TY - JOUR
T1 - Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy
AU - Alghamri, Mahmoud S.
AU - Banerjee, Kaushik
AU - Mujeeb, Anzar A.
AU - Mauser, Ava
AU - Taher, Ayman
AU - Thalla, Rohit
AU - McClellan, Brandon L.
AU - Varela, Maria L.
AU - Stamatovic, Svetlana M.
AU - Martinez-Revollar, Gabriela
AU - Andjelkovic, Anuska V.
AU - Gregory, Jason V.
AU - Kadiyala, Padma
AU - Calinescu, Alexandra
AU - Jiménez, Jennifer A.
AU - Apfelbaum, April A.
AU - Lawlor, Elizabeth R.
AU - Carney, Stephen
AU - Comba, Andrea
AU - Faisal, Syed Mohd
AU - Barissi, Marcus
AU - Edwards, Marta B.
AU - Appelman, Henry
AU - Sun, Yilun
AU - Gan, Jingyao
AU - Ackermann, Rose
AU - Schwendeman, Anna
AU - Candolfi, Marianela
AU - Olin, Michael R.
AU - Lahann, Joerg
AU - Lowenstein, Pedro R.
AU - Castro, Maria G.
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/6/28
Y1 - 2022/6/28
N2 - 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.
AB - 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.
KW - CXCL12/CXCR4
KW - glioma
KW - immunogenic cell death
KW - immunotherapy
KW - nanoparticles
KW - synthetic protein
KW - systemic delivery
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85131828718&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131828718&partnerID=8YFLogxK
U2 - 10.1021/acsnano.1c07492
DO - 10.1021/acsnano.1c07492
M3 - Article
C2 - 35616289
AN - SCOPUS:85131828718
SN - 1936-0851
VL - 16
SP - 8729
EP - 8750
JO - ACS nano
JF - ACS nano
IS - 6
ER -