Background: Despite its promise, immunotherapy shows limited efficacy in glioblastoma because of its poor therapeutic delivery to target tissues and the inability of monotherapy to overcome glioblastoma’s immune evasiveness and rapid growth. Here, we developed a local hydrogel chemoimmunotherapy (doxorubicin, cyclic dinucleotide) to concurrently eliminate tumor cells while generating a multifaceted tumor-specific immune response to prevent tumor growth and recurrence.
Methods: Therapeutic efficacy was evaluated by assessing tumor growth kinetics and survival in orthotopic, syngeneic tumor-bearing mice (GL261). All mice demonstrating long-term survival (>60 days) were rechallenged contralaterally to assess immune memory. Immunophenotyping (flow cytometry, ELISA) was performed to evaluate therapy-induced anti-tumor immune responses on Days 2 and 7. Drug delivery profiles were characterized using IVIS fluorescence imaging.
Results: The local administration of a single dose of hydrogel chemoimmunotherapy resulted in curative survival in over 90% of treated mice, stimulated potent multi-axis anti-tumor immune responses, induced immunological memory that prevented tumor regrowth upon rechallenge, and was well-tolerated. In comparison, intravenous or intratumoral delivery of free therapies did not improve survival.
Conclusions: This study demonstrates the therapeutic potential and significant immunomodulatory effects of local sustained delivery of cyclic dinucleotides in combination with immunogenic chemotherapy for the treatment of glioblastoma.