Wt1 peptide vaccine for the treatment of cancer
Yüklə 0,51 Mb. Pdf görüntüsü
|
|
Available online at www.sciencedirect.com WT1 peptide vaccine for the treatment of cancer Yoshihiro Oka 1 , 2 , Akihiro Tsuboi 2 , Yusuke Oji 3 , 4 , Ichiro Kawase 1 and Haruo Sugiyama 4 Wilms’ tumor gene WT1 is expressed in various kinds of cancers. Human WT1-specific cytotoxic T lymphocytes (CTLs) were generated, and mice immunized with WT1 peptide rejected challenges by WT1-expressing cancer cells without auto-aggression to normal organs. Furthermore, WT1 antibodies and WT1-specific CTLs were detected in cancer patients, indicating that WT1 protein was immunogenic. These findings provided us with the rationale for cancer immunotherapy targeting WT1. Clinical trials of WT1 peptide vaccination for cancer patients were started, and WT1 vaccination-related immunological responses and clinical responses, including reduction of leukemic cells, reduction of M-protein amount in myeloma, and shrinkage of solid cancer, were observed. Valuable information about immune responses against tumor antigens can be obtained by the analysis of samples from the vaccinated patients, which should lead to further improvement of cancer vaccine. Addresses 1 Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Japan 2 Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Japan 3 Department of Bioinformatics, Osaka University Graduate School of Medicine, Japan 4 Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Japan Corresponding authors: Oka, Yoshihiro ( yoshi@imed3.med.osaka-u.ac.jp ) and Sugiyama, Haruo ( sugiyama@sahs.med.osaka-u.ac.jp ) Current Opinion in Immunology 2008, 20:211–220 This review comes from a themed issue on Tumour Immunology Edited by Haruo Sugiyama Available online 24th May 2008 0952-7915/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2008.04.009 Introduction Wilms’ tumor gene WT1 was isolated as a gene respon- sible for a childhood renal neoplasm, Wilms’ tumor [ 1,2
]. This gene encodes a zinc finger transcription factor and plays important roles in cell growth and differentiation [ 3,4 ]. Although WT1 gene was categorized at first as a tumor-suppressor gene, it was recently demonstrated that the wild-type WT1 gene performed an oncogenic rather than a tumor-suppressor function in many kinds of malig- nancies. It is highly expressed in malignancies, including hematological malignancies such as acute myeloid leu- kemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML) and myelodys- plastic syndromes (MDS), and solid cancers [ 3–12
] (all the literature were not cited because of limited space) ( Table 1
). WT1 mRNA level in peripheral blood (PB) or bone marrow (BM) is now being used as a marker of minimal residual disease (MRD) of leukemia [ 3,5,7
]. CD8
+ cytotoxic T lymphocytes (CTLs) are the most important effectors for antitumor immune responses, and they recognize tumor-associated antigen (TAA)- derived peptides that are ‘processed’ and presented on cancer cell surface in association with major histocompat- ibility complex (MHC) class I molecules, leading to killing of the cancer cells [ 13,14 ]. Clinical evidence for effectiveness of antitumor immune responses was obtained in several clinical settings including graft-ver- sus-leukemia (GVL) effect after allogeneic hematopoie- tic stem cell transplantation (HSCT) [ 15 ].
might be a promising target antigen for cancer immu- notherapy [ 4,16–18 ]. Tumor escape from immune sur- veillance as a result of down-regulation of WT1 expression is unlikely to occur, because expression of WT1 seems to have an essential role in leukemogenesis or tumorigen- esis, and to be required to maintain the transformed phenotype/function [ 8,11,12
]. This is a theoretical advantage for using WT1 protein as a target antigen for cancer immunotherapy. Identification of WT1 protein-derived CTL epitopes and in vitro generation of WT1-specific CTLs For the development of WT1 peptide cancer vaccine, the identification of HLA class I-restricted CTL epitopes derived from WT1 protein is essential [ 4 ]. Several groups succeeded in the identification of the CTL epitopes with the restriction of HLA-A*0201 or HLA-A*2402, which was a frequent HLA class I type in Caucasian or Japanese, respectively [ 4,16,18–24 ] (
Table 2 ). These WT1 peptide- induced CTLs killed endogenously WT1-expressing can- cer cells [ 18–26 ], indicating that the epitope peptides were ‘processed’ from WT1 protein in cancer cells, followed by presentation on the cell surface in association with HLA class I molecules to be recognized by WT1-specific CTLs. A modified HLA-A*2402-restricted WT1 peptide, in which a single amino-acid substitution was introduced www.sciencedirect.com Current Opinion in Immunology 2008, 20:211–220
at an anchor residue of a natural peptide, was reported [ 27 ]. Binding affinity of the modified peptide to HLA- A*2402 molecule was much increased, and the peptide elicited WT1-specific CTLs more efficiently than the natural peptide. Thus, this modified peptide was con- sidered to be very useful for vaccination of HLA-A*2402 + cancer patients. Another modified peptide with the restriction of HLA-A*0201 was also reported recently [ 28 ]. Since several kinds of normal cells, including hematopoie- tic progenitor cells, physiologically express WT1, it is critical to know whether WT1-specific CTLs cause damage to normal tissues, if we apply WT1-directed immunotherapy to the clinical setting. It was demonstrated that WT1-specific CTLs, which killed WT1-expressing leukemia cells, did not inhibit colony-formation by BM cells, indicating that the CTLs did not attack WT1-expres- sing normal hematopoietic progenitor cells [ 18–20 ]. The
selective CTL killing of leukemia cells but not normal hematopoietic progenitor cells, both of which express WT1, may be explained by the difference in WT1 expression level between malignant and normal hematopoietic cells [ 19
