Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer

Slager, Elisabeth H.; Honders, M. Willy; Meijden, Edith D. van der; Luxemburg-Heijs, Simone A.P. van; Kloosterboer, Freke M.; Kester, Michel G.D.; Jedema, Inge; Marijt, W. A. Erik; Schaafsma, Martyn Ronald; Willemze, R.; Falkenburg, J.H. Frederik

doi:10.1182/blood-2005-09-3883

Cited by 59 publications

(82 citation statements)

References 41 publications

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“…Here, we analyzed the expression of the LRH-1-encoding P2X5 gene in a large panel of solid tumor cell lines and primary tumor specimens using real-time quantitative RT-PCR. SigniWcant P2X5 mRNA levels were detected in 31% of the solid tumor cell lines tested, including RCC, melanoma, colorectal carcinoma, [12,16], ECGF-1 [23], and BCL2A1 [2,24]. Enlargement of the panel of MiHA is essential for development of eVective post-transplantation immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it would be highly beneWcial to direct donor T cell immunity towards MiHA that are selectively co-expressed on hematopoietic cells and solid tumor cells by vaccination or T cell therapy. Only a few hematopoietic-restricted MiHA have been described that are aberrantly expressed on solid tumors, including HA-1 [12,16], ECGF-1 [23] and BCL2A1 [2,24]. Therefore, it is important to enlarge the panel of MiHA that can be used for immunotherapy of solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant expression of the hematopoietic-restricted minor histocompatibility antigen LRH-1 on solid tumors results in efficient cytotoxic T cell-mediated lysis

Overes

Levenga

Vos

et al. 2008

Cancer Immunol Immunother

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CD8 + T cells recognizing minor histocompatibility antigens (MiHA) on solid tumor cells may mediate eVective graft-versus-tumor (GVT) reactivity after allogeneic stem cell transplantation (SCT). Previously, we identiWed LRH-1 as a hematopoietic-restricted MiHA encoded by the P2X5 gene. Here, we report that LRH-1 is aberrantly expressed on solid tumor cells. P2X5 mRNA expression is demonstrated in a signiWcant portion of solid tumor cell lines, including renal cell carcinoma (RCC), melanoma, colorectal carcinoma, brain cancer and breast cancer. Importantly, P2X5 gene expression was also detected in a subset of primary solid tumor specimens derived from RCC, brain cancer and breast cancer patients. Furthermore, P2X5 expressing solid tumor cells can be eVectively targeted by LRH-1-speciWc cytotoxic T lymphocytes under inXammatory conditions. The expression of HLA-B7 and CD54 on tumor cells increases upon cytokine stimulation resulting in improved T cell activation as observed by higher levels of degranulation and enhanced tumor cell lysis. Overall, hematopoietic-restricted MiHA LRH-1 is aberrantly expressed on solid tumor cells and may be used as target in GVT-speciWc immunotherapy after SCT.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aberrant expression of the hematopoietic-restricted minor histocompatibility antigen LRH-1 on solid tumors results in efficient cytotoxic T cell-mediated lysis

Overes

Levenga

Vos

et al. 2008

Cancer Immunol Immunother

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“…9,35 Recently, a single nucleotide polymorphism found in an alternatively translated peptide of TP has been found to be associated with cytotoxic T lymphocyte immune response in multiple myeloma. 36 One limitation of the current study is the reliance on real-time PCR from archival tissue sections. These types of analyses rely on messenger RNA expression as a surrogate for protein expression, and activity and variability in sample collection and storage can likely affect the readout of gene expression.…”

Section: Discussionmentioning

confidence: 99%

Molecular determinants of efficacy for 5‐FU‐based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy‐related genes

Gustavsson

Kaiser

Carlsson

et al. 2008

Intl Journal of Cancer

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5‐Fluorouracil (5‐FU)‐based regimens remain a cornerstone in the treatment of colorectal cancer (CRC). However, the attendant toxicity prevents these regimens from reaching maximum therapeutic potential. In this retrospective analysis, we examined the pretreatment expression of 18 genes in archival tumor bank samples from patients with advanced CRC to determine if one or more of the selected genes showed promise as either a prognostic or predictive marker of 5‐FU‐based treatment outcomes. One hundred and forty‐four CRC patient samples (collected from 1983 to 2004) were analyzed via real‐time PCR for gene expression. Univariate analyses were used to correlate gene expression with efficacy and time‐to‐event variables. Low thymidine phosphorylase (TP), dihydrofolate reductase, dihydropyrimidine dehydrogenase (DPD), excision repair cross‐complementing 1 (ERCC1) and thymidylate synthase gene expression were associated with better time‐to‐progression in the entire population. Low TP, DPD and ERCC1 expression were independently associated with improved overall survival. Low TP gene expression was also predictive of response. This study suggests that TP gene expression in particular is a predictive as well as a prognostic biomarker for advanced CRC patients. Gene panels assessing pretreatment TP, DPD, ERCC1, dihydrofolate reductase and thymidylate synthase gene expression may help improve the therapeutic potential of 5‐FU‐ or other novel antifolate‐based regimens. Further analysis of the prognostic or predictive value of these genes in prospective trials in CRC patients seems warranted. © 2008 Wiley‐Liss, Inc.

