DC和抗肿瘤治疗
DC可作为肿瘤免疫治疗的重要成分。应用DC制作疫苗用于肿瘤的免疫治疗取得了令人鼓舞的初步结果，大量研究显示DC疫苗安全，易于操作，对于一系列类型的肿瘤均有免疫抑制作用。
黑素瘤
黑素瘤被认为是免疫原性肿瘤，其肿瘤相关抗原肽能以MHC I/II类限制形成被T细胞识别，正因如此，黑色瘤被用作DC疫苗的首要研究对象[32]。
Enk等发现黑素瘤病人DC功能与肿瘤分期相关。对化疗有应答的病人DC诱发同种T细胞增殖的能力较进展型病例大5倍。表型分析发现后一种病例DC
的CD86表达明显抑制。Cayeux等发现黑素瘤病人体外混合性淋巴细胞应答可被抗CD80、抗CD86、抗HLADR和抗HLA
I类抗体抑制，而这些病人体内DC的特征却与健康对照组无差异，因而认为DC功能不全是某种可溶性因子抑制的结果。
Meidenhauer等[1]应用DC疫苗治疗14例HLA-A1和HLA-A2阳性黑素瘤，共作83次治疗。他们从CD34＋造血前体细胞分离DC，再用抗原肽冲击。结果显示：①从CD34＋前体细胞分离的DC有足够数量，最少为5×106～5×107个CD1a+DC；②肽冲击的DC可以静脉静注，无明显副作用，也未引起自身免疫性疾病；③免疫学应答：在一例病人出现肽特异性DTH反应、循环中Melan-A和gp100反应性CD8＋CTL明显增加；一例病人出现临床抗肿瘤应答，在疫苗治疗期间出现全身性白斑（Vitiligo）。白斑是一种常见的进行性皮肤脱色素疾病，被认为系自身免疫介导的表皮黑素细胞破坏所致；④2例病人出现临床抗肿瘤应答，包括皮下转移灶完全退缩。
Netle等[33]报道16例黑素瘤接受DC疫苗治疗的结果。DC从外周血单个核细胞中分离，应用GM-CSF和IL-4培养。根据的人类白细胞抗原（HLA）类型，应用肿瘤裂解物或者黑素瘤肽冲击DC。治疗方法是将1×106个DC直接注入未受累的淋巴结中，每周一次。15例中5例在治疗后出现阳性DTH皮肤反应，16例中5例出现客观肿瘤应答，包括2例呈完全应答，持续15个月以上。
Thurner等[34]应用Mage-3A1肽冲击性DC治疗11例进展型黑素瘤，每2周注射一次，初3次注入皮肤，然后静脉注射2次，共5次，结果显示6例出现混合性应答，伴个别转移灶退缩，8例的抗原特异性CTL前体增加。嗣后，研究者又作了第二分临床试验。应用Mage-3A2-1肽冲击病人自身DC。共治疗8例病人，全部在治疗后出现抗原特异性CD8＋T细胞反应增强，但未见临床抗肿瘤效应。
Krause等采用肿瘤细胞与DC融合制作DC疫苗，8例进展性黑素瘤接受此种疫苗皮下注射，每月一次。结果显示1例病人呈现部分应答，某些转移淋巴结完全退缩，在肿瘤退缩同时，伴有头发局限性脱色素；另1例呈现混合型应答[1]。
肾细胞癌
肾细胞癌也被认为属于免疫性肿瘤，但癌细胞上肿瘤相关抗原的表达受到限制。因此，一般使用完整肿瘤细胞或肿瘤裂解物作为肿瘤抗原冲击DCHoltl等[35]先将自体未成熟DC与自身肿瘤细胞融合，然后再用TNF-α和PGE-2促进DC成熟。将混合性DC返输给7例肾细胞癌（原发性和转移性）病人，结果在1例呈现部分应答。