Human WT1-specific CTLs and the restricting HLA allele-matched WT1-expressing cancer cells were trans- planted in immunodeficient mice to investigate the CTLs’ killing activity in vivo [ 21,29,30 ]. In these exper- iments, inhibition of cancer cell growth because of attack by the CTLs and preferential accumulation of the CTLs to tumor site was observed. It was also shown that the CTLs did not inhibit engraftment of normal CD34 + hematopoietic stem cells [ 30 ]. These results strongly suggested that WT1-specific CTLs attacked cancer cells but not normal cells in vivo as well as in vitro. Spontaneous immune responses against WT1 protein in cancer patients Recent investigations demonstrated that
immune responses against WT1 protein, both humoral and cellu- lar, were naturally elicited in cancer patients, indicating that WT1 protein is immunogenic [ 31–36,37
]. These findings provided us with a rationale for developing WT1- targeting cancer immunotherapy. In a report, it was demonstrated that many patients with hematological malignancies such as AML, CML, and MDS responded to leukemia cell-derived WT1 protein and produced IgM-type and IgG-type WT1 antibody [ 33
but also T cells needed to induce class-switch of WT1 antibody were activated in these patients. Analysis of MDS patients revealed that class-switch of WT1 antibody from IgM to IgG occurred along with the disease pro- gression from refractory anemia (RA) to refractory anemia with excess of blast (RAEB), and further to RAEB in transformation (RAEB-t), that is with an increase in amount of tumor that stimulates patients’ immune sys- tem. Furthermore, in AML patients, WT1 antibody dis- appeared after the achievement of complete remission, suggesting that decrease in stimulation of the immune system by leukemia cell-derived WT1 protein gave rise to discontinuation of WT1 antibody production. 212
Tumour Immunology Table 1
Malignant diseases that express WT1 Hematopoietic malignancies Solid cancers Acute myeloid leukemia (AML) a Lung cancer a Acute lymphocytic leukemia (ALL) Breast cancer a Chronic myelogenous leukemia (CML) Head and neck squamous cell carcinoma Myelodysplastic syndromes (MDS) a Thyroid cancer Multiple myeloma (MM) a ,b Esophageal cancer Non-Hodgkin lymphoma (NHL) Gastric cancer Colorectal adenocarcinoma Biliary duct cancer Pancreatic ductal adenocarcinoma Renal cancer a Prostate cancer Ovarian cancer Uterus cancer Primary astrocytic cancer a Bone and soft-tissue sarcoma Malignant melanoma Malignant mesothelioma Testicular germ cell tumor a Diseases for which WT1 peptide vaccination-induced clinical responses were shown in the literature. b MM cells are susceptible to WT1-specific CTLs in spite of rather low expression of WT1 mRNA in MM cells (see text for details). Table 2
WT1 protein-derived CTL epitopes that elicit WT1-specific CTLs HLA-A*0201 restriction (the 2nd and 9th amino acids are anchor positions) RMFPNAPYL a [126]
SLGEQQYSV [187]
CMTWNQMNL b [235] YMFPNAPYL c [126] (modified at the 1st position of peptide-a) HLA-A*2402 restriction (the 2nd and 9th amino acids are anchor positions) CMTWNQMNL b [235]
CYTWNQMNL d [235] (modified at the 2nd position of peptide-b) RWPSCQKKF [417] b
HLA-A*0201 and HLA-A*2402. Peptide-c is not a natural WT1 peptide, but was modified from peptide-a. Peptide-d is not a natural WT1 peptide, but was modified from peptide-b. Numbers in brackets represent the first amino acid positions among the whole amino acid sequences of human WT1 protein. These peptides shown here are candidates for WT1 peptide vaccine. Current Opinion in Immunology 2008, 20:211–220 www.sciencedirect.com It was also demonstrated that Th1-type, but not Th2- type, WT1 antibody significantly increased in PB of patients with leukemia or MDS, compared to healthy volunteers [ 34 ], indicating that Th1-biased WT1-specific immune responses, which were essentially needed for cancer immunotherapy targeting WT1, might be elicited in these patients. The question of whether WT1-specific CD8 + T cell
responses, the most important responses in cancer immu- notherapy targeting WT1, spontaneously occurred in leukemia patients was investigated [ 35,36
]. T cells recog- nizing HLA-A*0201/WT1 peptide complex could be detected at a relatively high rate by ELISPOT or intra- cellular IFN-g detection assay in PBMCs of HLA- A*0201 +
35 ], which provided us direct evidence for spontaneous CTL responses against WT1 protein in leukemia patients. It is interesting that the responses to leukemia-related antigens, including WT1, were higher in CML or ALL patients after HSCT than those before HSCT [ 36,37
]. The increased responses to WT1 in these patients after HSCT may be one of the possible explanations for GVL effect of allogeneic HSCT. Using quantitative reverse transcription-PCR to measure IFN-gmRNA production by CD8 + T cells, T cell responses directed against HLA-A*0201-restricted WT1 epitopes in leukemia patients and healthy donors were also detected [ 38 ]. As for solid cancer, functional HLA-A*0201/WT1 tetra- mer-binding T cells were expanded from tumor-draining lymph nodes in patients with early stage breast cancer [ 39 ], which suggested that WT1 protein-responding CTLs were enriched or activated in the tumor-draining lymph nodes. One report strongly suggested that WT1- specific CTLs were involved in graft-versus-tumor (GVT) effect in HSCT for solid cancer [ 40 ]. In cancer patients with HLA-A*2402, as well as those with HLA-A*0201, it was also shown that HLA-A*2402/ WT1 tetramer-binding CD8 + T cells were detected in PB of patients with leukemia or solid cancer at higher fre- quencies than that of healthy donors [ 41
Mouse in vivo models for WT1 peptide cancer vaccine
Mouse models are very useful to see whether WT1 protein can serve as a tumor rejection antigen in vivo. When C57BL/6 mice were immunized with activated APCs pulsed with WT1 peptide (Db126: a.a.126–134, RMFPNAPYL: underlined letters represent anchor motifs for H-2D b ), which had relatively high-binding affinity for H-2D b molecules, WT1-specific CTLs were generated from the spleen cells [ 17 ]. Furthermore, the immunized mice rejected challenges by WT1-expressing cancer cells more efficiently than non-immunized mice, while the vaccination-induced CTLs did not give damage to normal tissues that physiologically expressed WT1 [ 17 ].