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“…These mHA-specific T cells recognized patient MM cells and characterization of these T-cell clones isolated from peripheral blood ultimately led to the molecular identification of the mHAs ADIR 6 and ECGF. 7 In this case report, the HLA-A3-restricted CTL clone 44 from our patient UPN8458 was isolated from BM, the site where the tumor resides. Quantitative analysis of CTL clone 44-specific TCR transcripts revealed the presence of CTL clone 44 in both peripheral blood and BM.…”

Section: Case Descriptionmentioning

confidence: 99%

“…4 In the setting of using unloaded recipient-derived DC vaccines, we aimed at the induction of alloreactive donor T-cell responses against both known and unknown mHA on myeloma tumor cells of the recipient. Previously, it has been reported that mHA-specific CTL isolated from transplanted MM patients are able to target mHA, like HA-1, 5 ADIR 6 and ECGF, 7 that are co-expressed by MM tumor cells and monocyte-derived DCs. In this study, we investigated mHA-specific-CD8 þ T-cell responses in a MM patient who successfully obtained long-term clinical remission (CR) in the absence of GVHD after treatment with reduced intensity conditioning (RIC) --SCT followed by DLI and recipient DC vaccination.…”

Section: Introductionmentioning

confidence: 99%

Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs

Broen

Greupink-Draaisma

Fredrix

et al. 2012

Bone Marrow Transplant

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Recently, we demonstrated that reduced intensity conditioning (RIC) followed by partial T-cell-depleted SCT creates a platform for inducing the graft-versus-myeloma effect by adjuvant immunotherapy. Here, we evaluated mHA-specific T-cell responses in a multiple myeloma (MM) patient who was treated with RIC --SCT followed by donor lymphocyte infusion (DLI) and subsequent recipient DC vaccination. We isolated a mHA-specific CTL clone with the capacity to target MM tumor cells from this patient experiencing long-term CR. This CTL clone recognizes an HLA-A3-restricted mHA and mediates killing of both primary MM cells and the MM-cell line U266, while BM-derived fibroblasts are not recognized. CTL-specific T-cell receptor (TCR) transcripts could be detected by quantitative PCR analysis in both peripheral blood and BM during tumor remission. Interestingly, a strong increase of CTL-specific TCR transcripts at the BM tumor site was observed following DLI and recipient DC vaccination, while the TCR signal in peripheral blood decreased. These findings illustrate that the approach of partial T-cell-depleted RIC --SCT followed by post-transplantation immunotherapy induces mHA-specific T-cell responses targeting MM tumor cells. Keywords: graft-versus-tumor; minor histocompatibility antigen; multiple myeloma; immunotherapy; cytotoxic T cells; DCs INTRODUCTIONAllo-SCT has the potential to cure patients with multiple myeloma (MM) due to the graft-versus-myeloma (GVM) effect. 1,2 This GVM effect can be mediated by alloreactive donor T cells targeting mHA expressed on myeloma tumor cells in the BM. Previously, we have established the potential of partial T-cell-depleted allo-SCT followed by pre-emptive donor lymphocyte infusion (DLI) to induce GVM immunity with limited risk of inducing GVHD. These studies showed that long-term CR can be induced in about one third of MM patients. 3 To further improve these results, we have explored the possibility of boosting GVM immunity, without the toxicity and morbidity due to GVHD, by means of recipient DC vaccination post-DLI. Although we showed that mature recipientderived DC could be generated, and that vaccination resulted in limited toxicity, no obvious direct effects on tumor load could be demonstrated. 4 In the setting of using unloaded recipient-derived DC vaccines, we aimed at the induction of alloreactive donor T-cell responses against both known and unknown mHA on myeloma tumor cells of the recipient. Previously, it has been reported that mHA-specific CTL isolated from transplanted MM patients are able to target mHA, like HA-1, 5 ADIR 6 and ECGF, 7 that are co-expressed by MM tumor cells and monocyte-derived DCs. In this study, we investigated mHA-specific-CD8 þ T-cell responses in a MM patient who successfully obtained long-term clinical remission (CR) in the absence of GVHD after treatment with reduced intensity conditioning (RIC) --SCT followed by DLI and recipient DC vaccination. Following DC vaccination, primary T-cell responses were elicited against keyhole limpet hemocyanin (...

show abstract

Identification of the angiogenic endothelial-cell growth factor-1/thymidine phosphorylase as a potential target for immunotherapy of cancer

Cited by 59 publications

References 41 publications

Aberrant expression of the hematopoietic-restricted minor histocompatibility antigen LRH-1 on solid tumors results in efficient cytotoxic T cell-mediated lysis

Aberrant expression of the hematopoietic-restricted minor histocompatibility antigen LRH-1 on solid tumors results in efficient cytotoxic T cell-mediated lysis

Molecular determinants of efficacy for 5‐FU‐based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy‐related genes

Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs

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