Kugler等[36]对17例进展型肾细胞癌病人，皮下注射由5×107个自身肿瘤细胞与5×107个DC融合成的DC疫苗。DC取自同种健康者。结果：6例出现临床应答，4例肿瘤完全退缩，2例部分退缩。
前列腺癌
前列腺癌是另一用于试验DC疫苗的模型。前列腺组织相关抗原有前列腺特异性抗原（PSA）、前列腺特异性膜抗原（PSMA）和前列腺碱性磷酸酶（PAP），这些抗原都曾被用来作为诱导特异性CTL反应的靶。
Murphy等[37]用2种HLA-A2限制性PSMA冲击单个核细胞来源的DC，制成DC疫苗，治疗51例耐激素性前列腺癌。DC输注量为6×106个，静脉注射，共6次。结果15例的血清PSA水平下降。Tjao等应用类似方法治疗33例患者，DC数为2×107个，也发现部分患者血清PSA降低。
Small等[38]应用一种改良方法从外周血分离单个核细胞，用由连接于GM-CSF的PAP组成的重组融合蛋白冲击DC，制备DC疫苗。给26例耐激素性前列腺癌患者中静脉注射这种疫苗，于10例（38%）出现抗PAP特异性T细胞反应，疾病进展相应减缓。
非何杰金淋巴瘤
Hsu等[39]首先报告4例滤泡型淋巴瘤DC疫苗治疗的结果。采用细胞分离器和密度梯度分离法获得自身DC，再与自身淋巴瘤的独特蛋白共培养。病人接受4次DC静脉注射和独特型蛋白皮下注射。所有病人均出现独特型抗原特异性细胞免疫反应，有2例出现临床应答。
脑胶质瘤
Insug等[40]从GL261胶质瘤细胞抽提RNA，再用RNA冲击取自骨骼的DC，制成DC疫苗，接种给颅内移植性GL261脑瘤鼠，诱发出特异性T细胞反应，免疫组化研究发现接种鼠颅内肿瘤内有明显CD4+和CD8+T细胞浸润。
Lian等[41]用9L胶质瘤细胞酸抽提性抗原冲击来自骨骼的DC前体，制成疫苗，每周3次给实验性胶质瘤鼠模型接种，结果显示接种鼠生存期明显长于对照组，肿瘤内和周围有大量CD4+和CD8+T细胞浸润，体外试验显示这种DC能诱发对胶质瘤细胞的特异性CTL反应。
Yoshida等[42]在19例脑恶性肿瘤，其中9例为高级别胶质瘤患者，分离外周血单个核细胞，加上GM-CSF和IL-4培养诱导成熟DC，再用自身肿瘤裂解物冲击，发现经过肿瘤裂解物冲击的DC具有强大的CTL活性，可杀灭自身瘤细胞的42.5±12.7%，与此同时，T细胞增殖。
Kikuchi等[43]应用DC和胶质瘤细胞融合性DC疫苗，治疗8例胶质瘤患者。DC细胞从外周血分离诱导而来；胶质瘤细胞来自病人自身手术切除标本。DC疫苗皮下注射于颈部淋巴结附近，每3周注射一次，共注射3-7次，结果显示外周血中CD16+和CD56+细胞轻度增加。2例呈现部分应答。无副反应发生。
肝细胞癌
Ninomiya等[44]发现，肝细胞癌病人的DC刺激同一种T细胞增殖的能力，明显低于从肝硬化和正常人分离的DC，DC的 HLA-DR表达水平和诱发IL-12生成的能力明显低下，而这些DC产生一氧化氮和TNF-?
