JP2018531618A - ナイーブt細胞集団からのhpv抗原特異的t細胞の生成 - Google Patents
ナイーブt細胞集団からのhpv抗原特異的t細胞の生成 Download PDFInfo
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Abstract
Description
本願は、2015年10月30日に出願された米国仮特許出願第62/248,818号(これを参照により援用する)に基づく優先権を主張するものである。本願は、「Generating virus or other antigen−specific cells for a naive T cell population」と題して2016年3月21日に出願されたPCT/US2016/23413(これは、2015年3月20日に出願された米国仮特許出願第62/135,851号及び第62/135,888号に基づく優先権を主張するものである)の関連出願であり;かつ、「Expansion of CMV−Specific T cells from CMV−Seronegative Donors」と題して2014年10月28日に出願されたPCT/US2014/62698(これは、2013年10月28日に出願された米国仮特許出願第61/896,296号に基づく優先権を主張するものである)の関連出願である。上記文献の全てを参照により援用する。
本研究は、Catherine M.Bollard及びElizabeth J.Shpallに対して授与されたアメリカ国立衛生研究所のアメリカ国立がん研究所からの助成金(助成金番号:NCI PO1 CA148600−02)によって一部資金提供を受けた。
本発明は、ヒトパピローマウイルス(すなわちHPV)抗原特異的T細胞及び、健常または未感作である提供者のT細胞からそれを製造する方法ならびに、ヒトパピローマウイルスによって引き起こされるかまたはそれに関連する疾患、障害または症状を処置するための、これらのHPV特異的T細胞を使用する細胞に基づく療法に関する。
現在のT細胞に基づく免疫療法のいくつかは、T細胞及び前駆T細胞を含有する試料から増殖させた、ウイルス及び腫瘍に特異的はT細胞を使用する。ウイルス特異的T細胞は、幹細胞移植後のウイルス感染症に対して有効であることが示された。ウイルス特異的T細胞集団を使用するT細胞に基づく細胞療法は、ウイルス感染細胞からの防護を提供することができ、また、抗ウイルス薬よりも少ない副作用に関連する1。増殖させたウイルス特異集団を使用するT細胞に基づく療法は、ウイルス発現性の悪性腫瘍に対する活性を有しており2、3、循環している白血病性芽球を除去する移植片対白血病効果を誘導した4。
HPV16−E6(タンパク質ID P03126)及びHPV16−E7(P03129)の重複ペプチドライブラリー(11アミノ酸だけ重複している15量体)をJPT Peptide Technologies(Berlin,Germany)から購入した。ペプチドをジメチルスルホキシド(DMSO)(Sigma−Aldrich,St.Louis,MO)で戻した。
1.Leen A.M., Bollard CM, Mendizabal AM,et al.Multicenter study of banked third−party virus−specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood.2013;121:5113−5123。
2.Foster AE, Dotti G, Lu A,et al.Antitumor activity of EBV−specific T lymphocytes transduced with a dominant negative TGF−beta receptor. Journal of Immunotherapy.2008;31:500−505。
3.Heslop HE, Slobod KS, Pule MA,et al. Long−term outcome of EBV−specific T−cell infusions to prevent or treat EBV−related lymphoproliferative disease in transplant recipients. Blood.2010;115:925−935。
4.Melenhorst JJ, Castillo P, Hanley PJ, et al.Graft versus leukemia response without graft−versus−host disease elicited by adoptively transferred multivirus−specific T−cells. Molecular therapy:the journal of the American Society of Gene Therapy.2015;23:179−183。
