Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

Clinical article

Eiichi Ishikawa M.D., Ph.D.1,2, Yoshihiro Muragaki M.D., Ph.D.5,6, Tetsuya Yamamoto M.D., Ph.D.1,2, Takashi Maruyama M.D., Ph.D.6, Koji Tsuboi M.D., Ph.D.2, Soko Ikuta Ph.D.5, Koichi Hashimoto Ph.D.3, Youji Uemae Ph.D.4,7, Takeshi Ishihara M.Sc.7, Masahide Matsuda M.D., Ph.D.1,2, Masao Matsutani M.D., Ph.D.8, Katsuyuki Karasawa M.D., Ph.D.9, Yoichi Nakazato M.D., Ph.D.10, Tatsuya Abe M.D., Ph.D.11, Tadao Ohno Ph.D.7, and Akira Matsumura M.D., Ph.D.1,2
View More View Less
  • 1 Department of Neurosurgery, Faculty of Medicine,
  • | 2 Proton Medical Research Center, Faculty of Medicine,
  • | 3 Tsukuba Critical Path Research and Education Integrated Leading (CREIL) Center, Faculty of Medicine, and
  • | 4 Graduate School of Comprehensive Human Science, University of Tsukuba;
  • | 5 Faculty of Advanced Techno-Surgery (FATS), Institute of Advanced Biomedical Engineering & Science, and
  • | 6 Department of Neurosurgery, Tokyo Women's Medical University, Tokyo;
  • | 7 Cell-Medicine, Inc., Ibaragi;
  • | 8 International Medical Center, Saitama Medical University, Saitama;
  • | 9 Department of Radiology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo;
  • | 10 Department of Human Pathology, Gunma University, Gunma; and
  • | 11 Department of Neurosurgery, Faculty of Medicine, Oita University, Oita, Japan
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

Object

Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM.

Methods

Twenty-four patients (age 16–75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle.

Results

This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response.

Conclusions

The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).

Abbreviations used in this paper:

AFTV = autologous formalin-fixed tumor vaccine; CREIL Center = Critical Path Research and Education Integrated Leading; CTCAE = Common Terminology Criteria for Adverse Events; DTH = delayed-type hypersensitivity; FRT = fractionated radiotherapy; GBM = glioblastoma multiforme; IDH1 = isocitrate dehydrogenase-1; JBTRC = Japan Brain Tumor Reference Center; KPS = Karnofsky Performance Scale; MGMT = O6-methylguanine-DNA methyltransferase; MHC = major histocompatibility complex; MRC = Medical Research Council; OS = overall survival; PFS = progression-free survival; RPA = recursive partitioning analysis; TMZ = temozolomide.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Address correspondence to: Eiichi Ishikawa, M.D., Ph.D., Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. email: e-ishikawa@md.tsukuba.ac.jp.

Please include this information when citing this paper: published online July 4, 2014; DOI: 10.3171/2014.5.JNS132392.

  • 1

    Al-Batran SE, , Rafiyan MR, , Atmaca A, , Neumann A, , Karbach J, & Bender A, et al. : Intratumoral T-cell infiltrates and MHC class I expression in patients with stage IV melanoma. Cancer Res 65:39373941, 2005

    • Search Google Scholar
    • Export Citation
  • 2

    Clarke JL, , Iwamoto FM, , Sul J, , Panageas K, , Lassman AB, & DeAngelis LM, et al. : Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 27:38613867, 2009

    • Search Google Scholar
    • Export Citation
  • 3

    Committee of Brain Tumor Registry of Japan: Report of Brain Tumor Registry of Japan (1969–1996). Neurol Med Chir (Tokyo) 43:Suppl ivii, 1111, 2003

    • Search Google Scholar
    • Export Citation
  • 4

    Curran WJ Jr, , Scott CB, , Horton J, , Nelson JS, , Weinstein AS, & Fischbach AJ, et al. : Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:704710, 1993

    • Search Google Scholar
    • Export Citation
  • 5

    Ishikawa E, , Tsuboi K, , Takano S, , Uchimura E, , Nose T, & Ohno T: Intratumoral injection of IL-2-activated NK cells enhances the antitumor effect of intradermally injected paraformaldehy-defixed tumor vaccine in a rat intracranial brain tumor model. Cancer Sci 95:98103, 2004

    • Search Google Scholar
    • Export Citation
  • 6

    Ishikawa E, , Tsuboi K, , Yamamoto T, , Muroi A, , Takano S, & Enomoto T, et al. : Clinical trial of autologous formalin-fixed tumor vaccine for glioblastoma multiforme patients. Cancer Sci 98:12261233, 2007

    • Search Google Scholar
    • Export Citation
  • 7

    Ishikawa E, , Yamamoto T, , Sakamoto N, , Nakai K, , Akutsu H, & Tsuboi K, et al. : Low peripheral lymphocyte count before focal radiotherapy plus concomitant temozolomide predicts severe lymphopenia during malignant glioma treatment. Neurol Med Chir (Tokyo) 50:638644, 2010

    • Search Google Scholar
    • Export Citation
  • 8

    Iversen TZ, , Brimnes MK, , Nikolajsen K, , Andersen RS, , Hadrup SR, & Andersen MH, et al. : Depletion of T lymphocytes is correlated with response to temozolomide in melanoma patients. OncoImmunology 2:e23288, 2013

