Immunotherapy In Mesothelioma Research Articles

Immunotherapy of mesothelioma: the evolving change of a long-standing therapeutic dream.

Pleural mesothelioma (PM) is an aggressive and rare disease, characterized by a very poor prognosis. For almost two decades, the world standard treatment regimen for unresectable PM has consisted of a platinum-based drug plus pemetrexed, leading to an overall survival of approximately 12 months. The dramatic therapeutic scenario of PM has recently changed with the entry into the clinic of immune checkpoint inhibition, which has proven to be an effective approach to improve the survival of PM patients. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced PM.

PPD04.01 Survival Associations of T cell Clusters with Immunotherapy in Mesothelioma

PPD04.01 Survival Associations of T cell Clusters with Immunotherapy in Mesothelioma

CONFIRM trial: what is the real efficacy of second-line immunotherapy in mesothelioma? – Authors' reply

CONFIRM trial: what is the real efficacy of second-line immunotherapy in mesothelioma? – Authors' reply

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

IntroductionThe favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected because this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Because chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy. MethodsPleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n = 44) before treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole-genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements and antigen processing and presentation gene set expression. Associations with overall survival (OS) were estimated using Cox models. An OS cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic curves. ResultsAlthough tumor junction burdens were not predictive of OS, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The “regulation of antigen processing and presentation of peptide antigen” gene set revealed an interaction with tumor junction burden and was predictive of OS. This interaction also predicted 1.5-year or greater survival with an area under the receiving operating characteristic curve of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors. ConclusionsAnalysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors.

Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. Median survival ranges from 14 to 20 months after initial diagnosis. As of November 2020, the FDA approved a combination of immune checkpoint inhibitors after promising intermediate results. Nonetheless, responses remain unsatisfying. Adequate patient stratification to improve response rates is still lacking. This retrospective study analyzed formalin fixed paraffin embedded specimens from a cohort of 22 MPM. Twelve of those samples showed sarcomatoid, ten epithelioid differentiation. Complete follow-up, including radiological assessment of response by modRECIST and time to death, was available with reported deaths of all patients. RNA of all samples was isolated and subjected to digital gene expression pattern analysis. Our study revealed a notable difference between epithelioid and sarcomatoid mesothelioma, showing differential gene expression for 304/698 expressed genes. Whereas antigen processing and presentation to resident cytotoxic T cells as well as phagocytosis is highly affected in sarcomatoid mesothelioma, cell-cell interaction via cytokines seems to be of greater importance in epithelioid cases. Our work reveals the specific role of the immune system within the different histologic subtypes of MPM, providing a more detailed background of their immunogenic potential. This is of great interest regarding therapeutic strategies including immunotherapy in mesothelioma.

Immunotherapy for mesothelioma: a critical review of current clinical trials and future perspectives.

At the clinical level the role of immunotherapy in cancer is currently at a pivotal point. Therapies such as checkpoint inhibitors are being approved at many levels in cancers such as non-small cell lung cancer (NSCLC). Mesothelioma is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Various clinical trials for checkpoint inhibitors have been conducted in this rare disease, and suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Most recently approved as a salvage therapy in mesothelioma was granted in Japan, regulatory approval for their use in the clinic elsewhere lags. In this article we review the current pertinent clinical trials of immunotherapies in malignant mesothelioma, discuss the current issues that may affect the clinical outcomes of such therapies and further evaluate potential candidate new avenues that may become future targets for immunotherapy in this cancer.

MS13.03 Con - Raphael Bueno Is Right (It Does Not Work)

Mesothelioma is a heterogeneous cancer and it is not always correctly staged in the absence of surgical extirpation. While some clinical trials utilizing a remarkably small number of patients showed some response to immunotherapy in mesothelioma, the response rate is relatively low (in the 10% rate) and it is unclear how durable. The heterogeneity of the tumor makes interpretation of such small number difficulties leading to the conclusion that at this time immunotherapy remains experimental in mesothelioma.

The role of immunotherapy in mesothelioma

Malignant pleural mesothelioma (MPM) is a rare tumour occurring after asbestos exposure. Most cases are unresectable at the time of diagnosis and the prognosis is very poor. Platinum based chemotherapy, with or without added antiangiogenics is standard first-line treatment. However, its efficacy is limited, patients with unresectable disease have a median 12 months overall survival and the benefit of treatment is only 3 months. The immune micro-environment plays a crucial role in tumour development. Local immunosuppression involving, but not limited to, the expression of T cell inhibitory receptors, favours tumour growth. Moreover, chronic stromal inflammatory response and the presence of lymphocytic infiltration and macrophages are all prognostic factors. Immune checkpoint inhibitors (ICIs) targeting programmed death protein 1 (PD-1), its ligand (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are able to block inhibitory signals on T cells, thus enhancing the immune anti-tumour response. PD-L1 is expressed in 60% of MPM and associated with poor prognosis. Several studies have shown encouraging results in single agent or combination checkpoint inhibition in MPM. Furthermore, T cell-mediated treatments are being developed with promising results, as are chimeric antigen receptor (CAR) T cells targeting mesothelin, a highly expressed protein in MPM. In this review, we examine currently available data, as well as ongoing trials in the field of immuno-oncology for MPM.

