JP2011521967A - 初代細胞由来生物製剤の作用機序 - Google Patents
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Abstract
【選択図】図1
Description
細胞培養に関連する全てのステップは滅菌状態で行われる。本明細書に記載されていない細胞免疫の一般的な方法は、Mishell及びShiigi(Selected Methods in Cellular Immunology、1981)などの細胞免疫技術に関する一般的な参考図書に記載され、当業者に周知の方法に従って行われる。
初代細胞由来生物製剤(IRX−2)の調製
実施例1
実施例2
臨床結果:
実施例3
染色、固定して得られた検体を、ベックマン・コールターFC500フローサイトメーター及びCXP TM分析ソフトウェアを使用して、多重パラメーターフローサイトメトリーにより分析した。フローカウントTMビーズを使用し、単一のプラットホーム(フローサイトメトリーのみ)でTリンパ球サブセットの絶対数を数える方法は、2種(血液測定器及びフローサイトメトリー)のプラットーホーム手法(Reimannら、2000)より正確であることが証明されている。下記の表3は、イムノサイト(ImmunoSite)により測定された免疫マーカーのリストとそれらの免疫における役割を示す。
組織学
H&S研究:方法及び分析
腫瘍周辺対腫瘍内LIの決定
実施例4
予め、腫瘍標本に対する生検の組織病理学の基準(Meneses)は、腫瘍の全体的な縮小、腫瘍の断片化及びリンパ球浸潤(LI)の増加である。本発明に従って、コントロール腫瘍に対する処置腫瘍についてここで新たな基準、即ち、壊死及び繊維化による腫瘍の破壊、及び腫瘍周辺よりも腫瘍内でのLIが増加していることを定める。H&NSCCのサイトカイン処置についてのさまざまな発見を下記表8にまとめる。重要なことは、IRX−2は免疫系の全ての部門に作用することが示されたことである。これは、他の複数のサイトカイン組成治療ではなされないことである。マルチカイン(MULTIKINE:Cel−Sci)はその製剤に複数のサイトカインを含むが、その作用は腫瘍自体への単一のものであり、免疫系には作用しない。
結論
参照文献
1.Dunn G, et al. Dendritic cells and HNSCC: A
potential treatment option? (Review).
Oncology Reports 13:3-10, 2005.
2.Egan JE, et al. IRX-2, a novel in vivo immunotherapeutic,
induces maturation and activation of human dendritic cells in vitro. J Immunother 30:624-633, 2007.
3.Galon J, et al. Type, density, and location
of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960, 2006.
4.Hadden JW, et al. Immunotherapy with natural interleukins
and/or thymosin alpha 1, potently augments T-lymphocyte responses of
hydrocortisone-treated aged mice.
Int J Immunopharm 17(10):821-828, 1995.
5.Hadden JW, et al. Sinc induces thymulin secretion from
human thymic epithelial cells in vitro and augments splenocytes and thymocyte
responses in vivo. Int J.
Immunopharm 17(9):729-733, 1995.
6.Kaech SM, et al. Effector and memory T-cell
differentiation: implications for vaccine development. Nature Rev Immunol 2:251, 2001.
7.Lanzavecchia A, et al. Understanding the generation and
function of memory T cell subsets.
Curr Opin Immunol 17:326, 2005.
8.Maass G, et al. Priming of tumor-specific T cells in the
draining lymph nodes after immunization with interleukin-2-secreting tumor
cells: Three consecutive stages may be required for successful tumor
vaccination. Proc Natl Acad Sci
92:5540, 1995.
9.Mantovani A, et al. Macrophage polarization: tumor
associated macrophages as a paradigm for polarized M2 mononuclear
phagocytes. Trends in Immunology,
23 (11) 2002.
10.Meneses A, et al. Lymph node histology in head and neck
cancer: impact of immunotherapy with IRX-2. Int’l Immunopharm. 3:1083-1091, 2003.
11.Pages F, et al. Effector memory T cells, early
metastasis, and survival in colorectal cancer. NEJM 353:2654-66, 2005.
12.Sallusto F, et al. Two subsets of memory T lymphocytes with
distinct homing potentials and effector functions. Nature 401:708, 1999.
13.Tomiyama H, et al. Phenotypic classification of human CD8+
T cells reflecting their function: inverse correlation between quantitative
expression of CD27 and cytotoxic effector function. Eur J Immunol 34:999, 2004.