5.Rooney CM, Leen AM, Vera JF, Heslop HE. T lymphocytes targeting native receptors. Immunological reviews.2014;257:39−55。
6.Stanley MA, Pett MR, Coleman N. HPV: from infection to cancer. Biochemical Society Transactions.2007;35:1456−1460。
7.Stanley MA, Sterling JC. Host responses to infection with human papillomavirus. Current problems in dermatology.2014;45:58−74。
8.Stanley M. Immunobiology of HPV and HPV vaccines. Gynecologic oncology.2008;109:S15−21。
9.Furniss CS, McClean MD, Smith JF,et al. Human papillomavirus 16 and head and neck squamous cell carcinoma. International Journal of Cancer.2007;120:2386−2392。
10.Psyrri A, DiMaio D. Human papillomavirus in cervical and head−and−neck cancer. Nature Clinical Practice Oncology.2008;5:24−31。
11.Miralles−Guri C, Bruni L, Cubilla AL, Castellsague X, Bosch FX, de Sanjose S. Human papillomavirus prevalence and type distribution in penile carcinoma. Journal of Clinical Pathology.2009;62:870−878。
12.Ramos CA, Narala N, Vyas GM,et al. Human papillomavirus type 16 E6/E7−specific cytotoxic T lymphocytes for adoptive immunotherapy of HPV−associated malignancies. J Immunother.2013;36:66−76。
13.de Jong A, van Poelgeest MI, van der Hulst JM,et al. Human papillomavirus type 16−positive cervical cancer is associated with impaired CD4+ T−cell immunity against early antigens E2 and E6. Cancer research.2004;64:5449−5455。
14.Hoots BE, Palefsky JM, Pimenta JM, Smith JS. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. International Journal of Cancer.2009;124:2375−2383。
15.Liu G, Markowitz LE, Hariri S, Panicker G, Unger ER. Seroprevalence of 9 Human Papillomavirus Types in the United States,2005−2006. The Journal of infectious diseases.2015。
16.Hanley PJ, Melenhorst JJ, Nikiforow S,et al. CMV−specific T cells generated from naive T cells recognize atypical epitopes and may be protective in vivo. Science translational medicine.2015;7:285ra263。
17.Hanley PJ, Lam S, Shpall EJ, Bollard CM. Expanding cytotoxic T lymphocytes from umbilical cord blood that target cytomegalovirus, Epstein−Barr virus, and adenovirus. Journal of visualized experiments:JoVE.2012:e3627。
18.Papadopoulou A, Gerdemann U, Katari UL,et al. Activity of broad−spectrum T cells as treatment for AdV,EBV,CMV,BKV,and HHV6 infections after HSCT. Science translational medicine.2014;6:242ra283。