length WT1 protein, the similar results were obtained [ 42 ]. WT1 peptide cancer vaccine Oka et al. 213 Figure 1
Elicitation of immune responses against WT1 protein in cancer patients. Cancer cell-derived WT1 protein is ingested by antigen-presenting cells (APCs) such as dendritic cells (DCs) (i), and is processed in them, followed by presentation of WT1 peptides in association with HLA class I or II molecules on the surface of the APCs (ii and iii), while the WT1 protein stimulates B lymphocytes to produce anti-WT1 antibody (iv). WT1 peptide/HLA class I complexes stimulate CD8 + T cells to make WT1-specific cytotoxic T lymphocytes (CTLs) (ii). WT1 peptide/HLA class II complexes stimulate CD4 + T cells to make WT1-specific helper T cells (iii), which more activate (‘help’) CTLs and B cells, respectively. Activated B cells produce anti-WT1 antibody of class-switched IgG-type as well as IgM-type. Activated WT1-specific CTLs attack cancer cells that have WT1 peptide/HLA class I complexes on the cell surfaces (v). www.sciencedirect.com Current Opinion in Immunology 2008, 20:211–220 214 Tumour Immunology Figure 2 Representative cases that showed clinical responses to WT1 peptide vaccination. (a) An MDS-derived overt AML patient. After a single injection of WT1 peptide, leukemic blast cells and WT1 mRNA levels in BM decreased (lower). At the same time, leukocytopenia appeared (upper) because hematopoiesis was mainly sustained by WT1-expressing malignant hematopoietic stem/progenitor cell-derived blood cells in MDS patients (see text for details). Modified from a figure in Int J Hematol 2003, 78:56–61 (Copyright). (b) A de novo AML patient. During WT1 peptide vaccination, leukemic blast cell percentage and WT1 mRNA level gradually decreased. In contrast to an MDS patient (a), leukocytopenia did not occur. Modified from a figure in Proc Natl Acad Sci U S A 2004, 101:13885–13890 (Copyright). (c) A CMML patient treated with a very low dose of WT1 peptide. During WT1 peptide vaccination, counts of white blood cells (open circles), monocytes (closed circles), and myelocytes plus metamyelocytes (open squares) as well as WT1 mRNA level ‘gradually’ decreased. This clinical course was in contrast to an MDS patient treated Current Opinion in Immunology 2008, 20:211–220 www.sciencedirect.com
The question of whether WT1 peptide vaccination had the potency to reject cancer cells in therapeutic settings was also addressed [ 43 ]. Intradermal injection of Mycobacterium bovis bacillus Calmette-Guerin cell wall skeleton (BCG- CWS) as an adjuvant to C57BL/6 mice, followed by intra- dermal injection of WT1 peptide (Db126) at the same site on the next day, generated WT1-specific CTLs and led to rejection of WT1-expressing cancer cells which had been implanted into the mice before the vaccinations. Mice treated with WT1 peptide and BCG-CWS survived sig- nificantly longer than those vaccinated with WT1 peptide alone, or injected with BCG-CWS alone. No damage in physiologically WT1-expressing normal
tissues was
observed in the treated mice. Clinical trials of WT1 peptide cancer vaccine On the basis of preclinical results, which strongly suggested occurrence of WT1-directed immune responses in patients ( Figure 1 ), clinical trials of WT1 peptide vaccine were started ( Table 2
). Clinical responses Patients with myeloid malignancies, including AML and MDS Oka et al. reported results about a phase I clinical trial of WT1 peptide vaccine for HLA-A*2402 + cancer patients [ 41 ,44,45 ]. 0.3, 1.0, or 3.0 mg of WT1 peptide was injected intradermally at two-week intervals with Mon- tanide ISA51 adjuvant. Clinical responses in leukemia or MDS patients were reported [ 41 ,44 ]. A patient with MDS-derived leukemia was injected with 0.3 mg of WT1 peptide emulsified with Montanide ISA51 ( Figure 2 a). The vaccination resulted in an increase in frequency of WT1-specific CTLs in PB, followed by a rapid reduction in leukemic blast cells and WT1 level in BM, accompanied with severe leukocytopenia in PB. It was speculated that leukocytopenia was induced because most normal-appearing hematopoietic cells in MDS patients were derived from WT1-expressing malignant hematopoietic stem/progenitor cells, which were attacked by the vaccination-induced CTLs. It is probably that leukocytopenia was specific to MDS patients in whom hematopoiesis was mainly sustained by transformed hematopoietic cells. Therefore, the induced leukocyto- penia was considered to be a clinical effect as well as an adverse effect. Another WT1 peptide-vaccinated MDS patient (collectively, two among two MDS patients) also showed the similar clinical course. In some de novo AML patients who were in hematological complete remission (CR) but had MRD at microscopic and/or molecular level, a decrease in leukemic cells and/ or WT1 mRNA level was observed ( Figure 2 b). In contrast to MDS patients, leukocytopenia was not observed, because normal hematopoiesis remained enough in de novo AML patients. In this phase I trial, of the 14 patients with leukemia, including de novo AML and MDS, 7 patients showed clinical responses such as a reduction of leukemic cells and/or WT1 mRNA level. Mailaender et al. reported a WT1 peptide-vaccinated HLA-A*0201 + AML patient [ 16,46 ]. Injections of WT1 peptide with GM-CSF and KLH led the patient to CR, and the remission persisted for more than one year. Very recently, Rezvani et al. reported results about a phase I trial in which WT1 peptide and proteinase 3- derived PR1 peptide in Montanide ISA51 were injected with GM-CSF to HLA-A*0201 + patients with myeloid malignancies [ 47 ]. Decrease in WT1 expression level, a MRD marker, was observed after the combined vaccina- tion in patients with AML or MDS. Patients with multiple myeloma (MM) WT1 mRNA level in myeloma cells was lower than that in acute leukemia cells, leading to a tentative conclusion that MM might not be a good target disease for WT1- directed cancer immunotherapy. However, a recent investigation showed that myeloma cells were lysed efficiently by WT1-specific CTLs in spite of rather low WT1 mRNA level in the cells [ 48 ]. The high sensi- tivity of myeloma cells to CTL-mediated cytotoxicity appeared to be because of high susceptibility of the cell membrane to perforin. On the basis of these findings, a clinical trial of WT1 peptide vaccination for MM patients was started [ 49 ]. Clinical responses, including decrease in M-protein amount in urine, decrease in myeloma cell percentages in BM, and improvement in bone scinti- gram, were observed in a WT1 peptide-vaccinated MM patient.
