Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

John H. Sampson; Kenneth D. Aldape; Gary E. Archer; April Coan; Annick Desjardins; Allan H. Friedman; Henry S. Friedman; Mark R. Gilbert; James E. Herndon; Roger E. McLendon; Duane A. Mitchell; David A. Reardon; Raymond Sawaya; Robert Schmittling; Weiming Shi; James J. Vredenburgh; Darell D. Bigner; Amy B. Heimberger

doi:10.1093/neuonc/noq157

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

John H. Sampson, Kenneth D. Aldape, Gary E. Archer, April Coan, Annick Desjardins, Allan H. Friedman, Henry S. Friedman, Mark R. Gilbert, James E. Herndon, Roger E. McLendon, Duane A. Mitchell, David A. Reardon, Raymond Sawaya, Robert Schmittling, Weiming Shi, James J. Vredenburgh, Darell D. Bigner, Amy B. Heimberger

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

248 Scopus citations

Abstract

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m² per 5 days) or dose-intensified (DI) TMZ (100 mg/m² per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3⁺ T-cell (P 5 .005) and B-cell (P 5 .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T_Reg; P 5 .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P 5 .037) and delayed-type hypersensitivity responses (P 5 .036) of greater magnitude. EGFRvIIIexpressing tumor cells were also eradicated in nearly all patients (91.6%; CI95: 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI₉₅: 11.0-18.5 months; hazard ratio [HR] 5 0.35; P 5 .024) and overall survival (23.6 months; CI₉₅: 18.5-33.1 months; HR 5 0.23; P 5 .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIIItargeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Original language	English (US)
Pages (from-to)	324-333
Number of pages	10
Journal	Neuro-oncology
Volume	13
Issue number	3
DOIs	https://doi.org/10.1093/neuonc/noq157
State	Published - Mar 2011
Externally published	Yes

Keywords

Epidermal growth factor receptor mutant III
Glioblastoma multiforme
Immune therapy
Temozolomide

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/noq157

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Sampson, J. H., Aldape, K. D., Archer, G. E., Coan, A., Desjardins, A., Friedman, A. H., Friedman, H. S., Gilbert, M. R., Herndon, J. E., McLendon, R. E., Mitchell, D. A., Reardon, D. A., Sawaya, R., Schmittling, R., Shi, W., Vredenburgh, J. J., Bigner, D. D., & Heimberger, A. B. (2011). Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-oncology, 13(3), 324-333. https://doi.org/10.1093/neuonc/noq157

@article{3d325523f0f248b995365457b571a1bb,

title = "Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma",

abstract = "Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m2 per 5 days) or dose-intensified (DI) TMZ (100 mg/m2 per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3+ T-cell (P 5 .005) and B-cell (P 5 .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (TReg; P 5 .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P 5 .037) and delayed-type hypersensitivity responses (P 5 .036) of greater magnitude. EGFRvIIIexpressing tumor cells were also eradicated in nearly all patients (91.6%; CI95: 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI95: 11.0-18.5 months; hazard ratio [HR] 5 0.35; P 5 .024) and overall survival (23.6 months; CI95: 18.5-33.1 months; HR 5 0.23; P 5 .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIIItargeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.",

keywords = "Epidermal growth factor receptor mutant III, Glioblastoma multiforme, Immune therapy, Temozolomide",

author = "Sampson, {John H.} and Aldape, {Kenneth D.} and Archer, {Gary E.} and April Coan and Annick Desjardins and Friedman, {Allan H.} and Friedman, {Henry S.} and Gilbert, {Mark R.} and Herndon, {James E.} and McLendon, {Roger E.} and Mitchell, {Duane A.} and Reardon, {David A.} and Raymond Sawaya and Robert Schmittling and Weiming Shi and Vredenburgh, {James J.} and Bigner, {Darell D.} and Heimberger, {Amy B.}",

year = "2011",

month = mar,

doi = "10.1093/neuonc/noq157",

language = "English (US)",

volume = "13",

pages = "324--333",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "3",

}

Sampson, JH, Aldape, KD, Archer, GE, Coan, A, Desjardins, A, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, R, Shi, W, Vredenburgh, JJ, Bigner, DD & Heimberger, AB 2011, 'Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma', Neuro-oncology, vol. 13, no. 3, pp. 324-333. https://doi.org/10.1093/neuonc/noq157

TY - JOUR

T1 - Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

AU - Sampson, John H.

AU - Aldape, Kenneth D.

AU - Archer, Gary E.

AU - Coan, April

AU - Desjardins, Annick

AU - Friedman, Allan H.

AU - Friedman, Henry S.

AU - Gilbert, Mark R.

AU - Herndon, James E.

AU - McLendon, Roger E.

AU - Mitchell, Duane A.

AU - Reardon, David A.

AU - Sawaya, Raymond

AU - Schmittling, Robert

AU - Shi, Weiming

AU - Vredenburgh, James J.

AU - Bigner, Darell D.

AU - Heimberger, Amy B.

PY - 2011/3

Y1 - 2011/3

N2 - Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m2 per 5 days) or dose-intensified (DI) TMZ (100 mg/m2 per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3+ T-cell (P 5 .005) and B-cell (P 5 .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (TReg; P 5 .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P 5 .037) and delayed-type hypersensitivity responses (P 5 .036) of greater magnitude. EGFRvIIIexpressing tumor cells were also eradicated in nearly all patients (91.6%; CI95: 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI95: 11.0-18.5 months; hazard ratio [HR] 5 0.35; P 5 .024) and overall survival (23.6 months; CI95: 18.5-33.1 months; HR 5 0.23; P 5 .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIIItargeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

AB - Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m2 per 5 days) or dose-intensified (DI) TMZ (100 mg/m2 per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3+ T-cell (P 5 .005) and B-cell (P 5 .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (TReg; P 5 .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P 5 .037) and delayed-type hypersensitivity responses (P 5 .036) of greater magnitude. EGFRvIIIexpressing tumor cells were also eradicated in nearly all patients (91.6%; CI95: 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI95: 11.0-18.5 months; hazard ratio [HR] 5 0.35; P 5 .024) and overall survival (23.6 months; CI95: 18.5-33.1 months; HR 5 0.23; P 5 .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIIItargeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

KW - Epidermal growth factor receptor mutant III

KW - Glioblastoma multiforme

KW - Immune therapy

KW - Temozolomide

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DO - 10.1093/neuonc/noq157

M3 - Article

C2 - 21149254

AN - SCOPUS:79955784386

SN - 1522-8517

VL - 13

SP - 324

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JO - Neuro-Oncology

JF - Neuro-Oncology

IS - 3

ER -

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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