Immune modulatory nanoparticle therapeutics for intracerebral glioma

Nasser K. Yaghi, Jun Wei, Yuuri Hashimoto, Ling Yuan Kong, Konrad Gabrusiewicz, Edjah K. Nduom, Xiaoyang Ling, Neal Huang, Shouhao Zhou, Brittany C.Parker Kerrigan, Jonathan M. Levine, Virginia R. Fajt, Gwendolyn Levine, Brian F. Porter, Eric G. Marcusson, Kiyoshi Tachikawa, Padmanabh Chivukula, David C. Webb, Joseph E. Payne, Amy B. Heimberger

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases. Methods: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects. Results: Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable. Conclusions: For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.

Original languageEnglish (US)
Pages (from-to)372-382
Number of pages11
JournalNeuro-oncology
Volume19
Issue number3
DOIs
StatePublished - Mar 1 2017

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Glioma
Nanoparticles
Neoplasms
Therapeutics
Glioblastoma
Ribonucleases
Immunosuppression
Canidae
Immune System
Clinical Trials
Lipids
Safety

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Yaghi, N. K., Wei, J., Hashimoto, Y., Kong, L. Y., Gabrusiewicz, K., Nduom, E. K., ... Heimberger, A. B. (2017). Immune modulatory nanoparticle therapeutics for intracerebral glioma. Neuro-oncology, 19(3), 372-382. https://doi.org/10.1093/neuonc/now198
Yaghi, Nasser K. ; Wei, Jun ; Hashimoto, Yuuri ; Kong, Ling Yuan ; Gabrusiewicz, Konrad ; Nduom, Edjah K. ; Ling, Xiaoyang ; Huang, Neal ; Zhou, Shouhao ; Kerrigan, Brittany C.Parker ; Levine, Jonathan M. ; Fajt, Virginia R. ; Levine, Gwendolyn ; Porter, Brian F. ; Marcusson, Eric G. ; Tachikawa, Kiyoshi ; Chivukula, Padmanabh ; Webb, David C. ; Payne, Joseph E. ; Heimberger, Amy B. / Immune modulatory nanoparticle therapeutics for intracerebral glioma. In: Neuro-oncology. 2017 ; Vol. 19, No. 3. pp. 372-382.
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abstract = "Background: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases. Methods: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects. Results: Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable. Conclusions: For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.",
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Yaghi, NK, Wei, J, Hashimoto, Y, Kong, LY, Gabrusiewicz, K, Nduom, EK, Ling, X, Huang, N, Zhou, S, Kerrigan, BCP, Levine, JM, Fajt, VR, Levine, G, Porter, BF, Marcusson, EG, Tachikawa, K, Chivukula, P, Webb, DC, Payne, JE & Heimberger, AB 2017, 'Immune modulatory nanoparticle therapeutics for intracerebral glioma', Neuro-oncology, vol. 19, no. 3, pp. 372-382. https://doi.org/10.1093/neuonc/now198

Immune modulatory nanoparticle therapeutics for intracerebral glioma. / Yaghi, Nasser K.; Wei, Jun; Hashimoto, Yuuri; Kong, Ling Yuan; Gabrusiewicz, Konrad; Nduom, Edjah K.; Ling, Xiaoyang; Huang, Neal; Zhou, Shouhao; Kerrigan, Brittany C.Parker; Levine, Jonathan M.; Fajt, Virginia R.; Levine, Gwendolyn; Porter, Brian F.; Marcusson, Eric G.; Tachikawa, Kiyoshi; Chivukula, Padmanabh; Webb, David C.; Payne, Joseph E.; Heimberger, Amy B.

In: Neuro-oncology, Vol. 19, No. 3, 01.03.2017, p. 372-382.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immune modulatory nanoparticle therapeutics for intracerebral glioma

AU - Yaghi, Nasser K.

AU - Wei, Jun

AU - Hashimoto, Yuuri

AU - Kong, Ling Yuan

AU - Gabrusiewicz, Konrad

AU - Nduom, Edjah K.

AU - Ling, Xiaoyang

AU - Huang, Neal

AU - Zhou, Shouhao

AU - Kerrigan, Brittany C.Parker

AU - Levine, Jonathan M.

AU - Fajt, Virginia R.

AU - Levine, Gwendolyn

AU - Porter, Brian F.

AU - Marcusson, Eric G.

AU - Tachikawa, Kiyoshi

AU - Chivukula, Padmanabh

AU - Webb, David C.

AU - Payne, Joseph E.

AU - Heimberger, Amy B.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Background: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases. Methods: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects. Results: Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable. Conclusions: For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.

AB - Background: Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases. Methods: We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects. Results: Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable. Conclusions: For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.

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SN - 1522-8517

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Yaghi NK, Wei J, Hashimoto Y, Kong LY, Gabrusiewicz K, Nduom EK et al. Immune modulatory nanoparticle therapeutics for intracerebral glioma. Neuro-oncology. 2017 Mar 1;19(3):372-382. https://doi.org/10.1093/neuonc/now198