14.Verastegui E, et al. Immunological approach in the evaluation
of regional lymph nodes of patients with squamous cell carcinoma of the head
and neck. Clin Immunol 102:37,
2002.
15.Whiteside TL. Immunobiology and immunotherapy of head
and neck cancer. Curr Onc Reports 3:46-55,
2001.
16.Wolf GT, et al. Lymphocyte subpopulations infiltration
squamous carcinomas of the head and neck: correlations with extent and tumor
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Surg 95:145, 1986.
Claims (38)
- 免疫系を抑制している免疫標的を処置し、免疫系を回復する方法であって、
初代細胞由来生物製剤の有効量を投与し、
血液中のB及びT細胞の数を修正し、
リンパ節を局所的に活性化し、
免疫標的に隣接する領域にヘルパーT及びB細胞を浸潤させ、
免疫標的にキラーT細胞及びマクロファージを浸潤させ、
免疫標的を処置して、免疫系を回復させる、ステップを有する方法。 - 前記修正するステップが、血液中のB及びT細胞の数を上方制御又は下方制御することとして更に定義される、請求項1に記載の方法。
- 前記修正するステップが、ナイーブT細胞及び早期メモリーT細胞の数を修正することとして更に定義される、請求項2に記載の方法。
- 前記修正するステップが、CD3+、CD45RA+及びCCR7+ナイーブT細胞の数を修正することとして更に定義される、請求項3に記載の方法。
- 前記修正するステップが、ナイーブT細胞をメモリー及びエフェクターT細胞に分化させることとして更に定義される、請求項4に記載の方法。
- セントラルメモリーT細胞を血流から流出させ、排液性リンパ節に移動させるステップを更に有する、請求項5に記載の方法。
- 前記修正するステップが、B細胞をリンパ節に補充し、B細胞を抗原に暴露し、B細胞を免疫標的に移動させ、免疫標的を攻撃させることとして更に定義される、請求項3に記載の方法。
- 前記攻撃するステップが、免疫標的を攻撃する抗体の作製及び抗体依存細胞性細胞毒性の支持からなる群から選択される作用として更に定義される、請求項7に記載の方法。
- 前記活性化するステップが、リンパ節を局所的に肥大させ、リンパ球を補充し、洞組織球増殖症を回復に向けさせることとして更に定義される、請求項1に記載の方法。
- 前記免疫標的に隣接する領域に浸潤させるステップが、免疫標的に隣接する領域にCD45RA+、CD3+及びCD4+Tリンパ球及びCD20+Bリンパ球を浸潤させることとして更に定義される、請求項1に記載の方法。
- 前記免疫標的に浸潤させるステップが、免疫標的にCD45RO+、CD3+及びCD8+Tリンパ球及びCD68+マクロファージを浸潤させることとして更に定義される、請求項1に記載の方法。
- 前記免疫標的に隣接する領域に浸潤させるステップ及び前記免疫標的に浸潤させるステップが、体液性及び細胞性免疫である、請求項1に記載の方法。
- 前記初代細胞由来生物製剤が、IRX−2として更に定義される、請求項1に記載の方法。
- 前記投与ステップが、更にIRX−2の投与前に低用量のシクロホスファミドを投与することを有し、更にレギュラトリーT細胞リンパ球により抑制を回復に向かわせるステップを有する、請求項13に記載の方法。
- 前記投与ステップが、更にインドメタシン及び亜鉛を毎日投与することを有することを特徴とする、請求項14に記載の方法。
- 前記投与ステップが、更にIRX−2を毎日又は断続的に週に3日、7日の内5日、5〜20日間皮下に投与することとして更に定義される、請求項14に記載の方法。
- 前記投与ステップが、更に1日当たり30〜700ユニットのIRX−2を投与することとして更に定義される、請求項16に記載の方法。
- 外因性抗原を投与するステップを更に有する、請求項1に記載の方法。
- 外科手術、放射線療法、化学療法又はそれらの組み合わせを行うステップを更に有する、請求項1に記載の方法。
- 前記免疫標的が、遺伝子異常、癌、感染、栄養不良、火傷、AIDS、HIV、化学療法及び放射線療法からなる群に起因する生物学的状態である、請求項1に記載の方法。
- 患者に免疫を誘発させることを有する方法であって、
初代細胞由来生物製剤の有効量を投与し、
