Neurological Surgery 脳神経外科33巻5号

2005年05月発行

海外だより

脳腫瘍の免疫治療におけるtranslational research

著者： 岡田秀穂¹

所属機関： ¹

ページ範囲：P.433 - P.442

Ⅰ．はじめに

　われわれの仕事は，いわゆる典型的な脳神経外科医の仕事ではなく，基礎研究の分野から悪性脳腫瘍の患者に有効な治療方法を見つけて試みてみよう，また，効果がみられた場合も，みられなかった場合も，それがどうしてなのかをもう1度研究室に戻って検証しようという，いわゆるtranslational research，あるいはtranslational medicineの分野である．具体的には，おもに悪性グリオーマや転移性脳腫瘍のT細胞性免疫の抗原を同定し，また脳という免疫学的に特異な場における免疫反応の特性を理解し，より有効な免疫治療を開発しようという試みである．

　大手製薬会社の製品開発力がすさまじく進歩した現在にあっても，比較的症例数の少ない原発性脳腫瘍という疾患は，いわゆるorphan diseaseと呼ばれる範疇に入り，大手製薬会社の開発方針の優先順位からはずれることもある．言うまでもなく，有効な治療法のない悪性脳腫瘍の治療の進歩のために，疾患の基礎と臨床の両面を理解する医師が，治療法開発の中心的役割を担うのが望ましい．

　本稿では，まずわれわれの最近の研究について紹介すると同時に，translational researchの現状，また，この分野を健全に進歩させていくために筆者の私見から重要と思われる点について述べたい．本稿が，免疫療法に携わる先生方のみならず，広くtranslational researchに関心のある脳神経外科の先生方に興味を持って読んでいただけたらありがたい．

参考文献

1）Astsaturov I, Petrella T, Bagriacik EU, de BM, Uger R, Lumber G, Berinstein N, Elias I, Iscoe N, Hammond C, Hamilton P, Spaner DE：Amplification of virus-induced antimelanoma T-cell reactivity by high-dose interferon-alpha2b：implications for cancer vaccines. Clin Cancer Res 9：4347-4355, 2003

2）Bedrosian I, Mick R, Xu S, Nisenbaum H, Faries M, Zhang P, Cohen PA, Koski G, Czerniecki BJ：Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 21：3826-3835, 2003

3）Boon T, Coulie PG, van den Eynde B：Tumor antigens recognized by T cells. Immunol Today 18：267-268, 1997

4）Cormier JN, Salgaller ML, Prevette T, Barracchini KC, Rivoltini L, Restifo NP, Rosenberg SA, Marincola FM：Enhancement of cellular immunity in melanoma patients immunized with a peptide from MART-1/Melan A. Cancer J Sci Am 3：37-44, 1997

5）Debinski W, Floyd JE, Harbaugh DL, Gibo DM：EphA2 receptor represents a new marker and therapeutic target in glioblastoma multiforme (GBM). Neuro-Oncol 6：336, 2004. Ref Type：Abstract

6）Debinski W, Gibo DM：Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol Med 6：440-449, 2000

7）Debinski W, Gibo DM, Slagle B, Powers SK, Gillespie GY：Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. Int J Oncol 15：481-486, 1999

8）Giezeman-Smits KM, Okada H, Brissette-Storkus SC, Villa LA, Attanucci J, Lotze MT, Pollack IF, Bozik ME, and Chambers WH：Cytokine gene therapy of gliomas：Induction of reactive CD4+ T cells by interleukin-4 transfected 9L gliosarcoma is essential for protective immunity. Cancer Res 60：2449-2457, 2000

9）Jager D, Jager E, and Knuth A：Vaccination for malignant melanoma：recent developments. Oncology 60：1-7, 2001

10）Lee P, Wang F, Kuniyoshi J, Rubio V, Stuges T, Groshen S, Gee C, Lau R, Jeffery G, Margolin K, Marty V, Weber J：Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma. J Clin Oncol 19：3836-3847, 2001

11）Mailliard RB, Wankowicz-Kalinska A, Cai Q, Wesa A, Hilkens CM, Kapsenberg ML, Kirkwood JM, Storkus WJ, Kalinski P：Alpha-type-1 polarized dendritic cells：a novel immunization tool with optimized CTL-inducing activity. Cancer Res 64：5934-5937, 2004

12）Marchand M, van BN, Weynants P, Brichard V, Dreno B, Tessier MH, Rankin E, Parmiani G, Arienti F, Humblet Y, Bourlond A, Vanwijck R, Lienard D, Beauduin M, Dietrich PY, Russo V, Kerger J, Masucci G, Jager E, De GJ, Atzpodien J, Brasseur F, Coulie PG, van der BP, Boon T：Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1. Int J Cancer 80：219-230, 1999

13）Monsurro V, Nagorsen D, Wang E, Provenzano M, Dudley ME, Rosenberg SA, Marincola FM：Functional heterogeneity of vaccine-induced CD8(+) T cells. J Immunol 168：5933-5942, 2002

14）Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D：Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nature Med 4：328-332, 1998

15）Okada H, Attanucci J, Giezeman-Smits KM, Brissette-Storkus SC, Fellows KW, Pollack IF, Pogue-Geile K, Lotze MT, Bozik ME, and Chambers WH：An antigen identified by cytokine tumor vaccine-assisted SEREX (CAS) suppressed growth of a rat 9L glioma in vivo. Cancer Res 61：2625-2631, 2001a

16）Okada H, Giezeman-Smits KM, Tahara H, Attanucci J, Fellows WK, Lotze MT, Chambers WH, Bozik ME：Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSV-TK tumor vaccine. Gene Ther 6：219-226, 1999

17）Okada H, Tahara H, Shurin MR, Attanucci J, Giezeman-Smits KM, Fellows KW, Lotze MT, Chambers WH, Bozik ME：Bone marrow derived dendritic cells pulsed with a tumor specific peptide elicit effective anti-tumor immunity against intracranial neoplasms. Int J Cancer 78：196-201, 1998

18）Okada H, Tsugawa T, Sato, H, Kuwashima N, Gambotto A, Okada K, Dusak JE, Fellows, W. K, Papworth GD, Watkins SC, ChambersWH, Potter D, Storkus WJ, Pollack IF：Delivery of interferon- transfected DCs into central nervous system tumors enhances the anti-tumor efficacy of peripheral peptide-based vaccines. Cancer Res 64：5830-5838, 2004

19）Okada H, Villa L.A, Attanucci J, Erff M, Fellows WK, Lotze MT, Pollack IF, Chambers WH：Cytokine gene therapy of gliomas： Effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells. Gene Ther 8：1157-1166, 2001b

20）Okano F, Storkus WJ, Chambers WH, Pollack IF, Okada H：Identification of a novel HLA-A*0201 restricted cytotoxic T lymphocyte epitope in a human glioma associated antigen, interleukin-13 receptor 2 chain. Clin Cancer Res 8：2851-2855, 2002

21）Old LJ, Chen YT：New paths in human cancer serology [comment]. J Exp Med 187：1349-1354, 1998

22）Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn,JH, White DE：Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nature Med 4：321-327, 1998

23）Walker PR, Calzascia T, De Tribolet N, Dietrich PY： T-cell immune responses in the brain and their relevance for cerebral malignancies. Brain Res Brain Res Rev 42：97-122, 2003