19.Steinman RM. The dendritic cell system and its role in immunogenicity. Annual review of immunology.1991;9:271−296。
20.Moodley M. Update on pathophysiologic mechanisms of human papillomavirus. Current opinion in obstetrics & gynecology.2005;17:61−64。
21.Cooper K, McGee JO. Human papillomavirus, integration and cervical carcinogenesis:a clinicopathological perspective. Molecular pathology:MP.1997;50:1−3。
22.Lowy DR, Schiller JT. Human papillomavirus biology. Journal of the National Cancer Institute. Monographs.1996:141−143。
23.Ngo MC, Ando J, Leen AM,et al. Complementation of antigen−presenting cells to generate T lymphocytes with broad target specificity. J Immunother.2014;37:193−203。
Claims (30)
- HPV抗原特異的T細胞を生じさせるプロセスであって、
(a)ナイーブ免疫細胞を含有する任意の細胞供給源からの単核球を数個の部分に分割することと;
(b)前記の試料の第1の部分を、PHAまたは別のマイトジェンと、IL−2とで刺激して、次回の刺激中に抗原提示機能を提供するATCすなわち活性化T細胞(「ATC」)を生じさせ、場合によって前記ATCを放射線または別の薬剤で処理してその増殖を抑制することと;
(c)T細胞及びT細胞前駆細胞を樹状細胞及び樹状前駆細胞から分離することと;
(d)前記T細胞及びT細胞前駆細胞を凍結保存あるいは保管することと;
(e)第2の部分の中の前記樹状細胞及び樹状前駆細胞を、樹状細胞を生成及び成熟させるサイトカイン(複数可)またはその他の薬剤(複数可)と、少なくとも1つのHPVペプチド抗原またはHPV抗原混合物とによって分化させて、少なくとも1つのHPVペプチド抗原を提示する抗原提示樹状細胞を生じさせ、場合によって前記抗原提示樹状細胞を、その増殖を抑制するのに十分な放射線または別の薬剤で処理することと;
(f)IL−7及びIL−15の存在下で、(d)からの前記凍結保存あるいは保管されたT細胞及びT細胞前駆細胞を、(e)で生じた前記樹状抗原提示細胞で刺激して、前記少なくとも1つのHPVペプチド抗原を認識する抗原特異的T細胞を生じさせることと;
(g)前記少なくとも1つのHPVペプチド抗原の存在下で、場合によってK562細胞またはその他の補助細胞の存在下、IL−2及び/またはIL−15の存在下で、(f)によって生じた抗原特異的T細胞を(b)の前記ATCで刺激し;場合によって(g)を1回以上繰り返することと;
(h)少なくとも1つのペプチド抗原を認識する抗原特異的T細胞を回収することと
を含む、前記プロセス。 - (a)の前に、ナイーブT細胞を含有する単核球を分離することをさらに含む、請求項1に記載のプロセス。
- 前記単核球が臍帯血から得られるものである、請求項1に記載のプロセス。
- 前記単核球が、前記少なくとも1つのHPVペプチド抗原に対して未感作である造血幹細胞から得られるものである、請求項1に記載のプロセス。
- 前記単核球が、幹細胞、前駆T細胞、または免疫系が前記少なくとも1つのHPVペプチド抗原に対して未感作である被験体からのT細胞を含有する試料から得られるものである、請求項1に記載のプロセス。
- (b)が、前記試料の第1の部分をPHAとIL−2とで刺激して活性化T細胞(「ATC」)を生じさせることを含む、請求項1に記載のプロセス。
- (b)において、およそ百万〜2千万個、好ましくは5百万〜1千5百万個、最も好ましくはおよそ8百万〜1千2百万個の単核臍帯血細胞をPHAとIL−2とで刺激することを含む、請求項1に記載のプロセス。
- (b)が、PHA芽球の代わりにT芽球、B芽球、リンパ芽球様細胞またはCD3−CD28芽球を活性化T細胞として生じさせることを含む、請求項1に記載のプロセス。
- T細胞及びT細胞前駆細胞が、細胞培養用のプレートまたは装置に前記第2の部分の中の細胞が付着するのに十分な条件下でプラスチック付着により前記第2の部分を培養することと、その後にT細胞及びT細胞前駆細胞を前記細胞培養用のプレートまたは装置から移すことと、固形培地に付着した樹状細胞及び樹状前駆細胞を回収することとによって前記樹状細胞及び樹状前駆細胞から分離される、請求項1に記載のプロセス。
