Synergizing enhanced radiotherapy with tumor-associated macrophages-targeted immunotherapy in glioblastoma with multimodal therapeutic nanoparticles

In glioblastoma (GBM), intrinsic and environmental factors are limiting the efficacy of radiation therapy (RT) and immunotherapy.

These factors include intrinsic cancer cells resistance, hypoxia, and the presence of immunosuppressive cells such as tumorassociated macrophages (TAMs).Considering these current limitations for RT efficacy and the specific deleterious role of TAMs in GBM, I designed an original therapeutic strategy combining enhanced RT and TAMs reprogramming with toll-like receptors (TLRs) agonists to synergize direct cytotoxicity to tumors cells at low radiation doses with immunotherapy for both local and recurrent tumor rejection.

For this, I will use relevant radio-sensitizing moieties for GBM: high Z atoms which can efficiently absorb, scatter, and emit radiation energy and catalase, an enzyme capable of converting H2O2 to oxygen in the tumor microenvironment (TME).

It will be simultaneously applied with the combination of the TLRs agonists poly(I:C) and resiquimod, which will be used to re-educate TAMs and prepare the TME to a strong anti-tumoral immune response.

The selected molecules will be incorporated in a new Multimodal Therapeutic NanoParticle (MTNP), based on a nanosized zeolite structure, allowing to combine the two approaches in a unique particle.The MTNPs will be tested in vitro and in vivo in murine model of GBM and patient-derived samples, to verify their effectiveness in enhancing RT and reeducating TAMs, and their effect on tumor growth.

The present multidisciplinary research program aims at supporting greater progress in the treatment of brain tumors and ultimately leading to improved outcomes for cancer patients.