的能力却比正常人和肝硬化患者的DC为高，提示肝癌病人DC成熟缺陷。
Lee等[45]应用肝癌细胞株Hepal-6裂解物致敏的DC治疗肝癌小鼠模型，使58.3%的早期肝癌小鼠肿瘤消失,对于大的肝癌也能使肿瘤缩小。
Iwashita等[46]对10例不能手术切除性原发性肝癌作DC免疫治疗。在体外用GM-CSF、IL-4诱导产生自身DC，再用肿瘤裂解物、TNF-α和keyhole
limpet hemocyanin(KLH)冲击DC，在第9天收集非粘附性细胞，将其注射于腹股沟淋巴结内。每隔4周接受1-10×106个DC细胞。结果：在7例出现抗KLH延迟型超敏反应；一例病人的肝内2个肿瘤中一个从13mm缩小至7mm，CT显示坏死性改变；2例的血清肿瘤标志明显降低。无不良反应发生。
Friedl等[47]在6例肝细胞癌患者从肿瘤分离出肿瘤浸润性淋巴细胞(TIL)，但活性甚弱。经自身肿瘤细胞裂解物冲击的DC致敏后，TIL活性则明显增强。
Ladhams等[48]应用经自身肿瘤抗原冲击的自体DC，治疗2例对其他方法无应答的肝癌患者。结果：1例病情无改变，几个月后死亡，另一例肿瘤退缩，己活存3年以上。
结直肠癌
I/II期临床试验显示DC疫苗对结直肠癌患者，能启动抗原特异性T细胞应答。Rain等用肿瘤RNA和KLH冲击的自身DC，治疗15例进展型结直肠癌。结果在11例出现阳性KLH皮肤试验，7例癌胚抗原(CEA)下降[49]。
甲状腺癌
Shott等[50]对7例组织学证实的髓质甲状腺癌应用DC疫苗治疗。DC由外周血单个核细胞经GM-CSF、IL-4和TNF-α诱导而来，再用calcitonin和CEA肽冲击，给予2-5×106个DC皮下注射。在治疗后平均随访13.1月期内，全部病例均发生强烈延迟型超敏皮肤反应，在血管周围和表皮内有CD4+记忆T细胞和CD8+Tc细胞浸润；3例血清calcitonin和CEA降低；一例肝内转移灶完全退缩，肺转移灶明显变小。Bachleitner-Hofmann等证明肿瘤溶解物冲击的DC能促进髓质甲状腺癌病人自身T细胞抗瘤反应
[51]。
乳腺癌
Candido等[52]报道DC注入实验性乳癌内引起肿瘤生长明显抑制，组织学大量单个核细胞浸润，肿瘤对放射性敏感性增加。Yu等[53]发现DC能纠正化疗引起的实验性乳腺癌鼠的T细胞功能抑制，此作用主要在DC注入肿瘤内后，而不见于静脉注射后。Xia等[54]发现DC/肿瘤融合细胞疫苗可有效地预防实验性自发性乳腺癌的发生。
Gabriolovich等评价了乳腺癌病人T细胞对有丝分裂原和特殊抗原的反应，发现在进展型病例对破伤风类毒素和流感病毒的应答呈现缺陷，DC刺激对照同种T细胞的能力明显降低，认为DC功能不全是病人细胞免疫缺陷的主要原因，推测DC疫苗对乳腺癌可能有效[2]。
Kobayashy等[55]报道一例Ⅳ期乳腺癌患者，锁骨上淋巴结转移，对化疗无应答。将自身肿瘤裂解物冲击的DC注入右侧锁骨上淋巴结内，共4次，引起双侧淋巴结转移退缩，组织学检查显示淋巴结内积聚CD45+T细胞。
鼻咽癌
Lin等[56]将鼻咽癌病人自身单个核细胞培育的DC，用EB病毒肽冲击，再注射于病人腹股沟淋巴结内。16例伴有局部复发或远处转移患者接受此项治疗，每周1次，共4次。结果引发Epitope特异性CD8+T细胞反应，并在3个月后外周血中仍可测到此种反应。
甲状旁腺癌1999 Schott等[57]应用用甲状旁腺激素(PTU)冲击的DC皮下注射，治疗2例甲状腺旁癌患者，引起体内呈现阳性抗PTH延迟型超敏反应。
2000年Schott等[58]对一转移性甲状旁腺患者，皮下和淋巴结内注射肿瘤裂解物冲击的成熟DC，5次后，加注作为CD4+辅助抗原的KLH，10次注射后，出现明显抗肿瘤裂解物的细胞免疫反应，T细胞增殖指数从治疗前0.9-1.1提高到1.8-5.7。
食管癌
Nagao等[59]应用经肿瘤裂解物冲击的DC局部注射，治疗一例复发性食管癌，引起皮肤转移灶消失。
存在问题和展望
DC疫苗应用于癌肿治疗，己展示出良好的前景，但目前尚有以下问题需要解决：
1．成熟抑或未成熟DC，哪一种最适宜？多数认为，成熟DC能更有效地刺激T细胞免疫反应，Morse等[60]发现，使用Flt3配体可增强DC前体活力，使循环和肿瘤内DC的百分数和绝对数均增加。
2．DC来源：单个核细胞源性或CD34+前体细胞源性DC和外周血DC，三者均具有抗肿瘤效应。有人比较前两种来源DC，发现在体外具有类似的表型和功能特性。但Mortarin等[61]认为CD34+源性DC是更强大的抗原呈递细胞，在激发低频度肽特异性CTL方面强于单个核细胞来源的DC。
3．DC剂量：大多数报道中使用的DC剂量为1×106~5×107个细胞。但临床和免疫反应不一定与细胞数有关，相对少量的DC同样可以长效地刺激免疫反应。
4．抗原选择：目前尚无定论。一般认为凋亡肿瘤细胞、肿瘤裂解物、细胞RNA或肿瘤细胞与DC融合，均适合用作DC疫苗。
