A quest for therapeutic antigens in bone and soft tissue sarcoma

Kawaguchi, Satoshi; Wada, Takuro; Tsukahara, Tomohide; Ida, Kazunori; Torigoe, Toshihiko; Sato, Noriyuki; Yamashita, Toshihiko

doi:10.1186/1479-5876-3-31

Cited by 17 publications

(6 citation statements)

References 57 publications

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“…The absence of information about the natural variability of tetramer-positive cells in patients, the low frequencies of tetramer-positive cells, and the absence of replicate analyses further suggests that tetramer-positive cells might not have been elicited with vaccination. A similar result and interpretation was found in the previous trial conducted by this group, in which they commented that other measures of immune response should be conducted in the future, such as by IFN-γ ELISPOT [4]. However, no other measures of immune response were employed in the current trial.…”

Section: Expert Commentarysupporting

confidence: 80%

“…No DTH responses were detected, a technique commonly used to detect memory T-cell immune responses elicited by peptide vaccines [9–11]. The absence of DTH responses to the native epitope in the current and previous [4] trials suggests memory-type responses were not elicited. In addition, the tetramer analysis was not uniformly conducted, making it impossible to compare results among treatment groups.…”

Section: Expert Commentarymentioning

confidence: 99%

“…They further identified that this epitope could be modified at an anchor residue (agretope-modified, K9I substitution – GYDQIMPKI) to increase HLA-A24 binding and generation of CTL responses in vitro with cross-reactivity to the native epitope [3]. They previously conducted a clinical trial evaluating the safety and immunological efficacy of the SS393 peptide in HLA-A24 + patients with recurrent synovial sarcoma [4]. In the current study, they evaluate this peptide as well as the K9I variant, alone or with IFN-α, in a trial of HLA-A24 + patients with metastatic synovial sarcoma [5].…”

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confidence: 99%

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Vaccination using peptides spanning the SYT–SSX tumor-specific translocation

Bloom

McNeel²,

Olson

2012

Expert Review of Vaccines

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The identification of genetic translocations as key tumor-initiating events has led to the development of novel antigen-specific vaccines targeting these tumor-specific breakpoint regions. Previous studies have evaluated vaccines targeting the breakpoints in the BCR-ABL translocation in patients with chronic myelogenous leukemia and EWS-FLI1 in patients with Ewing sarcoma. In the article under evaluation, the authors evaluated a peptide vaccine targeting the breakpoint in the SYT–SSX translocation, the genetic translocation essentially pathognomonic for synovial sarcoma. This is the second small clinical trial reported by this group using HLA-A24-binding peptides as vaccine antigens. In this four-arm trial, using a native or HLA-A24-optimized SYT–SSX peptide with or without adjuvant plus IFN-α, they immunized patients with metastatic synovial sarcoma. Immune responses were evaluated by delayed-type hypersensitivity testing and tetramer analysis. No robust evidence of immune response to the target epitope was detected. Some patients treated with peptide in adjuvant plus IFN-α had stable disease. These results suggest that future similar studies might best evaluate patients with a lower burden of disease, consider alternative immunization approaches to the SYT–SSX target antigen and consider the efficacy of IFN-α alone for the treatment of synovial sarcoma.

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Section: Expert Commentarysupporting

confidence: 80%

Section: Expert Commentarymentioning

confidence: 99%

mentioning

confidence: 99%

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Vaccination using peptides spanning the SYT–SSX tumor-specific translocation

Bloom

McNeel²,

Olson

2012

Expert Review of Vaccines

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“…Although most Ewing sarcoma tumors show only little infiltration by lymphocytes [ 37 ], the fact that BCL11B is expressed in normal T cells ( Supplementary Figure 2 ) should be taken into account when assessing immunoreactivity in small-round-cell tumors. In indeterminate cases, a CD3 staining may be helpful ( Supplementary Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets

Baldauf¹,

Orth²,

Dallmayer³

et al. 2017

Oncotarget

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Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics.To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4-, BCOR-CCNB3-, EWSR1-NFATc2-, and EWSR1-ETS-translocated sarcomas are distinct entities, and revealed that ATP1A1, BCL11B, and GLG1 constitute specific markers for Ewing sarcoma. Their high expression was validated by immunohistochemistry and proved to depend on EWSR1-FLI1-binding to highly active proximal super-enhancers. Automated cut-off-finding and combination-testing in a tissue-microarray comprising 174 samples demonstrated that detection of high BCL11B and/or GLG1 expression is sufficient to reach 96% specificity for Ewing sarcoma. While 88% of tested Ewing-like sarcomas displayed strong CD99-immunoreactivity, none displayed combined strong BCL11B- and GLG1-immunoreactivity.Collectively, we show that ATP1A1, BCL11B, and GLG1 are EWSR1-FLI1 targets, of which BCL11B and GLG1 offer a fast, simple, and cost-efficient way to diagnose Ewing sarcoma by immunohistochemistry. These markers may significantly reduce the number of misdiagnosed patients, and thus improve patient care.

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“…Moreover, there is evidence for both spontaneous regression as well-efficient immunosurveillance in sarcoma, prompting investigators to explore immunotherapy as a treatment modality (6,7). Recently, several clinical trials have included sarcoma patients in the testing of various immunotherapy strategies, including: (i) immune checkpoint blockade (8)(9)(10); (ii) tumorspecific or tumor-associated peptide vaccines (11)(12)(13)(14); and (iii) adoptive immune cell therapies with allogeneic NK cells (ongoing clinical trials), autologous T cells (15), CAR-T cells (ongoing clinical trials) and NY-ESO-1-specific T cells (16) to name a few (17). However, these studies aim to target general tumor markers found in a variety of solid tumors and hematological malignancies, not specifically targeting sarcomas.…”

Section: Introductionmentioning

confidence: 99%

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

et al. 2020

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Sayitoglu et al. Boosting NK Cell-Mediated Sarcoma Targeting cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1 + or NKG2D + GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.

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A quest for therapeutic antigens in bone and soft tissue sarcoma

Cited by 17 publications

References 57 publications

Vaccination using peptides spanning the SYT–SSX tumor-specific translocation

Vaccination using peptides spanning the SYT–SSX tumor-specific translocation

Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

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