Patients with MDS, vaccinated with ‘very low dose’ of WT1 peptide As we mentioned before, injection of 0.3 mg WT1 pep- tide, a usual dose in peptide vaccination therapy, induced severe leukocytopenia as well as a decrease in leukemic blast cells and/or WT1 mRNA level in MDS patients, which led us to construct new WT1 peptide treatment strategies for MDS patients with little normal hematopoi- esis [ 41
,44,45 ]. Very low dose (0.005 mg/body) of WT1 peptide vaccine was intradermally injected at two-week intervals with Montanide ISA51 to a patient with chronic WT1 peptide cancer vaccine Oka et al. 215
with a usual dose of WT1 peptide (a). Modified from a figure in Int J Hematol 2007, 85:426–429 (Copyright). (d) A breast cancer patient with lung metastasis. After the repeated WT1 peptide vaccination, tumor size of lung metastasis decreased. Modified from a figure in Proc Natl Acad Sci U S A 2004, 101:13885–13890 (Copyright). www.sciencedirect.com Current Opinion in Immunology 2008, 20:211–220
myelomonocytic leukemia ( Figure 2
c) [ 50 ]. The patient showed immunological responses such as an increase in WT1 tetramer + cell frequencies in PB, and the resultant clinical responses, including a ‘gradual’ decrease in leu- kocyte, monocyte, and immature cell count into a normal range, instead of ‘rapid’ leukocytopenia. Patients with solid cancer A phase I trial performed by Oka et al. also reported clinical responses in patients with lung or breast cancer [ 41
,51 ]. One clinical response-positive case is shown in Figure 2 d, in which breast cancer metastasis in lung regressed after vaccination. One lung cancer patient and one breast cancer patient have been vaccinated for more than one year with maintained clinical benefit and good quality-of-life (QOL), which may be characteristic of immunotherapy. Among 12 patients with lung or breast cancer, 5 patients showed clinical responses such as a decrease in tumor size or tumor marker [ 41 ]. A phase I/II trial of weekly injection of WT1 peptide vaccine for HLA-A*2402 + patients with various kinds of solid cancers was started. The phase I part composed of the first 10 patients was finished [ 52 ]. The vaccination- related systemic toxicities were not observed. As disease- specific phase II part of this trial, a result about 21 recurrent glioblastoma patients was reported [ 10,53
]. Two partial response (PR) and 10 stable disease (SD) in Response Evaluation Criteria in Solid Tumors (RECIST) were obtained. The median progression-free survival (PFS) period was 20.0 weeks, and PFS rate at 6 months was 33.3%. WT1 peptide vaccination was con- sidered active for the treatment of recurrent glioblastoma, because a review of the literature suggested that an agent demonstrating a six-month PFS rate of 10% or greater would be considered active [ 53 ].
[ 54 ]. No damage to normal tissues by WT1 peptide vaccination In phase I clinical trials for WT1 peptide vaccination, no damage to physiologically WT1-expressing normal tissues was reported [ 40,41
,49
], which was expected from preclinical data that was described before in this article [ 17–20
]. This result demonstrated that WT1 vac- cination-induced CTLs attacked WT1-expressing cancer cells, but not physiologically WT1-expressing normal cells. Even if WT1 peptide vaccination-related side effect might occur, the probability of occurrence of severe side effect should be very low. Immunological responses and their correlation with clinical responses In a phase I trial (AML, MDS, breast or lung cancer) reported by Oka et al., a significant correlation between immunological (increase in frequencies of WT1 tetra- mer
+ CD8
+ T cells in PB) and clinical responses was observed in the 19 evaluable patients, indicating that WT1-specific CTLs induced by WT1 vaccination played important roles in the clinical responses [ 41 ]. A case report (AML) by Mailaender et al. showed an increase in frequencies of WT1 tetramer + CD8 + T cells
in PB in correlation with a decrease in leukemic blast cells and WT1 mRNA level [ 46 ]. In a phase I trial (AML, MDS, and CML) reported by Rezvani et al., in which both WT1 and PR1 peptides were injected to patients, the emergence of WT1 or PR1 tetramer + CD8 + T cells
was associated with a decrease in WT1 mRNA level, suggesting a vaccine-driven antileukemic effect [ 47
They also showed that the loss of WT1 or PR1 response was associated with reappearance of WT1 transcripts, a MRD marker. In a phase II trial targeting glioblastoma and a case report for an MM patient, WT1 vaccination-driven induction of clinical responses was not obviously associated with an increase in frequencies of WT1 tetramer + CD8 + T cells in PB [ 49,53
]. However, these patients had relatively high frequencies of the tetramer + cells already before the vaccination [ 49,53
]. A case report for two renal cancer patients showed that delayed type hypersensitivity (DTH) response for WT1 peptide turned positive after the vaccination, associated with stabilization of disease [ 54 ]. In one of the two patients, an increase in frequencies of WT1 tetramer + CD8 + T cells in PB was also observed after the vaccina- tion. It is difficult to directly compare immunogenecity of WT1 protein with that of other TAAs in the clinical setting, because each clinical trial did not use the same protocol. For example, the following might be different: first, were a single kind of peptide or multiple kinds of peptide administered?; second, if multiple kinds of pep- tide were administered, were pre-existing immune responses against target antigens examined before vacci- nation for ‘selection’ of the kinds of peptide to be admi- nistered? [ 55 ]; third, what are the patient characteristics? (early or advanced stages?; hematological malignancies or solid cancers?); and fourth, what kind of adjuvant or cytokine was used? According to accumulating evidences, however, it seems obvious that WT1 protein-derived CTL epitopes (peptides) identified so far are highly immunogenic in the clinical setting. It is notable that only a single kind of WT1 peptide, such as WT1-126 or WT1-235, could induce an increase in WT1 tetramer + CD8
+ T cell frequencies and/or make the peptide- specific DTH reaction positive after vaccination, leading to the emergence of clinical responses [ 41,44,46,50,54 ]. It
was also shown that only a single injection of WT1 peptide could induce an increase in WT1 tetramer + CD8
+ T cells [ 44,47
216 Tumour Immunology Current Opinion in Immunology 2008, 20:211–220 www.sciencedirect.com Perspectives New target diseases for WT1-directed cancer immunotherapy Drakos et al. recently demonstrated that WT1 protein was frequently detected, primarily in the cytoplasm, of a subset of high-grade NHLs [ 56 ] (