5．输入途径：在生理情况下，未成熟DC在外周组织捕捉和加工抗原，然后成熟为两手手指交义状DC(interdigitating
DC)，移行至淋巴样组织，在此激活淋巴细胞。在体外生成的DC是否也能在体内转移至淋巴样组织，如脾和淋巴结？Meidenbaner等[1]研究了放射标记性DC静脉或淋巴管注射后体内转运情况，发现静脉注射的DC先被肺暂时性摄取，然后停留于脾和肝内至少7天。Morse等[62]也发现体外生成的人DC静脉注射后主要进入脾和肝。注入足背小淋巴管的DC，半小时后被腹股沟淋巴结摄取，24小时后，腹股沟和髂区摄取达最大量。膈上或对侧淋巴结未见摄取。4小时后胆囊和24小时后升、横结肠有放射性聚集。在理论上淋巴管注射可能最符合生理状态，但属侵袭性操作，操作较困难。皮内或皮下注射的DC可部分地从注射部位转运出去，但仅皮内注射的DC能进入区域淋巴结，皮下注射的DC则否。
临床实际应用的输入途径包含了静脉注射、皮下注射或直接注入淋巴结或肿瘤内。目前尚难说何种途径最优。Schuler-Thurner等[63]发现肽冲击DC先予皮下注射，3次注射后T细胞反应显著增加，最后2次改为静脉注射，
T细胞反应却明显减弱，提示静脉途径可能诱发机体对特异性抗原的耐受性。
尽管存在上述问题和困难，在理论上DC疫苗是目前生物治疗最可行的方法，也是当今研究最活跃、成果最大的课题。随着免疫学和临床研究进展的，相信DC疫苗一定会在肿瘤治疗中发挥重要作用。
参考文献
[1]Meidenbauer N, Andreesen R, Mackensen
A, Dendritic cells for specific cancer Immunotherapy.
Biol Chem 2001;382:507-520.
[2]Satthaporn S, Eremin O.Dendritic cells
( II ):role and therapeutic implications
in cancer. J R Coll Surg Edinb 2001;46:159-167
[3]Inaba K, Turley, S, Yamaide F, Iyoda
T, Mahnke K, Inaba M, Pack, M Subklewe M.,
Sauter B, Sheff D. et al. Efficient presentation
of phagocytosed cellular fragments on the
major histocompatibility complex class ll
products of dendritic cells. J Exp Med 1998;188:2163-2173.
[4]Cella M, Sallusto F, and Lanzavecchia
A.Origin, maturation and antigen presenting
function of dendritic cells Curr Opin. Immunol.
1997;9:10-16.
[5]Banchereau J, Briere F, Caux C, Davoust
J, Lebecque S, Liu Y.J, Pulendran B, and
Palucka K. Immunobiology of dendritic cells.
Annu Rev Immunol. 2000;18:767-811.
[6]Mailliard RB, Egawa S, Cai Q, Kalinska
A, Bykovskaya SN, Lotze MT, Kapsenberg ML,
Storkus WJ, Kalinski P.Complementary dendritic
cell-activating function of CD8+ and CD4+
T cells: helper role of CD8+ T cells in
the development of T helper type 1 responses.
J Exp Med 2002 ;195:473-483.
[7]Pulendran B, Banchereau J, Burkeholder
S, Kraus E, Guinet E, Chalouni C, Caron
D, Maliszewski C, Davoust J, Fay J, and
Palucka K. Flt3-ligand and granulocyte colony-stimulating
factor mobilize distinct human dendritic
cell subsets in vivo. J Immunol 2000;165:566-572.
[8]Rosenzwajg M, Canque B, and Gluckman
JC. Human dendritic cell differentiation
pathway from CD34+ hematopoietic precursor.
