Bcr/abl+ autologous dendritic cells for vaccination in chronic myeloid leukemia

Westermann, Jörg; Kopp, Joachim; Körner, Ida J.; Richter, Gregor; Qin, Zhihai; Blankenstein, Thomas; Dörken, Bernd; Pezzutto, Antonio

doi:10.1038/sj.bmt.1702354

Cited by 25 publications

(16 citation statements)

References 11 publications

(8 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These vaccines rather induced delayed-type hypersensitivity and/or CD4 proliferative responses. However, BCR-ABL-specific cytotoxic T cell responses were rarely detected, indicating that this antigen might be less antigenic (11)(12)(13)(14). In line with these observations, in patients with INF-g-treated CML, antigen-specific CTLs recognizing overexpressed antigens like proteinase 3 (PR3), which is also involved in Wegener's granulomatosis, were found to contribute to the elimination of malignant cells (15)(16)(17)(18).…”

Section: Introductionsupporting

confidence: 61%

BCR-ABL Is Not an Immunodominant Antigen in Chronic Myelogenous Leukemia

Grünebach

Mirakaj²,

Mirakaj³

et al. 2006

Cancer Research

View full text Add to dashboard Cite

In the present study, we analyzed the involvement of the BCR-ABL protein in the induction of antigen-specific CTL in order to develop an immunotherapeutic approach in patients with chronic myelogenous leukemia (CML). To accomplish this, we generated dendritic cells (DC) in vitro and electroporated them with various sources of RNA harboring the chimeric bcrabl transcript. These genetically engineered DCs were used as antigen-presenting cells for the induction of CTLs. By applying this approach, we found that the CTLs induced by DCs transfected with RNA extracted from bcr-abl-positive K-562 cells or CML blasts lysed DCs transfected with the corresponding RNA, but failed to recognize epitopes derived from the chimeric BCR-ABL fusion protein in 51 Cr-release assays. In contrast, they were able to lyse autologous DCs electroporated with RNA isolated from patients with acute myeloid leukemia, indicating that antigens shared among these malignant cells are involved and recognized by these CTLs. In patients with CML in complete cytogenetic remission during IFN-A treatment, we detected some reactivity of CD8 + T cells against BCR-ABL in IFN-; ELISPOT assays, which was weaker as compared with proteinase 3 (PR3)-or pramedirected responses, suggesting that the BCR-ABL protein is less immunogenic as compared with other CML-derived antigens. (Cancer Res 2006; 66(11): 5892-900)

show abstract

Section: Introductionsupporting

confidence: 61%

BCR-ABL Is Not an Immunodominant Antigen in Chronic Myelogenous Leukemia

Grünebach

Mirakaj²,

Mirakaj³

et al. 2006

Cancer Research

View full text Add to dashboard Cite

show abstract

“…More potent vaccines are also under investigation, including the use of dendritic cells derived from patients with CML or dendritic cells transfected by a recombinant adeno-associated virus that contains a p210 bcr-abl fusion domain DNA. 30,34,35 We observed significant reductions in the percentage of Ph ϩ in 3 of the 5 patients treated with interferon while in the trial; ultimately, all 5 of these patients reached a complete cytogenetic remission. This remarkable finding is difficult to interpret because of the concomitant and continued therapy with other drugs, but these data raise the question of an interaction between the interferon-alpha and the vaccine.…”

Section: Discussionmentioning

confidence: 88%

A multivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia

Cathcart

Pinilla‐Ibarz

Korontsvit

et al. 2004

Blood

183

103

View full text Add to dashboard Cite

A tumor-specific, bcr-abl-derived fusion peptide vaccine can be safely administered to patients with chronic myelogenous leukemia (CML) and can elicit a bcr-abl peptide-specific T-cell immune response. In the present phase 2 trial, 14 patients with CML in chronic phase were vaccinated with 6 fusion peptides mixed with Quillaja saponaria (QS-21). No significant toxic effects were observed. In 14 of 14 patients, delayed-type hypersensitivity (DTH) and/or CD4 proliferative responses developed after beginning vaccinations, and 11 of 14 patients showed interferon-gamma (IFN-gamma) release by CD4 enzyme-linked immunospot (ELIS-POT) at one or more time points. These responses were CD4 ؉ CD45RO ؉ . A peptidespecific CD8 ؉ interferon-gamma ELIS-POT was found in 4 patients. Four patients in hematologic remission had a decrease in Philadelphia chromosome (Ph) percentage (3 concurrently receiving interferon-alpha and 1 on imatinib mesylate), and 3 patients in molecular relapse after allogenic transplantation became transiently polymerase chain reaction (PCR) negative after vaccination; 2 of these patients received concurrent donor lymphocyte infusion (DLI). All 5 patients on IFN-alpha ultimately reached a complete cytogenetic remission. In conclusion, a tumor-specific bcr-abl breakpoint peptide-derived vaccine can be safely administered and can reliably elicit measurable peptide-specific CD4 immune responses, including in patients after bone marrow transplantation, on interferon, or on imatinib mesylate. A relationship between the clinical responses and vaccination cannot be determined from this trial. IntroductionChronic myelogenous leukemia (CML) presents a unique opportunity to develop therapeutic strategies using vaccination against a truly tumor-specific antigen that is also the oncogenic protein. The chimeric fusion protein is a tumor-specific antigen because the junctional regions of p210 contain a sequence of amino acids that is not expressed in a normal cell; in addition, as a result of the codon split on the fused message, a new amino acid (lysine in bcr-abl [b3a2]) is found. [1][2][3][4][5][6][7][8] Fusion peptides from the junctional sequences of CML can bind to several class I and class II molecules and also elicit human leukocyte antigen (HLA)-restricted cytotoxicity and proliferation in vitro. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Recently, Clark et al 24 have confirmed our previous supposition that peptides derived from the bcr-abl protein can be processed in the cytosol and loaded in HLA molecules that will be transported to the surface of the CML cell for potential T-cell recognition.These features provided the immunologic basis for our initial phase 1 trial in which a bcr-abl (b3a2)-derived peptide vaccine elicited a bcr-abl peptide-specific T-cell immune response, despite the presence of active disease in these patients. 25 The current phase 2 trial was designed to answer the following questions in a larger cohort of patients with CML in chronic phase: (1) whether a fixed dose of p...

show abstract

“…This was probably because all of the selected patients were in the advanced stage and the amount of the inoculated DCs was rather small (92). Thus, at least 10 × 106 DCs are required to elicit an immune response in patients with CML, and an autologous CML-specific T cell response has been detected (93)(94)(95). Additionally, infused CML-DCs induced the appearance of T cell clones expressing the same T cell receptor, suggesting that the immune repertoire included tumor-reactive T cells.…”

Section: Leukemia-derived Dcs For Clinical Use and Results Of Clinicamentioning

confidence: 99%