Table 1 ). Clinical trials of WT1 peptide vaccination for NHL patients should also be planned. Enhancement of clinical efficacy and usefulness of WT1 peptide vaccine Although it was revealed that WT1 peptide vaccination had clinical efficacy and usefulness at least for some patients [ 41 ,44–46,47
,49–54 ], we need to further improve the vaccine. Strategies to immunologically enhance the power of the vaccine may include first, to find or develop more strong adjuvants; second, to use HLA class II-restricted helper epitopes which enhance induction/activation of CTLs and make ‘memory’ CTLs in combination with CTL epitopes [ 57–59,60
,61
]; and third, to use multiple CTL epitopes [ 55,62
In addition to treatment using only cancer vaccine with appropriate adjuvant/cytokine, combined usage of cancer vaccine and other kinds of drugs, including molecular- target-based drugs such as imatinib [ 62
apy drugs [ 63–65
], might be another strategy to develop a novel modality for anticancer action. It was recently reported that addition of a multiple peptide vaccine against BCR-ABL-derived fusion protein to imatinib treatment in CML patients induced improved cytoge- netic responses [ 62
T cells by using approaches such as administration of cyclophosphamide or gemcitabine-containing che- motherapy might improve the efficacy of peptide vaccines [ 63–65
]. Gemcitabine was also revealed in a mouse model to eliminate splenic Gr-1 + /CD11b
+ myeloid
suppressor cells [ 65 ]. Optimization of WT1 peptide dose for the treatment of MDS patients is also a major subject. Although vaccina- tion of a CMML patient with a very low dose of WT1 peptide safely reduced leukocyte, monocyte and imma- ture cell count and WT1 mRNA level, these parameters started to increase again three months after the start of the vaccination. The dose (0.005 mg/body) might be too low to elicit enough immune reaction. Since human T cell receptors (TCRs) that recognized WT1peptide/HLA class I complex were cloned, WT1- specific T cell gene therapy is also expected [ 66–68
]. Translational research and reverse-translational research Translational research is composed of basic research and the subsequent clinical trials. The latter is based on ‘scientific’ data obtained from the former. Therefore, we can obtain ‘science’-based valuable information about TAA-directed immune responses by analyzing samples from the vaccinated patients. According to accumulating evidences, it seems convin- cing that WT1 vaccine has potential for anticancer action. As the next step, we must investigate what kind of immune responses are induced by the vaccination, and how the induced immune responses lead to clinical responses. Even after cancer cells are damaged by CTLs, immune reactions continue. For example, epitope (of WT1 protein)-spreading or antigen (other than WT1 protein)-spreading occurs, followed by the activation of various kinds of CTLs or helper T cells. To clarify these immune reactions lead to construction of ‘proof of concept’ for WT1 peptide vaccination, and may lead to establishment of reliable immune reaction- monitoring methods to predict clinical responses, or im- provement of cancer vaccine. Evaluation of cancer vaccine-induced clinical responses Cancer chemotherapy drugs directly attack cancer cells, while cancer vaccine does not. The latter indirectly give damage to cancer cells by the activation of immune system. Therefore, we may need cancer vaccine-specific response evaluation criteria [ 45,69,70 ]. It is probable that some of the cancer vaccine-treated patients survive long-term with good QOL even if tumor regression is not obvious [ 41
], or that the tumor growth may be stabilized after an initial increase in its size because immunotherapy is generally not as quick-acting as chemotherapy [ 45,69,70 ]. Therefore, when we evalu- ate vaccination-induced clinical responses with RECIST, which is a gold standard in the field of cancer chemother- apy, it may be recommended that SD is highly regarded in cancer immunotherapy, particularly when SD persists long-term. It may also be recommended that the stabil- ization of disease after initial progression of disease, which is categorized as progressive disease (PD) in RECIST, is also evaluated favorably, like ‘SD after PD’. Appropriate clinical settings for cancer vaccine Once we accumulate evidences that show the potential of WT1 peptide vaccine to induce WT1-specific immuno- logical responses that lead to clinical responses in early phase clinical trials, we should start clinical trials in ‘adjuvant setting’, in which disease is ‘morphologically or radiologically undetectable but high risk of relapse’ after operation and/or chemotherapy. In this setting, effecter/target ratio is high, and immuno-suppressive environment induced by high amount of cancer cells is improbable. Adjuvant setting should be the most appro- priate setting in which cancer vaccine show its ability. Recurrence of disease may be reduced or postponed by the vaccination. WT1 peptide cancer vaccine Oka et al. 217
www.sciencedirect.com Current Opinion in Immunology 2008, 20:211–220 Conclusion We summarized recent investigation about elicitation of cancer antigen WT1-directed immune responses, and its clinical application as WT1 peptide cancer vaccine. Our understanding of cancer antigen-directed immune
responses at the cellular and molecular level continues to grow, which should lead to further development of cancer immunotherapy. Acknowledgements This study was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture and the Ministry of Health, Labor, and Welfare, Japan. References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH et al.: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 1990, 60:509- 520.
2. Gessler M, Poustka A, Cavenee W, Neve RL, OrkinSH, Bruns GA: Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 1990, 343:774-778. 3. Sugiyama H: Wilms’ tumor gene WT1: its oncogenic function and clinical application. Int J Hematol 2001, 73:177-187. 4. Oka Y, Tsuboi A, Kawakami M, Elisseeva OA, Nakajima H, Udaka K, Kawase I, Sugiyama H: Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers. Curr Med Chem 2006, 13:2345-2352. 5. Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H, Kita K, Hiraoka A, Masaoka T, Nasu K et al.: WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994, 84:3071-3079. 6. Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E, Hoelzer D: High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 1997, 90:1217-1225. 7. Ogawa H, Tamaki H, Ikegame K, Soma T, Kawakami M, Tsuboi A, Kim EH, Hosen N, Murakami M, Fujioka T et al.: The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 2003, 101:1698- 1704. 8.