PO-387 Phenotypic and functional analysis of malignant mesothelioma tumor-infiltrating lymphocytes (TILs)

IntroductionGiven the growing interest and promising preliminary results of immunotherapy in mesothelioma, it has become important to more fully understand the immune landscape in this tumour. This may be especially important for deciding who might benefit most from checkpoint blockade or agonist antibody therapy. Although the phenotype of tumour infiltrating lymphocytes (TILs) in mesothelioma is being increasingly well described, there is very little functional analysis of mesothelioma TILs.Material and methodsFresh mesothelioma tissue and blood were sampled from patients enrolled in an on-going clinical trial of radical pleurectomy vs. radical pleurectomy and photodynamic therapy (PDT) at our institution. Following processing, single cell suspensions were used for phenotypic using flow cytometry. Functionality of TILs was accessed by measurement of cytokine (IFN-γ production) following overnight anti-CD3 antibody stimulation ex vivo. These data were compared to TILs from early stage lung cancer patients.Results and discussionsFlow cytometric analysis of 19 patient samples so far shows that the numbers of CD8-positive TILs are markedly low at around 3%–10% of total live cells. TILs have an effector memory phenotype enriched for CD103 +tissue memory cells, they show high expression of inhibitory receptors PD-1 (25%–80%) and TIGIT (50%–80%), and have an EomeshiT-Betlow phenotype. Unlike TILs from early stage lung cancers, which are generally able to make cytokines, TILs from advanced stage mesotheliomas show profound hypofunction in their ability to produce IFNγ (<20%), which is our readout for TIL function. Cells expressing high levels of the transcription factor EOMES and the surface marker CD28 seem especially dysfunctional.ConclusionOur results show that TILs from mesothelioma tumours are profoundly hypofunctional. Areas of active interest are to determine the mechanisms and best markers of T cell hypofunction. Such information might allow us to understand with TILs might be activated by checkpoint inhibitors. We also plan to correlate T cell function with clinical responses in our trial.

MS 08.04 Immunotherapy in MPM

MS 08.04 Immunotherapy in MPM

SC06.04 Immunotherapy of Malignant Pleural Mesothelioma and Thymic Malignancies: The End of the Beginning?

SC06.04 Immunotherapy of Malignant Pleural Mesothelioma and Thymic Malignancies: The End of the Beginning?

Abstract CT229: Autologous dendritic cells loaded with allogeneic tumor cell lysate in patients with mesothelioma: A phase I study

Abstract Malignant Mesothelioma (MM) is an aggressive disease without curative treatment options. Treatment with chemotherapy and surgery is accompanied with high incidences of local recurrences. Novel therapeutic treatment options are urgently needed and immunotherapy may be a new player in the field of MM. We have previously shown the feasibility of dendritic cell (DC) immunotherapy in MM (Hegmans, et al. Am J Respir Crit Care Med 2010). In these studies DC were loaded with autologous tumor cell lysate. Apart from safety also radiographical responses were found and survival was promising. However autologous tumor cell lysate has major drawbacks both in availability, quality and logistics. Therefore a new concept was developed, based on DC loading with a tumor cell lysate derived from human MM cell lines. In a murine MM model allogenic loading of DC's was equally safe, and effective as autologous (data submitted). We have developed a clinical grade allogenic batch of tumorcell lysate which is now used in a phase I study where patient diagnosed with MM are treated. This batch has been generated according to GMP and GLP regulations and a patent is pending. Orphan drug designation has been obtained from both FDA and EMA. For the trial, major inclusion criteria are chemonaïve patients or patients with a disease controle according to modified RECIST after standard chemotherapy. Patients with a need for high dosages of immunosuppressive therapy are excluded. In the study patients undergo a leukapheresis to collect monocytes. These monocytes are in vitro differentiated to DC's and pulsed with tumor lysate according to the previously described protocol. DCs are re-injected intravenous and intradermally every 2 weeks to determine toxicity. A 3*3 design study is initiated where chosen dosages are 10, 25 and 50* million cells. Primary endpoint is safety. Secondary endpoints are radiological responses according to modified RECIST for mesothelioma, progression free survival and overall survival. At present the study is open for inclusion. At the meeting results of the first dose cohorts will be presented. This will be the first in human study in MM with allogenic tumor cell loaded DC. In case no safety issues are encountered this may open the field of combination treatments (e.g. immunecheckpoint inhibition combined with DC treatment) to increase the population of patients who benefit from immunotherapeutic treatment options. Citation Format: Joachim G. Aerts, Robin Cornelissen, Cor van der Leest, Ferry Eskens, Koen bezemer, Margaretha Kaijen, Rudi Hendriks, Joost Hegmans, Henk C. Hoogsteden. Autologous dendritic cells loaded with allogeneic tumor cell lysate in patients with mesothelioma: A phase I study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT229. doi:10.1158/1538-7445.AM2015-CT229

