Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study - PubMed (original) (raw)

Case Reports

doi: 10.1215/15228517-2007-046. Epub 2007 Dec 13.

Wei Sun, S Farzana Hussain, Mahua Dey, Lamonne Crutcher, Ken Aldape, Mark Gilbert, Samuel J Hassenbusch, Raymond Sawaya, Bob Schmittling, Gary E Archer, Duane A Mitchell, Darell D Bigner, John H Sampson

Affiliations

Case Reports

Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study

Amy B Heimberger et al. Neuro Oncol. 2008 Feb.

Abstract

Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemotherapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Contrast-enhanced axial (top) and coronal (bottom) MR images in a patient with glioblastoma multiforme showing extent of the tumor prior to resection, after resection, and 1 year after treatment with temozolomide and immunotherapy.

Fig. 2

Fig. 2

Photomicrograph of immunohistochemically stained operative specimen demonstrating the features indicative of glioblastoma multiforme and with positive staining for epidermal growth factor receptor variant III (original magnification, ×200).

Fig. 3

Fig. 3

Study schema in a patient with glioblastoma multiforme (GBM) receiving temozolomide (TMZ) and the PEPvIII keyhole limpet hemocyanin (PEPvIII-KLH) vaccine. Abbreviation: XRT, radiation therapy.

Fig. 4

Fig. 4

Flow cytometric analysis of PEPvIII-specific humoral responses induced in the peripheral blood of a patient with glioblastoma multiforme. Before the patient received any vaccine (pre), there was no detectable humoral response to PEPvIII, but after the third vaccination, there was a marked induction of PEPvIII IgG-specific responses (post). These induced humoral responses did not appear to be diminished during the sequential administration of temozolomide and the PEPvIII-keyhole limpet hemocyanin vaccine. The numbers on the x-axis denote the vaccination number; mean fluorescence intensity (MFI) is indicated on the y-axis.

Fig. 5

Fig. 5

Flow cytometric analysis of PEPvIII-specific CD4 and CD8 T-cell responses induced in the peripheral blood of a patient with glioblastoma multiforme. To further clarify whether the temozolomide would affect the induced CD8+ cytotoxic responses to PEPvIII, the patient’s peripheral blood mononuclear cells (PBMCs) from each leukapheresis and monthly PBMCs were stimulated with the PEP-1 protein (HDTVYCVKGNKELE; 10 μg/ml) as a negative control or PEPvIII (10 μg/ml), a vaccine component. The induced immune responses were specific to the components of the vaccine and were sustained despite the sequential administration of temozolomide. As anticipated, gamma-interferon (γ-IFN) responses were initially detected, but later the patient developed PEPvIII-specific alpha-tumor necrosis factor (TNFα) responses. Abbreviations: FITC, fluorescein isothiocyanate–labeled; APC, allophycocyanin-labeled.

Fig. 6

Fig. 6

Flow cytometric determination of the absolute percentage of CD8+ T cells (gated on total lymphocytes) and regulatory T cells (Treg) (CD4+CD25+Foxp3+; gated on CD4+ T cells) in the peripheral blood of a glioblastoma multiforme patient during the course of treatment with temozolomide and immunotherapy. The vaccine was administered on day 23 during this particular cycle. Abbreviation: KLH, keyhole limpet hemocyanin.

Similar articles

Cited by

References

    1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. - PubMed
    1. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11:5515–5525. - PubMed
    1. Archer G, Bigner D, Friedman A, et al. Dendritic cell vaccine for intracranial tumors I (DC Victori Trial). Paper presented at: Society for Neuro- Oncology, Education Day and Ninth Annual Scientific Meeting; 2004; Toronto, Ontario, Canada.
    1. Su YB, Sohn S, Krown SE, et al. Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic implications. J Clin Oncol. 2004;22:610–616. - PubMed
    1. Heimberger AB, Archer GE, Crotty LE, et al. Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma. Neurosurgery. 2002;50:158–164. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources