Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk

Chiriva‐Internati, Maurizio; Wang, Zhiqing; Xue, Yuying; Bumm, Klaus; Hahn, Amy B.; Lim, Seah H.

doi:10.1002/1521-4141(200108)31:8<2277::aid-immu2277>3.0.co;2-z

Cited by 50 publications

(58 citation statements)

References 13 publications

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“…Therefore, it was not surprising that Sp17 specific CTLs were generated easily in our previous study. 12 In contrast, patients with advanced tumors often are suppressed immunologically due to the disease process and also to chemotherapy treatment. It also is conceivable that Sp17 specific T-cells may be deleted from the immune repertoire of these patients, especially those in whom Sp17 is expressed in tumor cells, as a form of a tumor immune escape mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Tumor vaccine for ovarian carcinoma targeting sperm protein 17

Chiriva‐Internati¹,

Wang²,

Salati³

et al. 2002

Cancer

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Section: Discussionmentioning

confidence: 99%

“…IL-2 was added to the culture every 3-4 days thereafter. Irradiated autologous PBMC feeder cells and Sp17 recombinant protein (50 g/mL), generated as described previously, 12 were added to the culture every week. The cells were harvested after four rounds of stimulation and used for cytotoxicity assays.…”

Section: In Vitro Generation Of Sp17 Specific Ctlmentioning

confidence: 99%

Tumor vaccine for ovarian carcinoma targeting sperm protein 17

Chiriva‐Internati¹,

Wang²,

Salati³

et al. 2002

Cancer

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“…6 It was found that Sp17 103-111 peptide-pulsed targets could indeed be recognized and killed by Sp17-specific HLA-A1-restricted CTLs. In contrast, target cell lysis was not observed when the LCLs were not pulsed with any synthetic peptide or pulsed with a scrambled sequence nonapeptide (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…4,8 Through these works, we have successfully generated an Sp17-specific HLA-A1-restricted CTL line from a healthy donor. 6 Since delineation of the CTL epitope may provide the tool for the future study and characterization of CD8 T-cell function in vivo and the generation of epitope-specific therapeutic strategies, we have in the present study used this T-cell line to determine the Sp17 CTL epitope restricted by the HLA-A1 element. …”

mentioning

confidence: 99%

Identification of a sperm protein 17 CTL epitope restricted by HLA‐A1

Chiriva‐Internati

Wang

Pochopien

et al. 2003

Intl Journal of Cancer

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Sperm protein 17 (Sp17) is a novel cancer-testis antigen. We previously reported the successful generation of Sp17-specific HLA-A1-restricted cytotoxic T-lymphocytes (CTLs) from the peripheral blood of a healthy donor using a recombinant Sp17 protein. These CTLs were able to kill not only target cells pulsed with the recombinant protein but also fresh Sp17؉ tumor cells. In the present study, we have identified a nonapeptide sequence within the Sp17 protein that is predicted to have a high binding affinity for the HLA-A1 molecules. We generated the synthetic nonapeptide and successfully propagated a peptide-specific CTL line. We confirmed that peptide Sp17 Sperm protein 17 (Sp17) is a spermatozoa-specific protein of unknown function, although it has been implicated in acrosome reactions during fertilization 1 and appears to bind heparan sulfate. 2 It is a highly immunogenic protein in vivo because a high proportion of vasectomized males spontaneously develops anti-Sp17 antibodies. We have identified Sp17 as a novel cancer-testis (CT) antigen in multiple myeloma 3 and ovarian cancer. 4 Sp17 expression is found at both the mRNA and protein levels and its normal tissue expression is limited to only testis and not any other normal tissues. The restricted normal tissue expression of Sp17 has now been confirmed independently, 5 suggesting that an Sp17-based tumor vaccine will be tumor-specific with very limited toxicities to normal tissues.The clinical relevance of our findings has been supported by further work demonstrating the ability to generate Sp17-specific cytotoxic T-lymphocytes (CTLs) that could kill Sp17-positive fresh autologous or HLA-matched tumor cells from healthy donors 6,7 and cancer-bearing patients. 4,8 Through these works, we have successfully generated an Sp17-specific HLA-A1-restricted CTL line from a healthy donor. 6 Since delineation of the CTL epitope may provide the tool for the future study and characterization of CD8 T-cell function in vivo and the generation of epitope-specific therapeutic strategies, we have in the present study used this T-cell line to determine the Sp17 CTL epitope restricted by the HLA-A1 element. MATERIAL AND METHODSPeripheral blood mononuclear cells (PBMCs) were separated from heparinized venous blood by Ficoll-Hypaque density gradient centrifugation. Dendritic cells (DCs) were generated from peripheral blood monocytes as previously described. 9 Briefly, PBMCs were seeded into 6-well culture plates containing 3 ml of RPMI 1640 and 10% FCS at 5-10 ϫ 10 6 per well. After 2 hr at 37°C, nonadherent cells were removed and the adherent cells were cultured at 37°C in RPMI 1640 supplemented with 10% FCS, 800 IU/ml GM-CSF and 1000 IU/ml IL-4. After 7 days of culture, DCs were harvested for pulsing with the synthetic peptide and used as antigen-presenting cells for the generation of Sp17 peptide-specific CTLs. Successful generation of DCs was confirmed in flow cytometry.Following culture, the DCs were washed twice and added to 50 ml polypropylene tubes. The DCs were pulsed with...

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“…Not only could Sp17-specific cytotoxic T lymphocytes (CTLs) be easily generated from the peripheral blood of healthy donors [34,35], they could also be generated from the peripheral blood of cancer-bearing patients, irrespective of the Sp17 status of their cancers [36,37]. More importantly, these CTLs were able to kill HLAmatched Sp17 + fresh tumor cells [35], indicating the potential for using Sp17 in tumor vaccines. As expected, the CTLs killed their target cells via the perforin-mediated pathway.…”

Section: Sp17 and Immunotherapymentioning

confidence: 99%

Cancer immunotherapy targeting Sp17: When should the laboratory findings be translated to the clinics?

et al. 2005

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Despite advances in chemotherapeutic agents, the prognosis for some cancers remains extremely poor, suggesting the need for other treatment modalities. Immunotherapy appears an ideal approach because the mechanisms of tumor cell killing induced by tumor vaccines are different from those from chemotherapy. Various investigations are ongoing to identify suitable targets for this purpose. Sperm protein 17 (Sp17) was originally identified by our group as a novel cancer-testis antigen in various malignancies, including multiple myeloma. Sp17 is a highly immunogenic protein and the observation that more than 90% of vasectomized males develop immunity against Sp17 suggests the opportunity and safety of Sp17 for tumor vaccines. Recent works by other workers suggest a low level of expression of Sp17 in some normal tissues, and investigators have questioned whether Sp17 is in fact a suitable target for immunotherapy. In this paper, we review the general principles of immunotherapy and provide evidence supporting the highly immunogenic nature of Sp17. We also address the discrepancies between the objectives of oncologists involved in treating cancer patients and their familiarity with acceptable levels of toxicity of any effective therapy and those of pure laboratory-based investigators. Finally, we present some early clinical data supporting the rationale for further investigations of Sp17 for tumor vaccines. Am.

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Sperm protein 17 (Sp17) in multiple myeloma: opportunity for myeloma-specific donor T cell infusion to enhance graft-versus-myeloma effect without increasing graft-versus-host disease risk

Cited by 50 publications

References 13 publications

Tumor vaccine for ovarian carcinoma targeting sperm protein 17

Tumor vaccine for ovarian carcinoma targeting sperm protein 17

Identification of a sperm protein 17 CTL epitope restricted by HLA‐A1

Cancer immunotherapy targeting Sp17: When should the laboratory findings be translated to the clinics?

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