A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor response by chimeric antigen receptor T cells

Sherly Mardiana, Liza B John, Melissa A. Henderson, Clare Y. Slaney, Bianca von Scheidt, Lauren Giuffrida, Alexander J Davenport, Joseph A. Trapani, Paul J. Neeson, Sherene Loi, Nicole M Haynes, Michael H. Kershaw, Paul A. Beavis, Phillip K. Darcy

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17 Citations (Scopus)

Abstract

Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solidmalignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses.Wetherefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4- 1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNg and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer.

Original languageEnglish
Pages (from-to)1296-1309
Number of pages14
JournalCancer Research
Volume77
Issue number6
DOIs
Publication statusPublished - 15 Mar 2017

Cite this

Mardiana, Sherly ; John, Liza B ; Henderson, Melissa A. ; Slaney, Clare Y. ; von Scheidt, Bianca ; Giuffrida, Lauren ; Davenport, Alexander J ; Trapani, Joseph A. ; Neeson, Paul J. ; Loi, Sherene ; Haynes, Nicole M ; Kershaw, Michael H. ; Beavis, Paul A. ; Darcy, Phillip K. / A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor response by chimeric antigen receptor T cells. In: Cancer Research. 2017 ; Vol. 77, No. 6. pp. 1296-1309.
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title = "A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor response by chimeric antigen receptor T cells",
abstract = "Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solidmalignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses.Wetherefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4- 1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNg and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer.",
author = "Sherly Mardiana and John, {Liza B} and Henderson, {Melissa A.} and Slaney, {Clare Y.} and {von Scheidt}, Bianca and Lauren Giuffrida and Davenport, {Alexander J} and Trapani, {Joseph A.} and Neeson, {Paul J.} and Sherene Loi and Haynes, {Nicole M} and Kershaw, {Michael H.} and Beavis, {Paul A.} and Darcy, {Phillip K.}",
year = "2017",
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doi = "10.1158/0008-5472.CAN-16-1831",
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journal = "Cancer Research",
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Mardiana, S, John, LB, Henderson, MA, Slaney, CY, von Scheidt, B, Giuffrida, L, Davenport, AJ, Trapani, JA, Neeson, PJ, Loi, S, Haynes, NM, Kershaw, MH, Beavis, PA & Darcy, PK 2017, 'A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor response by chimeric antigen receptor T cells', Cancer Research, vol. 77, no. 6, pp. 1296-1309. https://doi.org/10.1158/0008-5472.CAN-16-1831

A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor response by chimeric antigen receptor T cells. / Mardiana, Sherly; John, Liza B; Henderson, Melissa A.; Slaney, Clare Y.; von Scheidt, Bianca; Giuffrida, Lauren; Davenport, Alexander J; Trapani, Joseph A.; Neeson, Paul J.; Loi, Sherene; Haynes, Nicole M; Kershaw, Michael H.; Beavis, Paul A.; Darcy, Phillip K.

In: Cancer Research, Vol. 77, No. 6, 15.03.2017, p. 1296-1309.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A multifunctional role for adjuvant anti-4-1BB therapy in augmenting antitumor response by chimeric antigen receptor T cells

AU - Mardiana, Sherly

AU - John, Liza B

AU - Henderson, Melissa A.

AU - Slaney, Clare Y.

AU - von Scheidt, Bianca

AU - Giuffrida, Lauren

AU - Davenport, Alexander J

AU - Trapani, Joseph A.

AU - Neeson, Paul J.

AU - Loi, Sherene

AU - Haynes, Nicole M

AU - Kershaw, Michael H.

AU - Beavis, Paul A.

AU - Darcy, Phillip K.

PY - 2017/3/15

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N2 - Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solidmalignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses.Wetherefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4- 1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNg and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer.

AB - Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solidmalignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses.Wetherefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4- 1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNg and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer.

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U2 - 10.1158/0008-5472.CAN-16-1831

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SN - 0008-5472

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