Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells

Goff, Peter H.; Riolobos, Laura; LaFleur, Bonnie; Spraker, Matthew B.; Seo, Yongwoo David; Smythe, Kimberly S.; Campbell, Jean S.; Pierce, Robert H.; Zhang, Yuzheng; He, Qianchuan; Kim, Edward Y.; Schaub, Stephanie K.; Kane, Gabrielle; Mantilla, José G.; Chen, Eleanor; Ricciotti, Robert W.; Thompson, Marc; Cranmer, Lee D.; Wagner, Michael J.; Loggers, Elizabeth T.; Jones, Robin L.; Murphy, Erin; Blumenschein, Wendy M.; McClanahan, Terrill K.; Earls, Jon; Flanagan, Kevin C.; LaFranzo, Natalie A.; Kim, Teresa S.; Pollack, Seth M.

doi:10.1158/1078-0432.ccr-21-4239

Cited by 18 publications

(13 citation statements)

References 49 publications

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“…We saw large increases in the clonality of PBMCs, including expansion of TCR sequences observed in TILs, suggesting additional systemic potential for this therapy . In 1 patient, the expanded clonotypes in posttreatment TILs (with evidence of clonal convergence) were isolated in posttreatment PBMCs; single-cell analysis revealed that these clonotypes expressed a T H 1 phenotype.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

Seo,

Lu,

Black

et al. 2023

JAMA Oncol

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ImportanceMetastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts.ObjectiveTo evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions.Design, Setting, and ParticipantsThis phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022.InterventionsTwo doses of IT GLA-SE (5 μg and 10 μg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion.Main Outcomes and MeasuresPrimary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes.ResultsTwelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, −25%; range, −100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion −39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype.Conclusions and RelevanceIn this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted.Trial RegistrationClinicalTrials.gov Identifier: NCT02180698

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Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

Seo,

Lu,

Black

et al. 2023

JAMA Oncol

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“…Numerous studies have demonstrated impaired STING signaling or downregulation of STING in cancer cells, suggesting the stromal constituents of the TIME are the critical targets of STING activation (60)(61)(62)(63). As macrophages are highly sensitive to STING agonists (64)(65)(66) and are abundant in both human and pre-clinical sarcoma models (29,39,56,(67)(68)(69), we hypothesized that a reduction in tumor associated macrophages (TAMs) would mitigate the therapeutic response to STING agonism. Monocytes are known to contribute to the TAM populations, and the CCR2/CCL2 signaling is critical for TAM recruitment from monocyte lineages (55).…”

Section: Discussionmentioning

confidence: 99%

Intratumoral STING activation causes durable immunogenic tumor eradication in the KP soft tissue sarcoma model

Marritt

Hildebrand

et al. 2023

Front. Immunol.

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IntroductionSoft tissue sarcomas (STS) are highly metastatic, connective-tissue lineage solid cancers. Immunologically, sarcomas are frequently characterized by a paucity of tumor infiltrating lymphocytes and an immune suppressive microenvironment. Activation of the STING pathway can induce potent immune-driven anti-tumor responses within immunogenic solid tumors; however, this strategy has not been evaluated in immunologically cold sarcomas. Herein, we assessed the therapeutic response of intratumoral STING activation in an immunologically cold murine model of undifferentiated pleomorphic sarcoma (UPS).Materials and ResultsA single intratumoral injection of the murine STING agonist, DMXAA resulted in durable cure in up to 60% of UPS-bearing mice. In mice with synchronous lung metastases, STING activation within hindlimb tumors resulted in 50% cure in both anatomic sites. Surviving mice all rejected UPS re-challenge in the hindlimb and lung. Therapeutic efficacy of STING was inhibited by lymphocyte deficiency but unaffected by macrophage deficiency. Immune phenotyping demonstrated enrichment of lymphocytic responses in tumors at multiple timepoints following treatment. Immune checkpoint blockade enhanced survival following STING activation.DiscussionThese data suggest intratumoral activation of the STING pathway elicits local and systemic anti-tumor immune responses in a lymphocyte poor sarcoma model and deserves further evaluation as an adjunctive local and systemic treatment for sarcomas.

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“…Our report is retrospective, and interpretations are limited by its descriptive nature. Notably, the differences observed in immune microenvironment after specific treatments or between primary, recurrent, and metastatic tumors are exploratory by nature and would warrant longitudinal paired analyses to properly assess the role of treatments ( 33 , 53 ) and time ( 54 , 55 ). The heterogeneity of our cohort impacts our results most notably regarding preoperative treatments received and we have tried to address this by detailing associations in specific subgroups; however, subgroup analyses are limited by the smaller number of patients.…”

Section: Discussionmentioning

confidence: 99%

The immune landscape of undifferentiated pleomorphic sarcoma

et al. 2022

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IntroductionUndifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes.Material and methodsSurgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters.ResultsSamples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p<0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p<0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p<0.0001) and DFS (p<0.001).ConclusionWe identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.

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Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells

Cited by 18 publications

References 49 publications

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

Intratumoral STING activation causes durable immunogenic tumor eradication in the KP soft tissue sarcoma model

The immune landscape of undifferentiated pleomorphic sarcoma

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