- (e)において前記樹状細胞及び樹状前駆細胞を、樹状細胞の分化及び維持に必要な、IL−4及びGM−CSFを非限定的に含むサイトカインの存在下で増殖させる、請求項1に記載のプロセス。
- (e)においてIL−4及びGM−CSFと一緒に、LPS、TNF−α、IL−1β、IL−6、PGE−1、PGE−2及びその他の免疫賦活剤のうちの1つ以上から構成される群から選択される樹状細胞成熟性のサイトカインまたは薬剤を使用して、前記樹状細胞及び樹状前駆細胞を成熟化に供する、請求項1に記載のプロセス。
- (f)において、または(f)の前に、前記T細胞またはT細胞前駆細胞を処理してCD45RA陽性細胞を増殖させる、請求項1に記載のプロセス。
- (f)において、または(f)の前に、前記T細胞及びT細胞前駆細胞を処理してCD45RO陽性細胞を除去する、請求項1に記載のプロセス。
- 前記少なくとも1つの抗原が、HPVのタンパク質または抗原の全体にわたる一連の重複するペプチドを含む、請求項1に記載のプロセス。
- 院内で、もしくは医原的に罹患するか、または病院もしくは院内感染において被験体に伝染する、日和見HPVの少なくとも1つの抗原を、前記抗原特異的T細胞が認識する、請求項1に記載のプロセス。
- 前記少なくとも1つのペプチド抗原が、HPVの抗原またはペプチドライブラリーを含む、請求項1に記載のプロセス。
- 前記少なくとも1つのペプチド抗原が、HPV E1〜E5の抗原またはペプチドライブラリーを含む、請求項1に記載のプロセス。
- 前記少なくとも1つのペプチド抗原が、HPV E6またはE7の抗原またはペプチドライブラリーを含む、請求項1に記載のプロセス。
- 前記少なくとも1つのペプチド抗原が、HPV L1またはL2の抗原またはペプチドライブラリーを含む、請求項1に記載のプロセス。
- 前記少なくとも1つのペプチド抗原が、HPVに感染した部位、組織または細胞から単離されたT細胞によって認識されるものである、請求項1に記載のプロセス。
- 請求項1に記載のプロセスによって生じる、抗原特異的T細胞を含む組成物。
- 種々の細胞供給源から単離された単核球と、
これと同じ前記供給源に由来する抗原提示細胞と、
前記細胞の生存能を維持する培地と、
任意での、K562細胞、またはその他のT細胞を共刺激する非自家細胞と
を含み、場合により前記細胞が、増殖を防止すべく処理されたものである、組成物。 - 組成物であって、
i.樹状細胞及び樹状前駆細胞から分離された、HPVペプチド抗原に対して未感作であるT細胞及びT細胞前駆細胞と、
ii.培養期間の様々な時点においてIL−2、IL−6、IL−7、IL−12及びIL−15のうちの少なくとも1つを非限定的に含むサイトカインと、
iii.前記T細胞及びT細胞前駆細胞の生存能を維持する培地と
を含む、前記組成物。 - 少なくともHPVエピトープを認識し、かつ細胞表面表現型CD4+CD8+を有する、請求項1に記載のプロセスによって生じたT細胞。
- 少なくともHPVエピトープを認識し、かつ細胞表面表現型CD4+、CD45RO+及びCD27+を有する、請求項1に記載のプロセスによって生じたT細胞。
- 少なくともHPVエピトープを認識し、かつ細胞表面表現型CD27+及びCD28+を有する、請求項1に記載のプロセスによって生じたT細胞。
- HPVによる感染を防止または処置するための、請求項1に記載のプロセスによって生じたT細胞の用途。
- 請求項1に記載のプロセスによって生じたHPVペプチド抗原を認識するT細胞の1つ以上の試料を、貯蔵用または凍結用の培地と組み合わせて収容する、バンクまたは細胞貯蔵設備であって;場合によって、前記1つ以上の試料が、
完全もしくは部分的なDNA配列情報、
主要組織適合性及び/もしくは副組織適合性の抗原もしくはマーカーを含めて前記1つ以上の試料の組織適合性について記載する情報、及び/または
前記1つ以上の試料が含有または認識するペプチド抗原についての情報
を含む前記1つ以上の試料の供給源について記載する情報によって関連付けられるか同定されるかまたは指標付けされる、前記バンクまたは細胞貯蔵設備。 - 請求項1に記載のプロセスによって生じた、凍結保存あるいは保管された生HPV抗原特異的T細胞の多数の試料を含む、抗原特異的T細胞バンク。
- キットであって、
i.樹状細胞及び樹状前駆細胞から分離された、HPVペプチド抗原に対して未感作であるT細胞及びT細胞前駆細胞と、
ii.IL−2、IL−6、IL−7、IL−12及びIL−15のうちの少なくとも1つを非限定的に含むサイトカインと、
iii.前記T細胞及びT細胞前駆細胞の生存能を維持する培地と;
iv.前記T細胞及びT細胞前駆細胞から分離された樹状細胞または樹状前駆細胞と、
v.前記樹状細胞または樹状前駆細胞の生存能を維持する培地と;
vi.場合によって増殖を防止すべく処理された、K562細胞、またはその他のT細胞を共刺激する非自家細胞と、
vii.少なくとも1つのHPVペプチド抗原、またはHPVペプチドの混合物と
を含む、前記キット。
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