Blood 1996;87:535-544.
[9]Engels F.H, Kreisel D, Faries M B, Bedrosian
I, Koski GK, Cohen P A, and Czerniecki BJ.
Calcium ionophore activation of chronic
myelogenous leukemia progenitor cells into
dendritic cells is mediated by calcineurin
phosphatase. Leuk Res 2000;24:795-804.
[10]Chaperot L, Chokri M, Jacob MC, Drillat
P, Garban F, Egelhofer H, Molens JP, Sotto
JJ, Bensa JC, and Plumas J. Differentiation
of antigen-presenting cells (dendritic cells
and macrophages) for therapeutic application
in patients with lymphoma. Leukemia 2000;14:1667-1677.
[11]Banchereau J. Briere F, Caux C, Davoust
J, Lebecque S, Liu YJ, Pulendran B, and
Palucka K. Immunobiology of dendritic cells.
Annu. Rev. Immunol 2000;18:767-811.
[12] Paschen A, Dittmar KE, Grenningloh
R, Rohde M, Schadendorf D, Domann E, Chakraborty
T, and Weiss, S. Human dendritic cells infected
by Listeria monocytogenes: induction of
maturation, requirements for phagolysosomal
escape and antigen presentation capacity.
Eur J Immunol 2000;30:3447-3456.
[13]Singh-jasuja H, Scherer HU, Hilf N,
Arnold-schild D, Rammensee HG, Toes RE,
and Schild H. The heat shock protein gp96
induces maturation of dendritic cells and
down-regulation of its receptor. Eur J Immunol
2000;30:2211-2215.
[14]Gallucci S, Lolkema M, and Matzinger
P Natural adjuvants: endogenous activators
of dendritic cells. Nature Med 1999;5:1249-1255.
[15]Sauter B, Albert ML, Francisco L, Larsson
M, Somersan,S, and Bhardwaj N Consequences
of cell death: exposure to necrotic tumor
cells, but not primary tissue cells or apoptotic
cells. J Exp Med 2000;191:423-434.
[16]Oehler L, Berer A, Kollars M, Keil F,
Konig M, Waclavicek M, Haas O, Knapp W,
Lechner K, and Geissler K. Culture requirements
for induction of dendritic cell differentiation
in acute myeloid leukemia. Ann Hematol 2000;79:355-362.
[17]Kukutsch NA, Rossner S, Austyn JM, Schuler
G, and Lutz MB. Formation and kinetics of
MHC class 1-ovalbumin peptide complexes
on immature and mature murine dendritic
cells .J Invest Dermatol 2000;115:449-453.
[18]Hoffmann TK, Nakano K, Elder EM, Dworacki
G, Finkelstein SD, Appella E, Whiteside
TL, and DeLeo AB. Generation of T cells
specific for the wild-type sequence p53(264-272)
peptide in cancer patients: implications
for immunoselection of epitope loss variants.
J Immunol. 2000a;165:5938-5944.
[19]Chakraborty NG, Sporn JR, Tortora AF,
Kurtzman SH, Yamase H, Ergin MT and Mukherji
B.Immunization with a tumor-cell-lysate-loadedautologous-antigen-pressenting-cell-based
vaccine in melanoma. Cancer Immunol. Immunother.
1998;47:58-64.
[20]Nair SK, Boczkowski D, Snyder D, and
Gilboa, E. Antigen-presenting cells pulsed
with unfractionated tumor-derived peptides
are potent tumor vaccines. Eur J Immunol
1997;27:589-597.
[21]Herr W, Ranieri E, Olson W, Zarour H,
Gesualdo L, and Storkus WJ. Mature dendritic
cells pulsed with freeze-thaw cell lysates
define an effective in vitro vaccine designed
to elicit EBV-specific CD4+ and CD8+ T lymphocyte
responses. Blood 2000;96:1857-1864.
[22]Hoffmann TK, Meidenbauer N, Dworacki
G., Kanaya H, and Whiteside TL. Generation
of tumor-specific T-lymphocytes by cross-priming
with human dendritic cells ingesting apoptotic
tumor cells. Cancer Res 2000b;60:3542-3549.
[23]Gallucci S, Lolkema M, and Matzinger
P. Natural adjuvants: endogenous activators
of dendritic cells. Mature Med. 1999;5:1249-1255.
