Dual-specific chimeric antigen receptor T cells and an indirect vaccine eradicate a variety of large solid tumors in an immunocompetent, self-antigen setting

Clare Y. Slaney, Bianca Von Scheidt, Alexander J. Davenport, Paul A. Beavis, Jennifer A. Westwood, Sherly Mardiana, David C. Tscharke, Sarah Ellis, H. Miles Prince, Joseph A. Trapani, Ricky W. Johnstone, Mark J. Smyth, Michele W. Teng, Aesha Ali, Zhiya Yu, Steven A. Rosenberg, Nicholas P. Restifo, Paul Neeson, Phillip K. Darcy, Michael H. Kershaw

Research output: Contribution to journalArticle

Abstract

Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model. Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors. Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient. Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues.

Original languageEnglish (US)
Pages (from-to)2478-2490
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number10
DOIs
StatePublished - May 15 2017
Externally publishedYes

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Autoantigens
T-Cell Antigen Receptor
Vaccines
Neoplasms
Adoptive Transfer
T-Lymphocytes
Antigen Receptors
Vaccinia virus
Immunotherapy
Vaccination
Chemokine Receptors
Melanocytes
Cerebellum
Nervous System
Interleukin-2
Epitopes
Leukemia
Breast
Research Design
Breast Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dual-specific chimeric antigen receptor T cells and an indirect vaccine eradicate a variety of large solid tumors in an immunocompetent, self-antigen setting. / Slaney, Clare Y.; Von Scheidt, Bianca; Davenport, Alexander J.; Beavis, Paul A.; Westwood, Jennifer A.; Mardiana, Sherly; Tscharke, David C.; Ellis, Sarah; Prince, H. Miles; Trapani, Joseph A.; Johnstone, Ricky W.; Smyth, Mark J.; Teng, Michele W.; Ali, Aesha; Yu, Zhiya; Rosenberg, Steven A.; Restifo, Nicholas P.; Neeson, Paul; Darcy, Phillip K.; Kershaw, Michael H.

In: Clinical Cancer Research, Vol. 23, No. 10, 15.05.2017, p. 2478-2490.

Research output: Contribution to journalArticle

Slaney, CY, Von Scheidt, B, Davenport, AJ, Beavis, PA, Westwood, JA, Mardiana, S, Tscharke, DC, Ellis, S, Prince, HM, Trapani, JA, Johnstone, RW, Smyth, MJ, Teng, MW, Ali, A, Yu, Z, Rosenberg, SA, Restifo, NP, Neeson, P, Darcy, PK & Kershaw, MH 2017, 'Dual-specific chimeric antigen receptor T cells and an indirect vaccine eradicate a variety of large solid tumors in an immunocompetent, self-antigen setting', Clinical Cancer Research, vol. 23, no. 10, pp. 2478-2490. https://doi.org/10.1158/1078-0432.CCR-16-1860
Slaney, Clare Y. ; Von Scheidt, Bianca ; Davenport, Alexander J. ; Beavis, Paul A. ; Westwood, Jennifer A. ; Mardiana, Sherly ; Tscharke, David C. ; Ellis, Sarah ; Prince, H. Miles ; Trapani, Joseph A. ; Johnstone, Ricky W. ; Smyth, Mark J. ; Teng, Michele W. ; Ali, Aesha ; Yu, Zhiya ; Rosenberg, Steven A. ; Restifo, Nicholas P. ; Neeson, Paul ; Darcy, Phillip K. ; Kershaw, Michael H. / Dual-specific chimeric antigen receptor T cells and an indirect vaccine eradicate a variety of large solid tumors in an immunocompetent, self-antigen setting. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 10. pp. 2478-2490.
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T1 - Dual-specific chimeric antigen receptor T cells and an indirect vaccine eradicate a variety of large solid tumors in an immunocompetent, self-antigen setting

AU - Slaney, Clare Y.

AU - Von Scheidt, Bianca

AU - Davenport, Alexander J.

AU - Beavis, Paul A.

AU - Westwood, Jennifer A.

AU - Mardiana, Sherly

AU - Tscharke, David C.

AU - Ellis, Sarah

AU - Prince, H. Miles

AU - Trapani, Joseph A.

AU - Johnstone, Ricky W.

AU - Smyth, Mark J.

AU - Teng, Michele W.

AU - Ali, Aesha

AU - Yu, Zhiya

AU - Rosenberg, Steven A.

AU - Restifo, Nicholas P.

AU - Neeson, Paul

AU - Darcy, Phillip K.

AU - Kershaw, Michael H.

PY - 2017/5/15

Y1 - 2017/5/15

N2 - Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model. Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors. Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient. Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues.

AB - Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model. Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors. Results: ACTIV therapy induced durable complete remission of a variety of Her2+ tumors, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient. Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues.

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