Tatekawa T, Kawakami M, Asada M et al.: Expression of the Wilms’ tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Jpn J Cancer Res 1999, 90:194-204. 9. Oji Y, Miyoshi S, Maeda H, Hayashi S, Tamaki H, Nakatsuka S, Yao M, Takahashi E, Nakano Y, Hirabayashi H et al.: Overexpression of the Wilms’ tumor gene WT1 in de novo lung cancers. Int J Cancer 2002, 100:297-303. 10. Oji Y, Suzuki T, Nakano Y, Maruno M, Nakatsuka S, Jomgeow T, Abeno S, Tatsumi N, Yokota A, Aoyagi S et al.: Overexpression of the Wilms’ tumor gene W T1 in primary astrocytic tumors. Cancer Sci 2004, 95:822-827. 11. Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M, Kudoh T, Akiyama T, Murakami A, Maekawa T et al.: Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 1996, 87:2878-2884. 12. Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T, Oji Y, Tsuboi A, Kim EH, Kawakami M et al.: Wilms’ tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 1998, 91:2969-2976. 13. Melief CJ, Kast WM: T-cell immunotherapy of tumors by adoptive transfer of cytotoxic T lymphocytes and by vaccination with minimal essential epitopes. Immunol Rev 1995, 145:167-177. 14. Rosenberg SA: Progress in human tumour immunology and immunotherapy. Nature 2001, 411:380-384. 15. Ritz J: Tumor immunity: will new keys unlock the door? Clin Oncol 1994, 12:237-238. 16. Oka Y, Elisseeva OA, Tsuboi A, Ogawa H, Tamaki H, Li H, Oji Y, Kim EH, Som T, Asada M et al.: T-lymphocyte responses specific for peptides of the wild-type Wilms’ tumor gene (WT1) product. Immunogenetics 2000, 51:99-107. 17. Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K, Kishimoto T, Sugiyama H: Cancer immunotherapy targeting Wilms’ tumor gene WT1 product. J Immunol 2000, 164:1873- 1880. 18. Oka Y, Tsuboi A, Elisseeva OA, Udaka K, Sugiyama H: WT1 as a novel target antigen for cancer immunotherapy. Curr Cancer Drug Targets 2002, 2:45-54. 19. Gao L, Bellantuono I, Elsasser A, Marley SB, Gordon MY, Goldman JM, Stauss HJ: Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 2000, 95:2198-2203. 20. Ohminami H, Yasukawa M, Fujita S: HLA class I-restricted lysis of leukemia cells by a CD8(+) cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood 2000, 95:286-293. 21. Makita M, Hiraki A, Azuma T, Tsuboi A, Oka Y, Sugiyama H, Fujita S, Tanimoto M, Harada M, Yasukawa M: Antilung cancer effect of WT1-specific cytotoxic T lymphocytes. Clin Cancer Res 2002, 8:2626-2631. 22. Bellantuono I, Gao L, Parry S, Marley S, Dazzi F, Apperley J, Goldman JM, Stauss HJ: Two distinct HLA-A0201-presented epitopes of the Wilms tumor antigen 1 can function as targets for leukemia-reactive CTL. Blood 2002, 100:3835-3837. 23. Li Z, Oka Y, Tsuboi A, Masuda T, Tatsumi N, Kawakami M, Fujioka T, Sakaguchi N, Nakajima H, Fujiki F et al.: WT1(235), a ninemer peptide derived from Wilms’ tumor gene product, is a candidate peptide for the vaccination of HLA-A*0201-positive patients with hematopoietic malignancies. Int J Hematol 2005, 82:458-459. 24. Azuma T, Makita M, Ninomiya K, Fujita S, Harada M, Yasukawa M: Identification of a novel WT1-derived peptide which induces human leucocyte antigen-A24-restricted anti-leukaemia cytotoxic T lymphocytes. Br J Haematol 2002, 116: 601-603.
25. Savage P, Gao L, Vento K, Cowburn P, Man S, Steven N, Ogg G, McMichael A, Epenetos A, Goulmy E et al.: Use of B cell-bound HLA-A2 class I monomers to generate high-avidity, allo- restricted CTLs against the leukemia-associated protein Wilms tumor antigen. Blood 2004, 103:4613-4615. 26. Koesters R, Linnebacher M, Coy JF, Germann A, Schwitalle Y, Findeisen P, von Knebel M, Doeberitz M: WT1 is a tumor- associated antigen in colon cancer that can be recognized by in vitro stimulated cytotoxic T cells. Int J Cancer 2004, 109: 385-392.
27. Tsuboi A, Oka Y, Udaka K, Murakami M, Masuda T, Nakano A, Nakajima H, Yasukawa M, Hiraki A, Oji Y et al.: Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues. Cancer Immunol Immunother 2002, 51:614-620. 28. Pinilla-Ibarz J, May RJ, Korontsvit T, Gomez M, Kappel B, Zakhaleva V, Zhang RH, Scheinberg DA: Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein. Leukemia 2006, 20:2025- 2033.