[24]Gottfried E, Krieg R, Eichelberg C,
Andreesen R, Mackensen A, Krause SW.
Characterization of cells prepared by dendritic
cell-tumor cell fusion. Cancer Immunother
2002;2:15.
[25]Butterfield LH, Jilani SM, Chakraborty
NG, Bui LA, Ribas A, Dissette VB, Lau R,
Gamradt SC, Glaspy JA, McBride WH, et al.
Generation of melanoma-specific cytotoxic
T lymphocytes by dendritic cells transduced
with a MART-1 adenovirus. J Immunol. 1998;161:5607-5613.
[26]Brown M, Davies DH, Skinner MA, Bowen
G, Hollingsworth SJ, Mufti GJ, Arrand JR,
and Stacey SN. Antigen gene transfer to
cultured human dendritic cells using recombinant
avipoxvirus vectors. Cancer Gene Ther 1999;6:238-245.
[27]Heiser A, Dahm P, Yancey DR, Maurice
MA, Boczkowski D, Nair SK, Gilboa E, and
Vieweg J. Human dendritic cells transfected
with RNA encoding prostate-specific antigen
stimulate prostate-speciflc CTL responses
in vitro. J Immunol 2000;164:5508-5514.
[28]Boczkowski D, Nair SK, Nam JH, Lyerly
HK, and Gilboa E. Induction of tumor immunity
and cytotoxic T lymphocyte responses using
dendritic cells transfected with messenger
RNA amplified from tumor cells. Cancer Res
2000;60:1028-1034.
[29]Herr W, Ranieri E, Olson W, Zarour H,
Gesualdo L, and Storkus WJ. Mature dendritic
cells pulsed with freeze-thaw cell lysates
define an effective in vitro vaccine designed
to elicit EBV-specific CD4+ and CD8+ T lymphocyte
responses. Blood 2000;96:1857-1864.
[30]Pirtskhalaishvili G, Shurin GV, Gambotto
A, Esche C, Wahl M, Yurkovetsky ZR, Robbins
PD, and Shurin MR. Transduction of dendritic
cells with Bcl-xL increases their resistance
to prostate cancer-induced apoptosis and
antitumor effect in mice. J Immunol. 2000b;165:1956-1964.
[31]Brossart P, Zobywalski A, Grunebach
F, Behnke L, Stuhler G, Reichardt VL, Kanz
L, and Brugger W. Tumor necrosis factor
alpha and CD40 ligand antagonize the inhibitory
effects of interleukin 10 on T-cell stimulatory
capacity of dendritic cells. Cancer Res
2000a;60:4485-4492.
[32]Mackensen A, Herbst B, Chen JL, Kohler
G, Noppen C, Herr W, Spagnoli GC, Cerundolo
V, and Lindemann A. Phase I study in melanoma
patients of a vaccine with peptide-pulsed
dendritic cells generated in vitro from
CD34+ hematopoietic progenitor cells. Int
J Cancer 2000;86:385-392.
[33]Nestle FO, Alijagic S, Gilliet M, Sun
Y, Grabbe S, Dummer R, Burg G, and Schadendorf
D Vaccination of melanoma patients with
peptides. Nature Med 1998;4:328-332.
[34]Thurner B, Haendle l, Roder C, Dieckmann
D, Keikavoussi P, Jonuleit H, Bender A,
Maczek C, Schreiner D, von Den, DP, et al.
Vaccination with mage-3A1 peptide-pulsed
mature, monocyte-derived dendritic cells
expands specific cytotoxic T cells and induces
regression of some metastases in advanced
stage Ⅳ melanoma. J Exp Med 1999;190:1669-1678.
[35]Holtl L, Rieser C, Papesh C, Ramoner
R, Bartsch G, and Thurnher M .CD83+ blood
dendritic cells as a vaccine for immunotherapy
of metastatic renal-cell cancer. Lancet
1998;352:1358.
[36]Kugler A, Stuhler G, Walden P, Zoller
G, Zobywalski A, Brossart P, Trefzer U,
Ullrich S, Muller CA, Becker, V, et al Regression
of human metastatic renal cell carcinoma
after vaccineation with tumor cell-dendritic
cell hybrids. Nature Med 2000;6:332-336.
