tumors polarize host macrophages into tumor-associated macrophages (TAMs), which suppress the tumor-killing response and create a growth-conducive immune environment for cancer cells. As a result, TAMs are promising therapeutic targets but translational efforts targeting them have largely failed due to low response rates and high systemic toxicities. Therefore, a vehicle that carries immunotherapies into the brain, deep into solid tumors, and specifically to TAMs while remaining inactive in the body provides a promising clinical strategy. Here, we present hydroxyl-terminated polyamidoamine (PAMAM) dendrimers as novel targeted drug delivery systems to overcome these delivery challenges in the GL261 mouse model of glioblastoma. Upon systemic administration, these dendrimers, without any targeting ligands, are able to cross the blood-brain barrier, distribute uniformly throughout the solid glioblastoma tumor, and localize specifically within TAMs. Dendrimers display high tumor specificity (>5-fold compared to the contralateral hemisphere) and minimal systemic accumulation (< 5% initial dose remaining in livers or kidneys after 24 hours). We then conjugated BLZ945, a potent immunotherapy that prevents tumors from recruiting TAMs, to the dendrimer via pH-sensitive linkers for triggered intratumoral and intracellular release. We find that a single systemic dose of dendrimer-delivered BLZ945 halfway through disease progression prolongs survival by >30% compared to free BLZ945 and untreated cohorts. These survival benefits were accompanied by amelioration of disease progression and improved motor function. Finally, we demonstrate that repeat dosing of dendrimer-delivery BLZ945 in combination with current standard of care temozolomide provides robust, synergistic improvements to survival and disease severity. These studies validate the potential of dendrimers for localized immune manipulation in glioblastoma.