218 Tumour Immunology Current Opinion in Immunology 2008, 20:211–220 www.sciencedirect.com 29. Doubrovina ES, Doubrovin MM, Lee S, Shieh JH, Heller G, Pamer E, O’Reilly RJ: In vitro stimulation with WT1 peptide- loaded Epstein–Barr virus-positive B cells elicits high frequencies of WT1 peptide-specific T cells with in vitro and in vivo tumoricidal activity. Clin Cancer Res 2004, 10:7207-7219. 30. Gao L, Xue SA, Hasserjian R, Cotter F, Kaeda J, Goldman JM, Dazzi F, Stauss HJ: Human cytotoxic T lymphocytes specific for Wilms’ tumor antigen-1 inhibit engraftment of leukemia- initiating stem cells in non-obese diabetic-severe combined immunodeficient recipients. Transplantation 2003, 75:1429-1436. 31. Gaiger A, Reese V, Disis ML, Cheever MA: Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood 2000, 96:1480-1489. 32. Gaiger A, Carter L, Greinix H, Carter D, McNeill PD, Houghton RL, Cornellison CD, Vedvick TS, Skeiky YA, Cheever MA: WT1-specific serum antibodies in patients with leukemia. Clin Cancer Res 2001, 7:761s-765s. 33. Elisseeva OA, Oka Y, Tsuboi A, Ogata K, Wu F, Kim EH, Soma T, Tamaki H, Kawakami M, Oji Y et al.: Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. Blood 2002, 99:3272-3279. 34. Wu F, Oka Y, Tsuboi A, Elisseeva OA, Ogata K, Nakajima H, Fujiki F, Masuda T, Murakami M, Yoshihara et al.: Th1-biased humoral immune responses against Wilms tumor gene WT1 product in the patients with hematopoietic malignancies. Leukemia 2005, 19:268-274. 35. Scheibenbogen C, Letsch A, Thiel E, Schmittel A, Mailaender V, Baerwolf S, Nagorsen D, Keilholz U: CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 2002, 100:2132-2137. 36. Rezvani K, Grube M, Brenchley JM, Sconochia G, Fujiwara H, Price D, Gostick E, Yamada K, Melenhorst J, Childs R et al.: Functional leukemia-associated antigen-specific memory CD8
+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation. Blood 2003, 102:2892-2900. 37.
Price DA, Douek DC, Barrett AJ: Graft-versus-leukemia effect associated with detectable Wilms tumor-1 specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia. Blood 2007, 110:1924-1932. This paper suggested that WT1-specific T cells had important roles in anti-leukemia effect in lymphoid malignancies as well as myeloid malig- nancies. 38. Rezvani K, Brenchley JM, Price DA, Kilical Y, Gostick E, Sewell AK, Li J, Mielke S, Douek DC, Barrett AJ: T-cell responses directed against multiple HLA-A*0201-restricted epitopes derived from Wilms’ tumor 1 protein in patients with leukemia and healthy donors: identification, quantification, and characterization. Clin Cancer Res 2005, 11:8799-8807. 39. Gillmore R, Xue SA, Holler A, Kaeda J, Hadjiminas D, Healy V, Dina R, Parry SC, Bellantuono I, Ghani Y et al.: Detection of Wilms’ tumor antigen-specific CTL in tumor-draining lymph nodes of patients with early breast cancer. Clin Cancer Res 2006, 12:34-42. 40. Morita Y, Heike Y, Kawakami M, Miura O, Nakatsuka S, Ebisawa M, Mori S, Tanosaki R, Fukuda T, Kim SW et al.: Monitoring of WT1-specific cytotoxic T lymphocytes after allogeneic hematopoietic stem cell transplantation. Int J Cancer 2006, 119:1360-1367. 41.
Oka Y, Tsuboi A, Taguchi T, Osaki T, Kyo T, Nakajima H, Elisseeva OA, Oji Y, Kawakami M, Ikegame K, Hosen N et al.: Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci U S A 2004, 101:13885-13890. This paper described obvious clinical responses induced by WT1 peptide vaccination, and a correlation between immunological and clinical responses in the vaccinated patients. 42. Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Li H, Kawasaki K, Aozasa K, Kishimoto T, Udaka K, Sugiyama H: Cytotoxic T- lymphocyte responses elicited to Wilms’ tumor gene WT1 product by DNA vaccination. J Clin Immunol 2000, 20:195-202. 43. Nakajima H, Kawasaki K, Oka Y, Tsuboi A, Kawakami M, Ikegame K, Hoshida Y, Fujiki F, Nakano A, Masuda T et al.: WT1 peptide vaccination combined with BCG-CWS is more efficient for tumor eradication than WT1 peptide vaccination alone. Cancer Immunol Immunother 2004, 53:617-624. 44. Oka Y, Tsuboi A, Murakami M, Hirai M, Tominaga N, Nakajima H, Elisseeva OA, Masuda T, Nakano A, Kawakami M et al.: Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis. Int J Hematol 2003, 78:56-61. 45. Oka Y, Tsuboi A, Elisseeva OA, Nakajima H, Fujiki F, Kawakami M, Shirakata T, Nishida S, hosen N, Oji Y et al.: WT1 peptide cancer vaccine for patients with hematopoietic malignancies and solid cancers. TheScientificWorldJournal 2007, 7:649-665. 46. Mailaender V, Scheibenbogen C, Thiel E, Letsch A, Blau IW, Keilholz U: Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity. Leukemia 2004, 18:165-166. 47.