T及びB細胞の変化を検出し、
患者に免疫を誘発させる、ステップを有する方法。 - 腫瘍を破壊する方法であって、
初代細胞由来生物製剤の有効量を投与し、
未成熟樹状細胞を成熟させ、
ナイーブT細胞を活性化させ、
得られた成熟樹状細胞がナイーブT細胞を刺激し、
ナイーブT細胞をキラーT細胞に分化させ、
キラーT細胞を腫瘍に移動させ、
腫瘍を破壊する、ステップを有する方法。 - 初代細胞由来生物製剤がIRX−2として更に定義される、請求項22に記載の方法。
- 癌治療に有利な治療結果を予測する方法であって、
初代細胞由来生物製剤の有効量を投与し、
腫瘍周囲におけるヘルパーT及びB細胞及び腫瘍内におけるキラーT細胞及びマクロファージの増加を検出し、
癌治療に有利な治療結果を予測する、ステップを有する方法。 - 前記検出するステップが、腫瘍周辺のCD45RA+、CD3+及びCD4+Tリンパ球及びCD20+Bリンパ球の増加、及び腫瘍内のCD45RO+、CD3+及びCD8+Tリンパ球及びCD68+マクロファージの増加を検出することとして更に定義される、請求項24に記載の方法。
- 初代細胞由来生物製剤が、IRX−2として更に定義される、請求項24に記載の方法。
- 免疫予防の方法であって、
初代細胞由来生物製剤の有効量を投与し、
免疫抑制を防止する、ステップを有する方法。 - 前記防止するステップが、未成熟樹状細胞を成熟させ、ナイーブT細胞を活性化させ、得られた成熟樹状細胞がナイーブT細胞を活性化させ、活性化されたナイーブT細胞をアポトーシスから保護し、ナイーブT細胞をメモリー及びエフェクターT細胞に分化させ、免疫系が抑制されないようにリンパ節を局所的に活性化させることとして更に定義される、請求項27に記載の方法。
- 初代細胞由来生物製剤が、IRX−2として更に定義される、請求項28に記載の方法。
- 免疫回復の方法であって、
初代細胞由来生物製剤の有効量を投与し、
患者の免疫系を回復させる、ステップを有する方法。 - 前記回復させるステップが、未成熟樹状細胞を成熟させ、ナイーブT細胞を活性化させ、得られた成熟樹状細胞がナイーブT細胞を活性化させ、活性化されたナイーブT細胞をアポトーシスから保護し、血液中のB及びT細胞の数を修正し、リンパ節を局所的に活性化し、免疫標的に隣接する領域にヘルパーT及びB細胞を浸潤させ、免疫標的内にキラーT細胞及びマクロファージを浸潤させることとして更に定義される、請求項30に記載の方法。
- 初代細胞由来生物製剤が、IRX−2として更に定義される、請求項31に記載の方法。
- 免疫標的が腫瘍である、請求項32に記載の方法。
- 腫瘍を治療する方法であって、
初代細胞由来生物製剤の有効量を投与し、
血液中のB及びT細胞の数を修正し、
リンパ節を局所的に活性化し、
腫瘍周囲にヘルパーT及びB細胞を浸潤させ、
腫瘍内にキラーT細胞及びマクロファージを浸潤させ、
腫瘍を処置する、ステップを有する方法。 - 初代細胞由来生物製剤が、IRX−2として更に定義される、請求項34に記載の方法。
- 前記処置するステップが、腫瘍の軟化、腫瘍に起因する痛みの緩和、腫瘍の縮小、腫瘍の断片化、腫瘍の壊死及び腫瘍の線維化からなる群から選択される少なくとも1つの結果を提供する、請求項34に記載の方法。
- 腫瘍エスケープを防止する方法であって、
初代細胞由来生物製剤の有効量を投与し、
血液中のB及びT細胞の数を修正することによって腫瘍の免疫退化を形成し、
リンパ節を局所的に活性化し、
腫瘍周囲にヘルパーT及びB細胞を浸潤させ、
腫瘍内にキラーT細胞及びマクロファージを浸潤させ、
腫瘍エスケープを防止する、ステップを有する方法。 - 初代細胞由来生物製剤が、IRX−2として更に定義される、請求項37に記載の方法。
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CA2464228C (en) | 2000-10-27 | 2017-01-17 | Immuno-Rx, Inc. | Vaccine immunotherapy for immune suppressed patients |
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CA3017298C (en) | 2009-05-15 | 2021-09-28 | Irx Therapeutics, Inc. | Compositions comprising primary cell-derived biologics for enhancing immune responses in patients |
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