Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas

Kwang Soo Kim; Karl Habashy; Andrew Gould; Junfei Zhao; Hinda Najem; Christina Amidei; Ruth Saganty; Víctor A. Arrieta; Crismita Dmello; Li Chen; Daniel Y. Zhang; Brandyn Castro; Leah Billingham; Daniel Levey; Olivia Huber; Marilyn Marques; David A. Savitsky; Benjamin M. Morin; Miguel Muzzio; Michael Canney; Craig Horbinski; Peng Zhang; Jason Miska; Surya Padney; Bin Zhang; Raul Rabadan; Joanna J. Phillips; Nicholas Butowski; Amy B. Heimberger; Jian Hu; Roger Stupp; Dhan Chand; Catalina Lee-Chang; Adam M. Sonabend

doi:10.1093/neuonc/noae135

Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas

Kwang Soo Kim, Karl Habashy, Andrew Gould, Junfei Zhao, Hinda Najem, Christina Amidei, Ruth Saganty, Víctor A. Arrieta, Crismita Dmello, Li Chen, Daniel Y. Zhang, Brandyn Castro, Leah Billingham, Daniel Levey, Olivia Huber, Marilyn Marques, David A. Savitsky, Benjamin M. Morin, Miguel Muzzio, Michael CanneyCraig Horbinski, Peng Zhang, Jason Miska, Surya Padney, Bin Zhang, Raul Rabadan, Joanna J. Phillips, Nicholas Butowski, Amy B. Heimberger, Jian Hu, Roger Stupp, Dhan Chand^*, Catalina Lee-Chang^*, Adam M. Sonabend^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold"and immunotherapy-refractory cancers. Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs). Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge. Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).

Original language	English (US)
Pages (from-to)	2044-2060
Number of pages	17
Journal	Neuro-oncology
Volume	26
Issue number	11
DOIs	https://doi.org/10.1093/neuonc/noae135
State	Published - Nov 1 2024

Funding

This work was supported by the NIH grants 1R01NS110703-01A1 (A.M.S.), NIH 1R01CA245969-01A1 (A.M.S. and R.St.), 1U19CA264338-01 (A.M.S., R.St., B.Z., C.L.C., J.P., N.B.), P50CA221747 SPORE for Translational Approaches to Brain Cancer (A.M.S., R.St., A.B.H., C.L.C., J.M.), SPORE P50CA097257 (J.P., N.B.), R01 CA120813, RO1 NS120547 (A.B.H.) as well as generous philanthropic support from the Moceri Family Foundation and the Panattoni family. R35CA253126 and Vagelos Precision Medicine award (R.R. and J.Z.). Lunaphore COMET multiplex immunohistochemistry was enabled by a gracious gift from the Stephen M. Coffman trust to the Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Cancer Center. Schematic illustrations are created with BioRender.com.

Keywords

BBB
Fc-enhanced anti-CTLA-4
doxorubicin
glioblastoma
immunotherapy

ASJC Scopus subject areas

Oncology
Clinical Neurology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/neuonc/noae135

Cite this

Kim, K. S., Habashy, K., Gould, A., Zhao, J., Najem, H., Amidei, C., Saganty, R., Arrieta, V. A., Dmello, C., Chen, L., Zhang, D. Y., Castro, B., Billingham, L., Levey, D., Huber, O., Marques, M., Savitsky, D. A., Morin, B. M., Muzzio, M., ... Sonabend, A. M. (2024). Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas. Neuro-oncology, 26(11), 2044-2060. https://doi.org/10.1093/neuonc/noae135

@article{543750d904544c64a40809d2045622e5,

title = "Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas",

abstract = "Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in {"}cold{"}and immunotherapy-refractory cancers. Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs). Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge. Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).",

keywords = "BBB, Fc-enhanced anti-CTLA-4, doxorubicin, glioblastoma, immunotherapy",

author = "Kim, {Kwang Soo} and Karl Habashy and Andrew Gould and Junfei Zhao and Hinda Najem and Christina Amidei and Ruth Saganty and Arrieta, {V{\'i}ctor A.} and Crismita Dmello and Li Chen and Zhang, {Daniel Y.} and Brandyn Castro and Leah Billingham and Daniel Levey and Olivia Huber and Marilyn Marques and Savitsky, {David A.} and Morin, {Benjamin M.} and Miguel Muzzio and Michael Canney and Craig Horbinski and Peng Zhang and Jason Miska and Surya Padney and Bin Zhang and Raul Rabadan and Phillips, {Joanna J.} and Nicholas Butowski and Heimberger, {Amy B.} and Jian Hu and Roger Stupp and Dhan Chand and Catalina Lee-Chang and Sonabend, {Adam M.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s).",

year = "2024",

month = nov,

day = "1",

doi = "10.1093/neuonc/noae135",

language = "English (US)",

volume = "26",

pages = "2044--2060",

journal = "Neuro-oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "11",

}

Kim, KS, Habashy, K, Gould, A, Zhao, J, Najem, H, Amidei, C, Saganty, R, Arrieta, VA, Dmello, C, Chen, L, Zhang, DY, Castro, B, Billingham, L, Levey, D, Huber, O, Marques, M, Savitsky, DA, Morin, BM, Muzzio, M, Canney, M, Horbinski, C, Zhang, P, Miska, J, Padney, S, Zhang, B, Rabadan, R, Phillips, JJ, Butowski, N, Heimberger, AB, Hu, J, Stupp, R, Chand, D, Lee-Chang, C & Sonabend, AM 2024, 'Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas', Neuro-oncology, vol. 26, no. 11, pp. 2044-2060. https://doi.org/10.1093/neuonc/noae135

TY - JOUR

T1 - Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening

T2 - A novel combinatorial immunotherapy regimen for gliomas

AU - Kim, Kwang Soo

AU - Habashy, Karl

AU - Gould, Andrew

AU - Zhao, Junfei

AU - Najem, Hinda

AU - Amidei, Christina

AU - Saganty, Ruth

AU - Arrieta, Víctor A.

AU - Dmello, Crismita

AU - Chen, Li

AU - Zhang, Daniel Y.

AU - Castro, Brandyn

AU - Billingham, Leah

AU - Levey, Daniel

AU - Huber, Olivia

AU - Marques, Marilyn

AU - Savitsky, David A.

AU - Morin, Benjamin M.

AU - Muzzio, Miguel

AU - Canney, Michael

AU - Horbinski, Craig

AU - Zhang, Peng

AU - Miska, Jason

AU - Padney, Surya

AU - Zhang, Bin

AU - Rabadan, Raul

AU - Phillips, Joanna J.

AU - Butowski, Nicholas

AU - Heimberger, Amy B.

AU - Hu, Jian

AU - Stupp, Roger

AU - Chand, Dhan

AU - Lee-Chang, Catalina

AU - Sonabend, Adam M.

PY - 2024/11/1

Y1 - 2024/11/1

N2 - Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold"and immunotherapy-refractory cancers. Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs). Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge. Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).

AB - Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold"and immunotherapy-refractory cancers. Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs). Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge. Conclusions: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).

KW - BBB

KW - Fc-enhanced anti-CTLA-4

KW - doxorubicin

KW - glioblastoma

KW - immunotherapy

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AN - SCOPUS:85208287712

SN - 1522-8517

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Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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