Jafarpour B, Boss C, Barrett AJ: Leukemia-associated antigen specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood 2008, 111:236-242. This paper described association of leukemia-associated antigen (WT1 and PR1)-specific T cell responses with a decrease in WT1 mRNA level (a marker of MRD) in patients vaccinated with WT1 and PR1 peptide, suggesting the vaccination-driven antileukemia effect. 48. Azuma T, Otsuki T, Kuzushima K, Froelich CJ, Fujita S, Yasukawa M: Myeloma cells are highly sensitive to the granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes. Clin Cancer Res 2004, 10:7402-7412. 49. Tsuboi A, Oka Y, Nakajima H, Fukuda Y, Elisseeva OA, Yoshihara S, Hosen N, Ogata A, Kito K, Fujiki F et al.: Wilms’ tumor gene WT1 peptide-based immunotherapy induced minimal response in a patient with advanced, therapy-resistant multiple myeloma. Int J Hematol 2007, 86:414-417. 50. Kawakami M, Oka Y, Tsuboi A, Harada Y, Elisseeva OA, Furukawa Y, Tsukaguchi M, Shirakata T, Nishida S, Nakajima H et al.: Clinical and immunological responses to the vaccination with very low dose (5 mg/body) of WT1 peptide in a patient with chronic myelomonocytic leukemia. Int J Hematol 2007, 85:426-429. 51. Tuboi A, Oka Y, Osaki T, Kumagai T, Tachibana I, Hayashi S, Murakami M, Nakajima H, Elisseeva OA, Wu F et al.: WT1 peptide- based immunotherapy for patients with lung cancer: report of two cases. Microbiol Immunol 2004, 48:175-184. 52. Morita S, Oka Y, Tsuboi A, Kawakami M, Maruno M, Izumoto, Osaki T, Taguchi T, Ueda T, Myoui A et al.: A phase I/II trial of a WT1 (Wilms’ tumor gene) peptide vaccine in patients with solid malignancy: safety assessment based on the phase I data. Jpn J Clin Oncol 2006, 36:231-236. 53. Izumoto S, Tsuboi A, Oka Y, Suzuki T, Hashiba T, Kagawa N, Hashimoto N, Maruno M, Elisseeva OA, Shirakata T et al.: Phase II clinical trial of WT1 (Wilms tumor gene) peptide vaccination for patients with recurrent glioblastoma. J Neurosurg 2008, 108:963-971. 54. Iiyama T, Udaka K, Takeda S, Takeuchi T, Adachi YC, Ohtsuki Y, Tsuboi A, Nakatsuka S, Elisseeva OA, Oji Y et al.: WT1 (Wilms’ Tumor 1) peptide immunotherapy for renal cell carcinoma. Microbiol Immunol 2007, 51:519-530. 55. Noguchi M, Itoh K, Suekane S, Yao A, Suetsugu N, Katagiri K, Yamada A, Yamana H, Noda S: Phase I trial of patient-oriented vaccination in HLA-A2-positive patients with metastatic hormone-refractory prostate cancer. Cancer Sci 2004, 95: 77-84.
56. Drakos E, Rassidakis GZ, Tsioli P, Lai R, Jones D, Medeiros LJ: Differential expression of WT1 gene product in non-Hodgkin lymphomas. Appl Immunohistochem Mol Morphol 2005, 13: 132-137.
WT1 peptide cancer vaccine Oka et al. 219
www.sciencedirect.com Current Opinion in Immunology 2008, 20:211–220 57. Knights AJ, Zaniou A, Rees RC, Pawelec G, Muller L: Prediction of an HLA-DR-binding peptide derived from Wilms’ tumour 1 protein and demonstration of in vitro immunogenicity of WT1(124-138)-pulsed dendritic cells generated according to an optimised protocol. Cancer Immunol Immunother 2002, 51:271-281. 58. Muller L, Knights A, Pawelec G: Synthetic peptides derived from the Wilms’ tumor 1 protein sensitize human T lymphocytes to recognize chronic myelogenous leukemia cells. Hematol J 2003, 4:57-66. 59. Kobayashi H, Nagato T, Aoki N, Sato K, Kimura S, Tateno M, Celis E: Defining MHC class II T helper epitopes for WT1 tumor antigen. Cancer Immunol Immunother 2006, 55:850-860. 60.
Fujiki F, Oka Y, Tsuboi A, Kawakami M, Kawakatsu M, Nakajima H, Elisseeva OA, Harada Y, Ito K, Li Z et al.: Identification and characterization of a WT1 (Wilms tumor gene) protein-derived HLA-DRB1*0405-restricted 16-mer helper peptide that promotes the induction and activation of WT1-specific cytotoxic T lymphocytes. J Immunother 2007, 30:282-293. In this paper, it was demonstrated that an HLA class II-restricted, WT1- specific helper peptide had capacity to enhance induction/activation of WT1-specific CTLs. 61. May RJ, Dao T, Pinilla-Ibarz J, Korontsvit T, Zakhaleva V, Zhang RH, Maslak P, Scheinberg TA: Peptide epitopes from the Wilms’ tumor 1 oncoprotein stimulate CD4 + and CD8 + T cells
that recognize and kill human malignant mesothelioma tumor cells. Clin Cancer Res 2007, 13:4547-4555. 62.
Amabile M, Forconi F, Gozzetti A, Raspadori D et al.: Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet 2005, 365:657-662. This paper gave us evidence that TAA-derived peptide vaccination was a promising strategy for cancer treatment, particularly when the tumor burden was low. 63. Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP, Bieler JG, Emens LA, Reilly RT, Jaffee EM: Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med 2005, 201:1591-1602. 64. Chong G, Morse MA: Combining cancer vaccines with chemotherapy. Expert Opin Pharmacother 2005, 6:2813-2820. 65. Suzuki K, Kapoor V, Jassar AS, Kaiser LR, Albelda SM: Gemcitabine selectively eliminates slpenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005, 11:6713-6721. 66. Tsuji T, Yasukawa M, Matsuzaki J, Ohkuri T, Chamoto K, Wakita D, Azuma T, Niiya H, Miyoshi H, Kuzushima K et al.: Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. Blood 2005, 106:470-476. 67. Stauss HJ, Thomas S, Cesco-Gaspere M, Hart DP, Xue SA, Holler A, King J, Wright J, Perro M, Pospori C et al.: WT1-specific T cell receptor gene therapy: Improving TCR function in transduced T cells. Blood Cells Mol Dis 2008, 40:113-116. 68. Thomas S, Xue SA, Cesco-Gaspere M, San Jose E, Hart DP, Wong V, Debets R, Alarcon B, Morris E, Stauss HJ: Targeting the Wilms tumor antigen 1 by TCR gene transfer: TCR variants improve tetramer binding but not the function of gene modified human T cells. J Immunol 2007, 179:5803-5810. 69. Hori A, Kami M, Kim S-W, Murashige N, Sakiyama M, Kojima R, Hamaki T, Makimoto A, Miyakoshi S, Masuo S et al.: Urgent need for a validated tumor response evaluation system for use in immunotherapy. Bone Marrow Transplant 2004, 33:255-256. 70. Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, Urba W, Blumenstein B, Sacks N, Keilholz U et al.: A clinical development paradigm for cancer vaccines and related biologics. J Immunother 2007, 30:1-15. 220 Tumour Immunology Current Opinion in Immunology 2008, 20:211–220 www.sciencedirect.com Yüklə 0,51 Mb. Dostları ilə paylaş:
|