Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy

• Autores: Alghamri, Mahmoud S.; Banerjee, Kaushik; Mujeeb, Anzar A.; Mauser, Ava; Taher, Ayman; Thalla, Rohit; McClellan, Brandon L.; Varela, Maria L.; Stamatovic, Svetlana M.; Martinez Revollar, Gabriela; Andjelkovic, Anuska V.; Gregory, Jason V.; Kadiyala, Padma; Calinescu, Alexandra; Jiménez, Jennifer A.; Apfelbaum, April A.; Lawlor, Elizabeth R.; Carney, Stephen; Comba, Andrea; Faisal, Syed Mohd; Barissi, Marcus; Edwards, Marta B.; Appelman, Henry; Sun, Yilun; Gan, Jingyao; Ackermann, Rose; Schwendeman, Anna; Candolfi, Marianela; Olin, Michael R.; Lahann, Joerg; Lowenstein, Pedro R.; Castro, Maria G.
• Año de publicación: 2022
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: CXCL12/CXCR4; GLIOMA; IMMUNOGENIC CELL DEATH; IMMUNOTHERAPY; NANOPARTICLES; SYNTHETIC PROTEIN; SYSTEMIC DELIVERY; TUMOR MICROENVIRONMENT
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.
Fil: Alghamri, Mahmoud S.. University Of Michigan Medical School; Estados Unidos
Fil: Banerjee, Kaushik. University Of Michigan Medical School; Estados Unidos
Fil: Mujeeb, Anzar A.. University Of Michigan Medical School; Estados Unidos
Fil: Mauser, Ava. University of Michigan; Estados Unidos
Fil: Taher, Ayman. University Of Michigan Medical School; Estados Unidos
Fil: Thalla, Rohit. University Of Michigan Medical School; Estados Unidos
Fil: McClellan, Brandon L.. University Of Michigan Medical School; Estados Unidos
Fil: Varela, Maria L.. University Of Michigan Medical School; Estados Unidos
Fil: Stamatovic, Svetlana M.. University Of Michigan Medical School; Estados Unidos
Fil: Martinez Revollar, Gabriela. University Of Michigan Medical School; Estados Unidos
Fil: Andjelkovic, Anuska V.. University Of Michigan Medical School; Estados Unidos
Fil: Gregory, Jason V.. University of Michigan; Estados Unidos
Fil: Kadiyala, Padma. University Of Michigan Medical School; Estados Unidos
Fil: Calinescu, Alexandra. University Of Michigan Medical School; Estados Unidos
Fil: Jiménez, Jennifer A.. University of Michigan; Estados Unidos
Fil: Apfelbaum, April A.. University of Michigan; Estados Unidos
Fil: Lawlor, Elizabeth R.. University of Washington; Estados Unidos
Fil: Carney, Stephen. University of Michigan; Estados Unidos
Fil: Comba, Andrea. University Of Michigan Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Faisal, Syed Mohd. University Of Michigan Medical School; Estados Unidos
Fil: Barissi, Marcus. University Of Michigan Medical School; Estados Unidos
Fil: Edwards, Marta B.. University Of Michigan Medical School; Estados Unidos
Fil: Appelman, Henry. University Of Michigan Medical School; Estados Unidos
Fil: Sun, Yilun. Case Western Reserve University; Estados Unidos
Fil: Gan, Jingyao. University of Michigan; Estados Unidos
Fil: Ackermann, Rose. University of Michigan; Estados Unidos
Fil: Schwendeman, Anna. University of Michigan; Estados Unidos
Fil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina
Fil: Olin, Michael R.. University of Minnesota; Estados Unidos
Fil: Lahann, Joerg. University of Michigan; Estados Unidos
Fil: Lowenstein, Pedro R.. University of Michigan; Estados Unidos
Fil: Castro, Maria G.. University of Michigan; Estados Unidos