Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

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Tab. 9.1 (continued) 9.8 Phase I/II Clinical Trials Type of cancer Antigen Center DC type Route of Number of Response reported Reference immuni- individuals zation immunized Renal cell carcinoma Metastatic CEA expressing Metastatic CEA expressing cell lysate + KLH CAP-1 peptide/ RNA CAP-1 peptide Pancreas tumor lysate +KLH Gastrointestinal MAGE peptide Glioma Acid-eluted peptide Glioma tumor/auto DC fusion Solid tumors tumor lysate (pediatric) +KLH Innsbruck Ma Mo i.v. 12 renal cell carcinoma, normal kidney and KLH proliferation 146 Durham Im Mo i.v. 17 CEA-specific CTL equal response in peptide and RNA cohorts 118 Durham Im Mo i.v. 21 1 SD 158 Dusseldorf Ma Mo s.c. 1 vaccine DTH, lymphocyte proliferation, decreased marker; metastasis regression 179 Kyushu Im Mo i.v. 12 peptide-specific CTL 4/8; reduced tumor marker 7/12 180 Los Angeles Im Mo s.c. 7 CTL infiltrate in tumor; prolonged survival 163 Tokyo Ma Mo i.d. 8 2 PR 164 Ann Arbor Im Mo i.d. 8 tumor regression 162 CAE: carcinoembrionic antigen; CAP: peptide fragment of CAE; Ph1: Philadelphia chromosome; i.n.: intranodal; Im: Immature; Ma: mature; Mo: Mo-DC; SD: stable disease. variable outcome, but it is now recognized that on going vaccination may be necessary to maintain immunity. Multiple myeloma has also attracted attention. Again there is data to suggest patients can mount T-mediated anti-idiotype responses [136]. In vitro studies confirm the ability of autologous Mo-DCs to generate such responses [137, 138] and the one clinical study suggested that DCs generated anti-idiotype responses after autologous stem cell transplantation [139]. Multiple myeloma patients may be more immunosuppressed and idiotype may be a weak TAA, but as all these studies have employed the i.v. route of immunization this may account for the relatively low frequency of anti-idiotype responses (four of 26 versus 24 of 26 KLH control in [140]). Interestingly, three-quarters of responders in the later study were in complete disease remission. Another study performed in the post-transplant setting [107] remains to be fully reported; however, it too suggests responses may occur in the MRD setting 191
192 9 Dendritic Cells and Cancer: Prospects for Cancer Vaccination after autologous stem cell transplant for multiple myeloma. A remarkable nine out of 18 clinical responses [ five complete responses (CRs) and four partial responses (PRs)] were seen in this context (F. H. Valone, personal communication) It is perhaps in melanoma that greatest interest was aroused and there are a plethora of trials in progress. Few have been formally reported, but the follow-up from the first description of the use of Mo-DCs and melanoma peptides/tumor lysates [132] shows two CRs and three PRs in 21 patients with metastatic disease, indicating an ongoing control of disease in the proportion of patients who responded with a mean survival of over 47 months in responder patients. This protocol induced peptide-specific T cell responses in 10 out of 10 HLA-A2 patients. A second trial [141] used Mo- DCs matured in monocyte-conditioned medium s.c. and i.d. induced specific CTL expansion in eight out of 11 HLA/A1 patients, but notably these responses declined after further i.v. injections. Regression of metastases occurred in six out of 11 patients. Notably, the same group has reported poor clinical results (no regressions in eight evaluable patients) in a third study involving HLA-A2 individuals, but using the same MAGE-3 antigen. Curiously, the later patient group had active melanoma peptide-specific IFN-g effector CD8 + T cells (confirmatory cytotoxic studies were not performed) present and received DCs by the possibly more optimal s.c. protocol. However, a fourth published study [76] using immature Mo-DCs administered i.d. produced poor cytotoxic responses and had only one partial clinical response in seven patients evaluated. A protocol which used CD34 + -derived DCs administered s.c. enhanced immunity in at least one assay (ELISPOT or proliferation) in 16 of 18 patients ± DTH responses were independent of blood assay results [91]. During a 10week evaluation, four patients with multiple lesions experience regression at one or more disease sites and three with limited disease cleared evidence of the disease. In broad terms, immunological responses predicted for disease response. Another trial made use of CD34 + -derived DCs but gave them i.v. ± the monitoring of immunological responses was limited, but these patients had a lesser clinical response, again suggesting that perhaps the i.v. route is less effective [89]. A consensus (including unpublished studies) is emerging despite the different approaches that in advanced melanoma some 20±30% of patients have a significant clinical response. The use of immature Mo-DCs may be associated with a lesser outcome [89, 142] in melanoma unless their preparation and antigen loading involves activation, as may have occurred in the first trial. Immunological tests may predict for the group with some clinical response [143]. A formal comparison of immature versus mature Mo-DCs used different DCs preparations and antigens in the same patients [144]; it was not possible to allocate the positive clinical outcomes to a particular preparation although, as commented earlier, differences in Tcell responses were seen. Other most encouraging results have been obtained in renal cell carcinoma [145± 147]. The use of allogeneic tumor cell±DC hybrids was pioneered in this area [117] ± the excellent results are being investigated further. Again, it is perhaps relevant that this is a disease in which immune responses are known to occur, e.g. following IL- 2/LAK therapy. There has been a large cohort of prostate cancer patients studied by two groups [72, 148±157], perhaps in part because prostate organ-specific antigens [e.g. prostate-spe-
