Identification of NY-ESO-1 Peptide Analogues Capable of Improved Stimulation of Tumor-Reactive CTL

Chen, J L; Dunbar, P. Rod; Gileadi, Uzi; Jäger, Elke; Gnjatic, Sacha; Nagata, Yasunobu; Stockert, Elisabeth; Panicali, Dennis; Chen, Y T; Knuth, Alexander; Old, Lloyd J.; Cerundolo, Vincenzo

doi:10.4049/jimmunol.165.2.948

Cited by 160 publications

(160 citation statements)

References 23 publications

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“…Heteroclitic peptides, selected on the basis of in vitro or in silico testing, contain amino-acid substitutions that increase the stability of the peptide/MHC complex and often generate robust cytotoxic T-cell responses that cross-react with the native peptide epitope. [50][51][52][53][54][55] WT1 has emerged as a potentially important target in PCM, after it was shown that the patients who received DLI following T-cell-depleted allo-HCT developed increased WT1-specific T-cell responses post DLI, which were associated with reduction in paraprotein. 56 An ongoing study at the Memorial Sloan-Kettering Cancer Center targets residual myeloma post auto-HCT with a heteroclitic WT1 peptide vaccine combined with three WT1 SLPs and delivered with montanide and GM-CSF adjuvant.…”

Section: Myeloma Vaccinesmentioning

confidence: 99%

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Lendvai

Cohen

Cho

2015

Bone Marrow Transplant

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Autologous hematopoietic cell transplantation (auto-HCT) is the standard consolidation therapy for plasma cell myeloma patients following induction therapy. Auto-HCT improves disease-free survival (DFS), but is generally not curative. The allogeneic HCT experience demonstrated that T-cell immunotherapy can confer long-term DFS. Preclinical and clinical data indicate that myelomaassociated Ags elicit humoral and cellular immune responses (IRs) in myeloma patients. These findings strongly suggest that the immunotherapeutic strategies, including immune checkpoint inhibitors, therapeutic cancer vaccines and adoptive cellular therapies, are promising avenues of clinical research that may be most applicable in the minimal residual disease state following auto-HCT. These strategies are designed to prime or augment antimyeloma IRs and promote a 'host-vs-myeloma' effect that may result in durable DFS. Innovative clinical trials investigating immune checkpoint inhibitors and cancer vaccines have demonstrated that robust immunity against myeloma-associated Ags can be elicited in the setting of auto-HCT. A diverse array of immunotherapeutic strategies have entered clinical trials in myeloma, including PD-1/PD-L1 inhibitors, DC/myeloma cell fusion vaccines and adoptive chimeric Ag receptor T-cell therapy, and further investigation of combinations of immunologic and pharmaceutical agents are expected in the near future. In this review, we will discuss the preclinical data supporting immunotherapy in auto-HCT for myeloma, clinical investigation of these strategies and the future prospects of immunotherapy in pursuit of the goal of curative therapy.

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Section: Myeloma Vaccinesmentioning

confidence: 99%

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Lendvai

Cohen

Cho

2015

Bone Marrow Transplant

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“…Ten days after DNA priming, mice were boosted by i.v. injection of recombinant vaccinia virus (rVV) expressing the minigene NY-ESO-1 157-165 containing a Val at position 165 (40). Seven days after vaccinia boosting, mice were killed and splenocytes stimulated in vitro in the presence of 10 M NY-ESO-1 157-165 peptide in medium containing 100 U/ml IL-2 (PeproTech, Rocky Hill, NJ).…”

Section: Murine Ctl Linesmentioning

confidence: 99%

High Avidity Antigen-Specific CTL Identified by CD8-Independent Tetramer Staining

Choi

Chen

Wooldridge

et al. 2003

The Journal of Immunology

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Tetrameric MHC/peptide complexes are important tools for enumerating, phenotyping, and rapidly cloning Ag-specific T cells. It remains however unclear whether they can reliably distinguish between high and low avidity T cell clones. In this report, tetramers with mutated CD8 binding site selectively stain higher avidity human and murine CTL capable of recognizing physiological levels of Ag. Furthermore, we demonstrate that CD8 binding significantly enhances the avidity as well as the stability of interactions between CTL and cognate tetramers. The use of CD8-null tetramers to identify high avidity CTL provides a tool to compare vaccination strategies for their ability to enhance the frequency of high avidity CTL. Using this technique, we show that DNA priming and vaccinia boosting of HHD A2 transgenic mice fail to selectively expand large numbers of high avidity NY-ESO-1157–165-specific CTL, possibly due to the large amounts of antigenic peptide delivered by the vaccinia virus. Furthermore, development of a protocol for rapid identification of high avidity human and murine T cells using tetramers with impaired CD8 binding provides an opportunity not only to monitor expansion of high avidity T cell responses ex vivo, but also to sort high avidity CTL clones for adoptive T cell transfer therapy.

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“…21 To overcome this problem, amino acid substitutions have been tested in several tumor antigens, such as NY-ESO-1, gp100 as well as MART-1. 22,23 Several modifications successfully improved the binding affinity for HLA and immunogenicity.…”

Section: Induction Of Gp2-specific Tumor-reactive Ctl By In Vitro Stmentioning

confidence: 99%

Modification of the HER2NEU‐derived tumor antigen GP2 improves induction of GP2‐reactive cytotoxic T lymphocytes

et al. 2001

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GP2 (IISAVVGIL), the p654 -662 HER2/neu-derived tumor antigen, induces HLA-A2-restricted cytotoxic T lymphocytes (CTL) reactive to various epithelial cancers. The binding affinity of GP2 for HLA-A2, however, is very low. To improve the immunogenicity of GP2, we tested 10 different amino acid substitutions into GP2 at the C-and N-terminus. Five out of 10 modified peptides, especially those containing phenylalanine at position 1 (1F), showed a significantly improved binding affinity to HLA-A2. 1F-based modified peptides were well recognized by GP2-specific CTL. These peptides were used to stimulate peripheral blood lymphocytes from HLA-A2 healthy donors using peptide-pulsed autologous dendritic cells (DC). After 3 or more weekly stimulations, CTL activity against GP2 pulsed T2 (T2-GP2) and HER2/neuoverexpressing tumor cells was measured in 51 Cr release and IFN-␥ secretion assays. The modified peptides significantly enhanced GP2-specific CTL activity in some donors. In particular, the peptide with phenylalanine at position 1, leucine at position 2 and valine at position 10 (1F2L10V) maximized the CTL activity against both T2-GP2 and HER2/neu-positive tumor cells. Peptide 1F2L10V increased not only the binding affinity to HLA-A2 but also improved recognition of GP2. These data suggest that DC ؉ modified GP2 may improve immune therapies for the treatment of HER2/neu overexpressing tumors.

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Identification of NY-ESO-1 Peptide Analogues Capable of Improved Stimulation of Tumor-Reactive CTL

Cited by 160 publications

References 23 publications

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

High Avidity Antigen-Specific CTL Identified by CD8-Independent Tetramer Staining

Modification of the HER2NEU‐derived tumor antigen GP2 improves induction of GP2‐reactive cytotoxic T lymphocytes

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