[37]Murphy G, Tjoa B, Ragde H, Kenny G,
and Boynton A. Phase 1 clincal trial: T-cell
therapy for prostate cancer using autologous
dendritic cells pulsed with HLA-A0201-specific
peptides from prostate-specific membrane
antigen. Prostate 1996;29:371-380.
[38]Small EJ, Fratesi P, Reese DM, Strang
G, Laus R, Peshwa MV, and Valone, FJ. Immunotherapy
of hormone-refractory prostate cancer with
antigen-loaded dendritic cells. J Clin.
Oncol 2000;18:3894-3903.
[39]Hsu FJ, Benike, C, Fagnoni, F, Liles,
TM, Czerwinski, D, Taidi B, Engleman EG,
and Levy R. Vaccination of patients with
B-cell lymphoma using autologous antigen-pulsed
dendritic cells. Nature Med 1996;2:52-58.
[40]Insug O, Ku G, Ertl HC, Blaszczyk-Thurin
M. A dendriteic cell vaccine induces protective
immunity to intracranial growth of glioma.Anticancer
Res 2002;22:613-621.
[41]Liau LM, Black KL, Prins RM, Sykes SN,
Dipatre PL, Cloughesy TF, Becker DP, Bronstein
JM. Treatment of intracranial gliomas with
bone marrow-derived dendritic cells pulsed
with tumor antigens. J Neurosurg. 1999;90:1115-1124.
[42]Yoshida S, Morii K, Watanabe M, Saito
T, Yamamoto K, Tanaka R. The generation
of anti-tumoral cells using dendritic cells
from the peripheral blood of patients with
malignant brain tumors. Cancer Immunol Immunother.2001;50:321-327.
[43]Kikuchi T, Akasaki Y, Irie M, Homma
S, Abc T, Ohno T. Results of a phase I clinical
trial of vaccination of glioma patients
with fusions of dendritic and glioma cells.
Cancer Immunol Immunother 2001;50:337-344.
[44]Ninomiya T, Akbar SM, Masumoto T, Horiike
N, Onji M.Dendritic cells with immature
phenotype and defective function in the
peripheral blood from patients with hepatocellular
carcinoma. J Hepatol 1999 ;31(2):323-331.
[45]Lee W C, Wang H C, Jeng L B, Chang Y
J, Lia C R, Huang P F, Chen M F, Qian S,
Lu A L. Effective treatment of small murine
hepatocellular carcinoma by dendritic cells.
Hepatology 2001;34:896-905.
[46]Iwashita Y, Tahara K, Goto S, Sasaki
A, Kai S, Seike M, Chen CL, Kawano K, Kitano
S.A phase I study of autologous dendritic
cell-based immunotherapy for patients with
unresectable primary liver cancer. Cancer
Immunol Immunother. 2003 ;52:155-61.
[47]Friedl J, Stift A, Paolini P, Roth E,
Steger GG, Mader R, Jakesz R, Gnant MF.
Tumor antigen pulsed dendritic cells enhance
the cytolytic activity of tumor infiltrating
lymphocytes in human heaptocellular cancer.
Cancer Biother Radiopharm 2000;15:477-486.
[48]Lakhams A, SChmidt C, Sing G, Butterworth
L, Fielding G, Tesar P, Strong R, Leggett
B, Powell L, Maddern G, Ellem K, Cooksley
G. Treatment of non-resectable hepatocellular
carcinoma with autologous tumor-pulsed dendritic
cells.J Gasrtroenterol Hepatol 2002;17:889-896.
[49]Rains N, Cannan RJ, Chen W, Stubbs RS.
Development of a dendritic cell (DC)-based
vaccine for patients with advanced colorectal
cancer. Hepatogastroenterology 2001;38:347-351.
[50]Schott M, Seissler J, Lettmann M, Fouxon
V, Scherbaum WA, Feldkamp J. Immunotherapy
for medullary thyroid carcinoma by dendritic
cell vaccination. J Clin Endocrinol Metab
2001;86:4965-4969.
[51]Bachleitner-Hofmann T, Stift A, Friedl
J, Pfragner R, Radelbauer K, Dubsky P, Schuller
G, Benko T, Niederle B, Brostjan C, Jakesz
R, Gnant M.Stimulation of autologous antitumor
T-cell responses against medullary thyroid
carcinoma using tumor lysate-pulsed dendritic
cells. J Clin Endocrinol Metab. 2002 ;87:1098-1104.