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Cancer Immune Therapie: Current and
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Editors: Dr. Gernot Stuhler Univers
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VI Preface Recent years have seen a
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VIII Contents 2.5.3 Antigens Encode
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X Contents 6.4.2 Natural Killer (NK
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XII Contents 9.6 Loading DC with An
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XIV Contents 14.2.2.1 Cancer-specif
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List of Contributors Richard Bucala
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Color Plates Fig. 5.2 The MHC class
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Fig. 5.5 Different immune effector
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Fig. 5.17 Possible pathway for the
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Fig. 6.2 T lymphocytes in the tumor
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Index a acidic and basic fibroblast
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±, see also tumors cationic lipids
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e EBV see Epstein-Barr virus EDR se
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immature Mo-DCs 184 immune cells ±
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MHC class I antigen-processing mach
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±, onco- 209 ±, over-expressed ce
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TICD see tumor-induced cell death T
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Part 1 Tumor Antigenicity Cancer Im
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4 1 Search for Universal Tumor-Asso
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10 1 Search for Universal Tumor-Ass
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18 2 Serological Determinants On Tu
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30 Cancer Immune Therapie: Current
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32 3 Processing and Presentation of
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42 4 T Cells In Tumor Immunity cult
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44 4 T Cells In Tumor Immunity cell
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46 4 T Cells In Tumor Immunity to T
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48 4 T Cells In Tumor Immunity Alth
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50 4 T Cells In Tumor Immunity Tab.
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52 4 T Cells In Tumor Immunity rest
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54 4 T Cells In Tumor Immunity 53 T
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Part 2 Immune Evasion and Suppressi
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60 5 Major Histocompatibility Compl
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68 Tab. 5.1 HLA class I loss attrib
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96 6 Immune Cells in the Tumor Micr
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98 6 Immune Cells in the Tumor Micr
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100 6 Immune Cells in the Tumor Mic
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Tab. 7.1 Effects of tumor-derived m
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122 7 Immunosuppresive Factors in C
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Page 173 and 174: 138 7 Immunosuppresive Factors in C
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Page 213 and 214: 180 9 Dendritic Cells and Cancer: P
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Page 239 and 240: 206 10 The Immune System in Cancer:
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Page 265 and 266: 232 11 Hybrid Cell Vaccination for
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242 11 Hybrid Cell Vaccination for
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254 12 Principles and Strategies Em
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270 13 Applications of CpG Motifs f
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288 14 The T-Body Approach: Towards
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300 15 Bone Marrow Transplantation
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312 16 Immunocytokines: Versatile M
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348 17 Immunotoxins and Recombinant
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382 Glossary tion to the variable d
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384 Glossary suppressor gene produc
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386 Glossary press the proper recep
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388 Glossary gp96 See Chaperone. Gr
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390 Glossary cytes and addressing l
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392 Glossary T bodies are being tes
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Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

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