Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors

Kosari, Farhad; Disselhorst, Maria; Yin, Jun; Peikert, Tobias; Udell, Julia; Johnson, Sarah H.; Smadbeck, James B.; Murphy, Stephen J.; McCune, Alexa; Karagouga, Giannoula; Desai, Aakash; Schaefer-Klein, Janet; Borad, Mitesh J.; Cheville, John C.; Vasmatzis, George; Baas, Paul; Mansfield, Aaron S.

doi:10.1016/j.jtho.2021.10.022

Cited by 14 publications

(14 citation statements)

References 30 publications

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“…With these six APP gene sets, the HRs representing associations between tumor junction burdens and OS favored patients with high APP scores (all HRs < 1) more so than patients with low APP scores (all HRs > 1). Moreover, patients with a low APP gene expression and a high tumor junction burden showed a worse prognosis compared to patients with high APP score and high tumor junction burden when treated with ICIs (42). This is in line with the concept that ICIs need neoantigens presentation on cancer cells to activate cytotoxic T-cell antitumor response (42).…”

Section: Genomic Biomarkerssupporting

confidence: 75%

“…• Specific genomic alterations can explain an higher neoantigens formation and/or the mechanisms underlying a greater or poorer immune activation (7,(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54) • Limited data about potentially useful specific genomic alterations.…”

Section: Genomic Biomarkermentioning

confidence: 99%

“…Mansfield et al observed wide inter-and intrachromosomal rearrangements in the form of chromo-anagenesis, such as chromoplexy or chromothripsis, in 86% of MM samples analyzed (40). Chromothripsis is a pattern of different chromosomal rearrangements resulting from multiple double-strand breaks and reassembly of a long segment or an entire chromosome (42). Chromothripsis has been associated with a worse prognosis in MM patients (40).…”

Section: Genomic Biomarkersmentioning

confidence: 99%

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Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress

et al. 2023

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Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient’s selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated.In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed.

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Section: Genomic Biomarkerssupporting

confidence: 75%

Section: Genomic Biomarkermentioning

confidence: 99%

Section: Genomic Biomarkersmentioning

confidence: 99%

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Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress

et al. 2023

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“…5 We will have to wait for the TMA results from Checkmate 743 in the future; however, a fascinating "hot off the press" publication from one of these authors (A.M.) found a relationship between tumor junction burden and antigen presenation which predicted overall survival in patients treated with dual or single check point inhibitors. 6 To confuse us further, previously untreated, unresectable MPM treated with durvalumab with platinum-pemetrexed responding to chemoimmunotherapy in the PrE0505 trial 1,7 had a 20.4-month median survival (especially epithelioid tumors), and had higher nonsynonymous missense TMB and a more clonal mutation repertoire than nonresponding tumors! Additionally, responding tumors had specific alterations associated with immunogenic mutations proven with in vitro T cell clonal expansion techniques.…”

Section: Harvey I Pass Mdmentioning

confidence: 99%

Commentary: A chess game for mesothelioma treatment: Not checkmate yet!

Pass

2023

The Journal of Thoracic and Cardiovascular Surgery

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“…These results promoted us to explore the use of DMXAA as an alternative anti-angiogenic in a preclinical setting that may offer longer survival with minimal toxicity. Mesothelioma is also responsive to immunotherapy which has now entered into standard care (6)(7)(8)(9)(10)(11) and there is evidence it may be responsive to Stimulator of Interferon Genes (STING) agonists (12) which is reported to target tumor blood vessels and the immune system.…”

Section: Introductionmentioning

confidence: 99%

The STING agonist, DMXAA, reduces tumor vessels and enhances mesothelioma tumor antigen presentation yet blunts cytotoxic T cell function in a murine model

et al. 2022

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We assessed the murine Stimulator of Interferon Genes (STING) agonist, DMXAA, for anti-mesothelioma potential using the AE17-sOVA model that expresses ovalbumin (OVA) as a neo tumor antigen. Dose response experiments alongside testing different routes of administration identified a safe effective treatment regimen that induced 100% cures in mice with small or large tumors. Three doses of 25mg/kg DMXAA given intra-tumorally every 9 days induced tumor regression and long-term survival (>5 months). Re-challenge experiments showed that tumor-free mice developed protective memory. MTT and propidium-iodide assays showed that DMXAA exerted direct cytotoxic effects at doses >1mg/ml on the murine AE17 and AB1 mesothelioma cell lines. In-vivo studies using a CFSE-based in-vivo proliferation assay showed that DMXAA improved tumor-antigen presentation in tumor-draining lymph nodes, evidenced by OVA-specific OT-1 T cells undergoing more divisions. An in-vivo cytotoxic T lymphocyte (CTL) assay showed that DMXAA blunted the lytic quality of CTLs recognizing the dominant (SIINFEKL) and a subdominant (KVVRFDKL) OVA epitopes. DMXAA reduced tumor vessel size in-vivo and although the proportion of T cells infiltrating tumors reduced, the proportion of tumor-specific T cells increased. These data show careful dosing and treatment protocols reduce mesothelioma cell viability and modulate tumor vessels such that tumor-antigen specific CTLs access the tumor site. However, attempts to enhance DMXAA-induced anti-tumor responses by combination with an agonist anti-CD40 antibody or IL-2 reduced efficacy. These proof-of-concept data suggest that mesothelioma patients could benefit from treatment with a STING agonist, but combination with immunotherapy should be cautiously undertaken.

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Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated With Immune Checkpoint Inhibitors

Cited by 14 publications

References 30 publications

Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress

Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress

Commentary: A chess game for mesothelioma treatment: Not checkmate yet!

The STING agonist, DMXAA, reduces tumor vessels and enhances mesothelioma tumor antigen presentation yet blunts cytotoxic T cell function in a murine model

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