[52]Candido KA, Shimizu K, McLaughlin JC,
Kunkel R, Fuller JA, Redman BG, Thomas EK,
Nickoloff BJ, Mule JJ. Local administration
of dendritic cells inhibits established
breast tumor growth: implications for apoptosis-inducing
agents. Cancer Res. 2001 ;61:228-236.
[53]Yu B, Kusmartsev S, Cheng F, Paolini
M, Nefedova Y, Sotomayor E, Gabrilovich
D.Effective combination of chemotherapy
and dendritic cell administration for the
treatment of advanced-stage experimental
breast cancer. Clin Cancer Res. 2003 ;9:285-294.
[54]Xia J, Tanaka Y, Koido S, Liu C, Mukherjee
P, Gendler SJ, Gong J.Prevention of spontaneous
breast carcinoma by prophylactic vaccination
with dendritic/tumor fusion cells. J Immunol.
2003 ;170:1980-1986.
[55]Kobayashi T, Shinohara H, Toyoda M,
Iwamoto S, Tanigawa N.Regression of lymph
node metastases by immunotherapy using autologous
breast tumor-lysate pulsed dendritic cells:
report of a case. Surg Today 2001;31:513-516.
[56]Lin CL, Lo WF, Lee TH, Ren Y, Hwang
SL, Cheng YF, Chen CL, Chang YS, Lee SP,
Rickinson AB, Tam PK.Immunization with Epstein-Barr
Virus (EBV) peptide-pulsed dendritic cells
induces functional CD8+ T-cell immunity
and may lead to tumor regression in patients
with EBV-positive nasopharyngeal carcinoma.
Cancer Res. 2002 ;62:6952-6958.
[57]Schott M, Seissler J, Feldkamp J, von
Schilling C, Scherbaum WA.Dendritic cell
immunotherapy induces antitumour response
in parathyroid carcinoma and neuroendocrine
pancreas carcinoma.Horm Metab Res. 1999;31:662-664.
[58]Schott M, Feldkamp J, Schattenberg D,
Krueger T, Dotzenrath C, Seissler J, Scherbaum
WA.Induction of cellular immunity in a parathyroid
carcinoma treated with tumor lysate-pulsed
dendritic cells. Eur J Endocrinol. 2000;142:300-306.
[59]Nagao N, Katoh M, Kumazawa I, Tomita
H, Sugiyama Y, Kunieda K, Miya K, Saji S.A
recurrent case of esophageal cancer in which
metastatic skin tumor disappeared after
local injection of activated lymphocytes
with tumor-pulsed dendritic cells Gan To
Kagaku Ryoho. 1999;26:1937-1939.
[60]Morse MA, Nair S, Fernandez-Casal M,
Deng Y, St Peter M, Williams R, Hobeika
A, Mosca P, Clay T, Cumming RI, et al. Preoperative
mobilization of circulating dendritic cells
by fit3 ligand administration to patients
with metastatic colon cancer. J Clin. Oncol
2000;18:3883-3893.
[61]Mortarini R, Anichini A, Di Nicola M,
Siena S, Bregni M, Belli F, Molla A, Gianni
AM, and Parmiani G. Autologous dendritic
cells derived from CD34+ progenitors and
fron monocytes are not functionally equivalent
antigen-fresenting cells in the induction
of melan-A/Mart-1(27-35)-specific CTLs fron
peripheral blood lymphocytes of melanoma
patients with low frequency of CTL precursors.
Cancer Res 1997;57:5534-5541.
[62]Morse MA, Coleman RE, Akabani G, Niehaus
N, Coleman D, and Lyerly HK. Migration of
human dendritic cells after injection in
patients with metastatic malignancies. Cancer
Res 1999; 59:56-58.
[63]Schuler-Thurner B, Dieckmann D, Keikavoussi
P, Bender A, Maczek C, Jonuleit H, Roder
C, Haendle I, Leisgang W, Dunbar R, et al.
Mage-3 and influenza-matrix peptide-specific
cytotoxic T cells are inducible in terminal
stage HLAA2.1+ melanoma patients by mature
monocyte-derived dendritic cells. J Immunol.
2000;165:3492-3496.
