T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

Vroman, Heleen; Balzaretti, G; Belderbos, Robert A.; Klarenbeek, Paul L.; Nimwegen, Menno van; Bezemer, Koen; Cornelissen, Robin; Niewold, Ilse T.G.; Schaik, B.D. van; Kampen, Antione H van; Aerts, Joachim; Vries, Niek de; Hendriks, Rudolf W.

doi:10.1136/jitc-2019-000251

Cited by 20 publications

(22 citation statements)

References 26 publications

(20 reference statements)

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“…The median PFS was 8.8 months and median OS was not reached at a median follow-up of 22.8 months [ 137 ]. In a follow up analysis of the peripheral blood T cell receptor β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy, it was found that clinical responses to DC-mediated immunotherapy was dependent on both the pre-existing TCRβ repertoire of total CD3 + T cells and on therapy-induced changes, in particular expanding PD1 + CD8 + T cell clones, and therefore TCRβ repertoire profiling could potentially allow for the selection of MPM patients that might benefit from DC-based immunotherapy [ 138 ].…”

Section: Beyond Checkpoint Inhibitorsmentioning

confidence: 99%

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

Gray

2021

BMC Pulm Med

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Background The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Main text While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may affect the clinical outcomes of such therapies in this cancer. Conclusions The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratification, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer.

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Section: Beyond Checkpoint Inhibitorsmentioning

confidence: 99%

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

Gray

2021

BMC Pulm Med

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“…In our opinion, these findings show the potency of DC vaccination therapy in the long-term activation of the immune system. Translational research performed in these studies did reveal that DC vaccination was able to induce a tumor-directed anti-T-cell response, the essential step for effective immunotherapy [ 13 , 17 , 18 ]. This opens the potential for combination immunotherapy with DC therapy as a backbone.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Follow-Up of Mesothelioma Patients Treated with Dendritic Cell Therapy in Three Phase I/II Trials

et al. 2021

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Background: Malignant pleural mesothelioma (MPM) is a fatal neoplasm with, if untreated, poor survival of approximately nine months from diagnosis. Until recently, phase II–III immunotherapy trials did not show any significant benefit. The lack of immunotherapy efficacy can be explained by the fact that mesothelioma is a tumor with an “immune desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of DCs, which were ex-vivo cultured, exposed to (tumor-associated) antigens, and subsequently activated, this “immune desert” phenotype might be turned into an “inflamed” phenotype. Three phase I/II studies have been performed and published using activated DCs, which support this concept. We here report on the long-term survival of patients treated with DCs in three phase I/II studies. Methods: Survival data of the phase I/II trials using DC therapy in MPM patients were obtained and subsequently analyzed. In the first two trials, DCs were loaded with autologous tumor lysate. In the third trial, DCs were loaded with allogeneic mesothelioma tumor cell line lysate. Results: In the three studies combined, 29 patients with MPM were treated with DC vaccination between 2006 and 2015. At data cut-off, the median OS was 27 months (95% CI: 21–47 months). OS at 2 years was 55.2% (95% CI: 39.7–76.6%), and OS at 5 years was 20.7% (95% CI: 10.1–42.2%). Conclusions: The long-term survival of DC therapy in MPM in these three trials is promising, which is the basis for the randomized phase II/III DENIM study. This DENIM study is currently enrolling, and the results of which have to be awaited for definite conclusions.

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“…The diversity of TCR repertoire increases during the evolution of tumor progression with increased neoantigens and TAAs in both TME and sentinel lymph nodes [ 54 – 56 ]. Patients with higher TCR diversity have improved clinical responses to ICIs than those with lower TCR diversity in lung and cervical cancer [ 56 , 60 , 61 ]. The clonality and diversity of T-cell repertoires to neoantigens vary in tumors, non-tumor tissues and peripheral blood [ 56 , 60 ], which can evolve during cancer progression.…”

Section: Cancer Neoantigensmentioning

confidence: 99%

“…Patients with higher TCR diversity have improved clinical responses to ICIs than those with lower TCR diversity in lung and cervical cancer [ 56 , 60 , 61 ]. The clonality and diversity of T-cell repertoires to neoantigens vary in tumors, non-tumor tissues and peripheral blood [ 56 , 60 ], which can evolve during cancer progression. Anti-tumor immune responses require the functional presentation of tumor antigens and a TME that is replete with competent immune effectors.…”

Section: Cancer Neoantigensmentioning

confidence: 99%

Cancer neoantigens as potential targets for immunotherapy

Pham

2021

Clin Exp Metastasis

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Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programed cell death protein 1 (PD-1) or its ligand PD-L1 have increased the survival and cure rates for patients with many cancer types in various disease settings. However, only 10–40% of cancer patients benefited from these ICIs, of whom ~ 20% have treatment interruption or discontinuation due to immune-related adverse events that can be severe and even fatal. Current efforts in precision immunotherapy are focused on improving biomarker-based patient selection for currently available ICIs and exploring rationale combination and novel strategies to expand the benefit of immunotherapy to more cancer patients. Neoantigens arise from ~ 10% of the non-synonymous somatic mutations in cancer cells, are important targets of T cell-mediated anti-tumor immunity for individual patients. Advances in next generation sequencing technology and computational bioinformatics have enable the identification of genomic alterations, putative neoantigens, and gene expression profiling in individual tumors for personal oncology in a rapid and cost-effective way. Among the genomic biomarkers, defective mismatch DNA repair (dMMR), microsatellite instability high (MSI-H) and high tumor mutational burden (H-TMB) have received FDA approvals for selecting patients for ICI treatment. All these biomarkers measure high neoantigen load and tumor antigenicity, supporting the current development of neoantigen-based personalized cancer vaccines for patients with high TMB tumor. Several studies have shown neoantigen vaccines are feasible, safe and have promising clinical activity in patients with high TMB tumors in both metastatic and adjuvant settings. This review summarizes the emerging data and technologies for neoantigen-based personalized immunotherapy.

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T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma

Cited by 20 publications

References 26 publications

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

Long-Term Follow-Up of Mesothelioma Patients Treated with Dendritic Cell Therapy in Three Phase I/II Trials

Cancer neoantigens as potential targets for immunotherapy

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