1. Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences; The Developmental Therapeutics Program, Massey Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA.
2. Department of Radiation Oncology, School of Medicine; The Developmental Therapeutics Program Program, Massey Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA.
3. Department of Chemistry, University of Miami, Coral Gables, FL 33146, USA.
4. Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, 100084, China.
5. Department of Pathology, School of Medicine; Cancer Biology Program, Massey Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA.
6. Department of Pharmaceutical Sciences, College of Pharmacy; Biointerfaces Institute. University of Michigan, Ann Arbor, MI 48109, USA.
Glioblastoma multiforme (GBM) is the most common and lethal type of adult brain cancer. Current GBM standard of care, including radiotherapy, often ends up with cancer recurrence, resulting in limited long-term survival benefits for GBM patients. Immunotherapy, such as immune checkpoint blockade (ICB), has thus far shown limited clinical benefit for GBM patients. Therapeutic vaccines hold great potential to elicit anti-cancer adaptive immunity, which can be synergistically combined with ICB and radiotherapy. Peptide vaccines are attractive for their ease of manufacturing and stability, but their therapeutic efficacy has been limited due to poor vaccine co-delivery and the limited ability of monovalent antigen vaccines to prevent tumor immune evasion. To address these challenges, here, we report GBM radioimmunotherapy that combines radiotherapy, ICB, and multivalent lymph-node-targeting adjuvant/antigen-codelivering albumin-binding vaccines (AAco-AlbiVax). Specifically, to codeliver peptide neoantigens and adjuvant CpG to lymph nodes (LNs), we developed AAco-AlbiVax based on a Y-shaped DNA scaffold that was site-specifically conjugated with CpG, peptide neoantigens, and albumin-binding maleimide-modified Evans blue derivative (MEB). As a result, these vaccines elicited antitumor immunity including neoantigen-specific CD8+ T cell responses in mice. In orthotopic GBM mice, the combination of AAco-AlbiVax, ICB, and fractionated radiation enhanced GBM therapeutic efficacy. However, radioimmunotherapy only trended more efficacious over radiotherapy alone. Taken together, these studies underscore the great potential of radioimmunotherapy for GBM, and future optimization of treatment dosing and scheduling would improve the therapeutic efficacy.
Keywords: albumin, DNA engineering, neoantigen vaccine, vaccine codelivery, glioblastoma immunotherapy