Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

Groisberg, Roman; Hong, David S.; Amini, Behrang; Hess, Kenneth R.; Janků, Filip; Piha-Paul, Sarina A.; Naing, Aung; Fu, Siqing; Benjamin, Robert S.; Patel, Shreyaskumar; Somaiah, Neeta; Conley, Anthony P.; Meric‐Bernstam, Funda; Subbiah, Vivek

doi:10.1186/s40425-017-0301-y

Cited by 118 publications

(109 citation statements)

References 37 publications

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“…The dissociation in the expression of CD8 and and PD1/PD-L1 axis suggests that adenosarcoma is a less favorable target for PD1/PD-L1 checkpoint inhibitors [27] and may use an alternate immune escape mechanism. Further investigations are required to identify immunologic therapeutic targets that may affect uterine adenosarcoma or other soft tissue sarcomas [8,10,28].…”

Section: Discussionmentioning

confidence: 99%

The immune microenvironment of uterine adenosarcomas

et al. 2020

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Background: Uterine adenosarcoma (UA) is an extremely rare sarcoma subtype. There has been limited evaluation of the immune microenvironment in these tumors. The objective of this study is to examine and describe the immune infiltrate and PD-1/PD-L1 expression in UA and to correlate these changes in the tumor micro-environment with the overall survival status or the disease-free survival status (DFSS), respectively.Methods: Patients (pts) treated at our center from 1982 to 2014 with UA were identified. Fifteen cases had tumor paraffin-embedded blocks available. Immunohistochemistry studies for CD3, CD8, FOXP3, CD163, PD-1 and PD-L1 (clone 22C3) were performed. Image analysis was used to assess the density (cells/mm 2 ), except in PD-L1, where the percentage of membranous staining on tumor cells was noted.Results: Immune infiltrate analysis median (range) density in cells/mm 2 varied broadly: CD3 178 (15-802); CD8 117 (11-661); FoxP3 4.8 (0.2-82); CD163 791 (264-1861); and PD1 5 (1-65). 3 cases had rare (1%) PD-L1 tumor membranous labeling. The reports yielded that ten pts were alive, and 5 were dead. Pts who were alive had significant higher CD3 and CD8 median densities in tumors than those who were dead (p = 0.040). There was no correlation between DFSS and CD3 or CD8 median densities. Patients who had no local recurrence had significantly higher CD3 and CD8 median densities in tumors than those who had local recurrence (p = 0.040). Conclusions:In conclusion, this is the first report characterizing the presence of immune infiltrate and PD-1/PD-L1 expression in UA. CD3+ CD8+ T-cells density may be prognostic. The immune-responsiveness of UA needs to be further investigated in a larger study.

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Section: Discussionmentioning

confidence: 99%

The immune microenvironment of uterine adenosarcomas

et al. 2020

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“…In STS patients, current clinical trials have indicated that the response to PD-1/PD-L1 blockade therapy varied in different subtypes and only a few liposarcoma patients had objective responses to pembrolizumab. 25,26 Due to the small sample size and uncertain effectiveness, further application of immune checkpoint inhibitors in RLPS is limited to date. 27 Several studies have been undertaken to evaluate the immune landscape in patients with STS.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive immune characterization and T‐cell receptor repertoire heterogeneity of retroperitoneal liposarcoma

et al. 2019

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Retroperitoneal liposarcoma (RLPS) is one of the most common subtypes of retroperitoneal soft tissue sarcomas and lacks effective treatment. This study aimed to provide a thorough profile of immune characteristics of RLPS. This study included 56 RLPS patients. Multisite tumor tissues were collected from 16 patients. Immunohistochemistry was carried out to identify CD4+, CD8+, FoxP3+, CD20+, or programmed cell death‐1 (PD‐1)+ tumor infiltrating lymphocytes (TILs) and Programmed cell death ligand‐1 (PD‐L1) expression in tumor tissues. Ultradeep sequencing of T‐cell receptor (TCR) β‐chain gene was carried out in 42 tumor samples as well as peripheral blood samples collected from 6 patients. In RLPS, TILs were distributed in 3 patterns and T cells were more prevalent than B cells. Generally, the proportion of TILs decreased and PD‐L1 expression increased with tumor progression. Patients with higher PD‐1/PD‐L1 expression tended to have poorer prognosis, whereas patients with tertiary lymphoid structure tended to have a favorable disease‐free survival. Although T‐cell clones in tumors were quite different from those in peripheral blood, TCR sequencing showed low TCR repertoire reads as well as polyclonal status within tumors, which indicated limited T cell response in the tumors. Both TILs distribution and TCR repertoires suggested spatial immune heterogeneity in RLPS. Our research described the immune landscape of RLPS, and suggested RLPS might be a kind of tumor with low T cell infiltration as well as great immune heterogeneity. Therefore, strategies that can facilitate lymphocytic infiltration and immune reactivity need to be developed in the future to improve the efficacy of immunotherapy.

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“…Of note, other investigators have demonstrated stable disease for 33% (3/9) in patients with metastatic or unresectable GIST treated with checkpoint inhibitor-based trials. 16 Interestingly, this tumor had a low density of CD3 + T cells, which is unique for this patient given that higher levels of CD3+ infiltrates may portend a superior PFS. 17 Furthermore, while the co-localization of CD163+ and PD-L1 was expected, the expression of FOXP3 largely in the absence of CD3+ and CD4+ was surprising.…”

Section: Discussionmentioning

confidence: 85%

“…21 Because imatinib has activity against IDO in the GIST microenvironment, 22 the combination of imatinib and anti-PD1 has been investigated in murine models with promising synergy, 14 but this has been less evident in a phase I clinical trial. 16 However, PD1 is probably critical because when KIT inhibition was combined with the CTLA-4 inhibitor ipilimumab, clinical outcomes did not appear improved. 23 PD-L1 expression in GIST can be heterogenous, particularly in higher-risk tumors, further strengthening the argument for combination immunotherapy, and a trial is now ongoing at UCLA (NCT02880020) comparing single-agent nivolumab (anti-PD-1) alone or in combination with ipilimumab (anti-CTLA-4).…”

Section: Discussionmentioning

confidence: 99%

Durable tumor regression in highly refractory metastatic KIT/PDGFRA wild-type GIST following treatment with nivolumab

et al. 2020

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2020) Durable tumor regression in highly refractory metastatic KIT/PDGFRA wild-type GIST following treatment with nivolumab, OncoImmunology, 9:1, 1710064, ABSTRACTGastrointestinal stromal tumor (GIST) is a devastating disease, especially in the setting of metastasis. The natural progression of GIST has been significantly altered by the development of small molecule tyrosine kinase inhibitors (TKIs), including imatinib, sunitinib, and regorafenib, all of which are FDA approved. However, TKIs are not always well-tolerated, and the refractory disease continues to be a problem. For these reasons, alternative treatments are needed. In this report, we discuss a patient with metastatic wild-type (WT) GIST refractory to multiple TKIs, but with a durable clinical response to the antiprogrammed cell death protein 1 (PD-1) antibody, nivolumab. This report suggests that continued research evaluating checkpoint inhibitors in GIST is warranted. ARTICLE HISTORY

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Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

Cited by 118 publications

References 37 publications

The immune microenvironment of uterine adenosarcomas

The immune microenvironment of uterine adenosarcomas

Comprehensive immune characterization and T‐cell receptor repertoire heterogeneity of retroperitoneal liposarcoma

Durable tumor regression in highly refractory metastatic KIT/PDGFRA wild-type GIST following treatment with nivolumab

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