    • Search Google Scholar
    • Export Citation
  • 9

    Kim IH, , Park CK, , Heo DS, , Kim CY, , Rhee CH, & Nam DH, et al. : Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase III trial. J Neurooncol 103:595602, 2011

    • Search Google Scholar
    • Export Citation
  • 10

    Kim TG, , Kim CH, , Park JS, , Park SD, , Kim CK, & Chung DS, et al. : Immunological factors relating to the antitumor effect of temozolomide chemoimmunotherapy in a murine glioma model. Clin Vaccine Immunol 17:143153, 2010

    • Search Google Scholar
    • Export Citation
  • 11

    Kocher M, , Frommolt P, , Borberg SK, , Rühl U, , Steingräber M, & Niewald M, et al. : Randomized study of postoperative radiotherapy and simultaneous temozolomide without adjuvant chemotherapy for glioblastoma. Strahlenther Onkol 184:572579, 2008

    • Search Google Scholar
    • Export Citation
  • 12

    Kuang M, , Peng BG, , Lu MD, , Liang LJ, , Huang JF, & He Q, et al. : Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 10:15741579, 2004

    • Search Google Scholar
    • Export Citation
  • 13

    Liu G, , Black KL, & Yu JS: Sensitization of malignant glioma to chemotherapy through dendritic cell vaccination. Expert Rev Vaccines 5:233247, 2006

    • Search Google Scholar
    • Export Citation
  • 14

    Mitchell DA, , Cui X, , Schmittling RJ, , Sanchez-Perez L, , Snyder DJ, & Congdon KL, et al. : Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood 118:30033012, 2011

    • Search Google Scholar
    • Export Citation
  • 15

    Muragaki Y, , Maruyama T, , Iseki H, , Tanaka M, , Shinohara C, & Takakura K, et al. : Phase I/IIa trial of autologous formalin-fixed tumor vaccine concomitant with fractionated radiotherapy for newly diagnosed glioblastoma. Clinical article. J Neurosurg 115:248255, 2011. (Erratum in J Neurosurg 118: 709, 2013)

    • Search Google Scholar
    • Export Citation
  • 16

    Ohno T: Autologous formalin-fixed tumor vaccine. Curr Pharm Des 11:11811188, 2005

  • 17

    Sakamoto N, , Ishikawa E, , Yamamoto T, , Satomi K, , Nakai K, & Sato M, et al. : Pathological changes after autologous formalin-fixed tumor vaccine therapy combined with temozolomide for glioblastoma. Three case reports. Neurol Med Chir (Tokyo) 51:319325, 2011

    • Search Google Scholar
    • Export Citation
  • 18

    Sampson JH, , Heimberger AB, , Archer GE, , Aldape KD, , Friedman AH, & Friedman HS, et al. : Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28:47224729, 2010

    • Search Google Scholar
    • Export Citation
  • 19

    Sanchez-Perez LA, , Choi BD, , Archer GE, , Cui X, , Flores C, & Johnson LA, et al. : Myeloablative temozolomide enhances CD8+ T-cell responses to vaccine and is required for efficacy against brain tumors in mice. PLoS ONE 8:e59082, 2013

    • Search Google Scholar
    • Export Citation
  • 20

    Smith KA, , Ashby LS, , Gonzalez LF, , Brachman DG, , Thomas T, & Coons SW, et al. : Prospective trial of gross-total resection with Gliadel wafers followed by early postoperative Gamma Knife radiosurgery and conformal fractionated radiotherapy as the initial treatment for patients with radiographically suspected, newly diagnosed glioblastoma multiforme. J Neurosurg 109:Suppl 106117, 2008. (Errata in J Neurosurg 110:1323–1324, 2009, and J Neurosurg 111: 639, 2009)

    • Search Google Scholar
    • Export Citation
  • 21

    Steiner HH, , Bonsanto MM, , Beckhove P, , Brysch M, , Geletneky K, & Ahmadi R, et al. : Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 22:42724281, 2004

    • Search Google Scholar
    • Export Citation
  • 22

    Stummer W, , Meinel T, , Ewelt C, , Martus P, , Jakobs O, & Felsberg J, et al. : Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery. J Neurooncol 108:8997, 2012

    • Search Google Scholar
    • Export Citation
  • 23

    Stupp R, , Hegi ME, , Mason WP, , van den Bent MJ, , Taphoorn MJ, & Janzer RC, et al. : Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459466, 2009

    • Search Google Scholar
    • Export Citation
  • 24

    Takano S, , Kato Y, , Yamamoto T, , Kaneko MK, , Ishikawa E, & Tsujimoto Y, et al. : Immunohistochemical detection of IDH1 mutation, p53, and internexin as prognostic factors of glial tumors. J Neurooncol 108:361373, 2012

    • Search Google Scholar
    • Export Citation
  • 25

    Trotti A, , Colevas AD, , Setser A, , Rusch V, , Jaques D, & Budach V, et al. : CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176181, 2003

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 363 254 9
Full Text Views 982 45 3
PDF Downloads 324 45 3
EPUB Downloads 0 0 0