Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy

Jingyu Zhang; Dai Liu; Guangfu Li; Kevin F. Staveley-O'Carroll; Julie N. Graff; Zihai Li; Jennifer D. Wu

doi:10.1126/sciadv.1602133

Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy

Jingyu Zhang, Dai Liu, Guangfu Li, Kevin F. Staveley-O'Carroll, Julie N. Graff, Zihai Li, Jennifer D. Wu^*

^*Corresponding author for this work

Urology

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

32 Scopus citations

Abstract

Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti-CTLA4 antibody therapy are not well defined. We report the impact of a cancer-derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (solublemajor histocompatibility complex I chain-relatedmolecule), on the therapeutic outcome of anti-CTLA4 antibody using anMIC transgenic spontaneousTRAMP(transgenic adenocarcinomaof the mouse prostate)/ MIC tumor model. Unexpectedly, animals with elevated serum sMIC (sMIC^hi) responded poorly to anti-CTLA4 antibody therapy, with significantly shortened survival due to increased lung metastasis. These sMIC^hi animals also developed colitis in response to anti-CTLA4 antibody therapy. Coadministration of an sMIC-neutralizing monoclonal antibody with the anti-CTLA4 antibody alleviated treatment-induced colitis in sMIC^hi animals and generated a cooperative antitumor therapeutic effect by synergistically augmenting innate and adoptive antitumor immune responses. Our findings imply that a new combination therapy could improve the clinical response to anti-CTLA4 antibody therapy. Our findings also suggest that prescreening cancer patients for serum sMIC may help in selecting candidates who will elicit a better response to anti-CTLA4 antibody therapy.

Original language	English (US)
Article number	e1602133
Journal	Science advances
Volume	3
Issue number	5
DOIs	https://doi.org/10.1126/sciadv.1602133
State	Published - May 1 2017

Funding

This work was supported by the NIH-National Cancer Institute (NCI) grants 1R01CA149405, 1R01CA208246, and 1R01CA204021; by the Department of Defense-Prostate Cancer Research Program award W81XWH-15-1-0406 (to J.D.W.); partly by the Flow Cytometry Core Facility Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313); and by CanCure LLC (1R41CA206688). Z.L. was funded by NIH-NCI (P01CA186866) (funding period: 01 September 2015 to 31 August 2020). D.L., G.L., and K.F.S.-O. were supported by NIH-NCI grant 1R01CA164335-01A1.

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title = "Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy",

abstract = "Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti-CTLA4 antibody therapy are not well defined. We report the impact of a cancer-derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (solublemajor histocompatibility complex I chain-relatedmolecule), on the therapeutic outcome of anti-CTLA4 antibody using anMIC transgenic spontaneousTRAMP(transgenic adenocarcinomaof the mouse prostate)/ MIC tumor model. Unexpectedly, animals with elevated serum sMIC (sMIChi) responded poorly to anti-CTLA4 antibody therapy, with significantly shortened survival due to increased lung metastasis. These sMIChi animals also developed colitis in response to anti-CTLA4 antibody therapy. Coadministration of an sMIC-neutralizing monoclonal antibody with the anti-CTLA4 antibody alleviated treatment-induced colitis in sMIChi animals and generated a cooperative antitumor therapeutic effect by synergistically augmenting innate and adoptive antitumor immune responses. Our findings imply that a new combination therapy could improve the clinical response to anti-CTLA4 antibody therapy. Our findings also suggest that prescreening cancer patients for serum sMIC may help in selecting candidates who will elicit a better response to anti-CTLA4 antibody therapy.",

author = "Jingyu Zhang and Dai Liu and Guangfu Li and Staveley-O'Carroll, {Kevin F.} and Graff, {Julie N.} and Zihai Li and Wu, {Jennifer D.}",

note = "Funding Information: This work was supported by the NIH-National Cancer Institute (NCI) grants 1R01CA149405, 1R01CA208246, and 1R01CA204021; by the Department of Defense-Prostate Cancer Research Program award W81XWH-15-1-0406 (to J.D.W.); partly by the Flow Cytometry Core Facility Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313); and by CanCure LLC (1R41CA206688). Z.L. was funded by NIH-NCI (P01CA186866) (funding period: 01 September 2015 to 31 August 2020). D.L., G.L., and K.F.S.-O. were supported by NIH-NCI grant 1R01CA164335-01A1. Publisher Copyright: {\textcopyright} 2017 The Authors, some rights reserved.",

year = "2017",

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doi = "10.1126/sciadv.1602133",

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AU - Liu, Dai

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AU - Li, Zihai

AU - Wu, Jennifer D.

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N2 - Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti-CTLA4 antibody therapy are not well defined. We report the impact of a cancer-derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (solublemajor histocompatibility complex I chain-relatedmolecule), on the therapeutic outcome of anti-CTLA4 antibody using anMIC transgenic spontaneousTRAMP(transgenic adenocarcinomaof the mouse prostate)/ MIC tumor model. Unexpectedly, animals with elevated serum sMIC (sMIChi) responded poorly to anti-CTLA4 antibody therapy, with significantly shortened survival due to increased lung metastasis. These sMIChi animals also developed colitis in response to anti-CTLA4 antibody therapy. Coadministration of an sMIC-neutralizing monoclonal antibody with the anti-CTLA4 antibody alleviated treatment-induced colitis in sMIChi animals and generated a cooperative antitumor therapeutic effect by synergistically augmenting innate and adoptive antitumor immune responses. Our findings imply that a new combination therapy could improve the clinical response to anti-CTLA4 antibody therapy. Our findings also suggest that prescreening cancer patients for serum sMIC may help in selecting candidates who will elicit a better response to anti-CTLA4 antibody therapy.

AB - Antibody therapy targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4) elicited survival benefits in cancer patients; however, the overall response rate is limited. In addition, anti-CTLA4 antibody therapy induces a high rate of immune-related adverse events. The underlying factors that may influence anti-CTLA4 antibody therapy are not well defined. We report the impact of a cancer-derived immune modulator, the human-soluble natural killer group 2D (NKG2D) ligand sMIC (solublemajor histocompatibility complex I chain-relatedmolecule), on the therapeutic outcome of anti-CTLA4 antibody using anMIC transgenic spontaneousTRAMP(transgenic adenocarcinomaof the mouse prostate)/ MIC tumor model. Unexpectedly, animals with elevated serum sMIC (sMIChi) responded poorly to anti-CTLA4 antibody therapy, with significantly shortened survival due to increased lung metastasis. These sMIChi animals also developed colitis in response to anti-CTLA4 antibody therapy. Coadministration of an sMIC-neutralizing monoclonal antibody with the anti-CTLA4 antibody alleviated treatment-induced colitis in sMIChi animals and generated a cooperative antitumor therapeutic effect by synergistically augmenting innate and adoptive antitumor immune responses. Our findings imply that a new combination therapy could improve the clinical response to anti-CTLA4 antibody therapy. Our findings also suggest that prescreening cancer patients for serum sMIC may help in selecting candidates who will elicit a better response to anti-CTLA4 antibody therapy.

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Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy

Abstract

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