Mesothelioma

Mesothelioma

Dendritic Cell-Based Immunotherapy in Mesothelioma

Mesothelioma is a rare thoracic malignancy with a dismal prognosis. Current treatment options are scarce and clinical outcomes are rather disappointing. Due to the immunogenic nature of mesothelioma, several studies have investigated immunotherapeutic strategies to improve the prognosis of patients with mesothelioma. In the last decade, progress in knowledge of the modulation of the immune system to attack the tumor has been remarkable, but the optimal strategy for immunotherapy has yet to be unraveled. Because of their potent antigen-presenting capacity, dendritic cells are acknowledged as a promising agent in immunotherapeutic approaches in a number of malignancies. This review gives an update and provides a future perspective in which immunotherapy may improve the outcome of mesothelioma therapy.

Abstract 2514: CSPG4 as a target of antibody-based immunotherapy for malignant mesothelioma

Abstract Malignant mesothelioma (MM) is an aggressive tumor, resistant to conventional therapies, with median survival of 1 year from diagnosis. The lack of effective therapies available prompted us to implement antibody-based immunotherapy against novel targets and to investigate possible synergies with chemotherapy on MM. CSPG4 is involved in the onset and progression of melanoma and other tumors, as well as in neo-angiogenesis. CSPG4-specific monoclonal antibodies (mAb) have shown anti-tumor effects in both preclinical and clinical trials of melanoma. We hypothesized that targeting CSPG4 with a CSPG4-specific mAb would have therapeutic efficacy against MM. We found that chondroitin sulphate proteoglycan 4 (CSPG4) was aberrantly expressed in 6 out of 8 MM cell lines and in 24 out of 40 MM biopsies, with minimal expression in surrounding non-malignant cells. The expression of CSPG4 in MM was higher upon engagement of extracellular matrix components (ECM) and was associated with increased MM cell viability and motility. Silencing of CSPG4 expression by siRNAs supported this functional significance of CSPG4 in MM. Consistently, the CSPG4-specific mAb TP41.2 inhibited MM cell attachment to the ECM, resulting in decreased phosphorylation of FAK and AKT, decreased expression of cyclin D1 and apoptosis. Moreover, TP41.2 significantly reduced MM cell motility, migration and invasiveness, and inhibited MM growth in soft agar. TP41.2 prevented the outgrowth of human MM tumors in SCID mice and inhibited the growth of established MM xenografts, resulting in significantly extended survival of tumor-bearing mice. These results represent a novel approach for CSPG4 mAb-based immunotherapy of MM. Combinatorial strategies with chemotherapeutic agents and with mAbs targeting c-Met related receptor are ongoing, aimed at translating CSPG4-specific mAb into clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2514. doi:1538-7445.AM2012-2514

New Roads Open Up for Implementing Immunotherapy in Mesothelioma

Treatment options for malignant mesothelioma are limited, and the results with conventional therapies have been rather disappointing to this date. Chemotherapy is the only evidence-based treatment for mesothelioma patients in good clinical condition, with an increase in median survival of only 2 months. Therefore, there is urgent need for a different approach to battle this malignancy. As chronic inflammation precedes mesothelioma, the immune system plays a key role in the initiation of this type of tumour. Also, many immunological cell types can be found within the tumour at different stages of the disease. However, mesothelioma cells can evade the surveillance capacity of the immune system. They build a protective tumour microenvironment to harness themselves against the immune system's attacks, in which they even abuse immune cells to act against the antitumour immune response. In our opinion, modulating the immune system simultaneously with the targeting of mesothelioma tumour cells might prove to be a superior treatment. However, this strategy is challenging since the tumour microenvironment possesses numerous forms of defence strategies. In this paper, we will discuss the interplay between immunological cells that can either inhibit or stimulate tumour growth and the challenges associated with immunotherapy. We will provide possible strategies and discuss opportunities to overcome these problems.

Abstract 2323: Inhibition of in vitro growth of human mesothelioma cells by CSPG4-specific monoclonal antibodies

Abstract The membrane bound chondroitin sulphate protidoglycan 4 (CSPG4), also known as high molecular weight-melanoma associated antigen (HMW-MAA), plays a role in tumor cell proliferation, growth and differentiation, as well as in angiogenesis and extracellular matrix remodeling. Contrary to the early reports which had described CSPG4 expression restricted to melanoma cells, this molecule is expressed by various types of malignant tumors. Because of its high expression on tumor cells, including cancer stem cells, and its restricted distribution in normal tissues, CSPG4 represents an attractive target for immunotherapy. The lack of effective conventional therapy and the paucity of suitable targets for immunotherapy in mesothelioma have prompted us to test whether CSPG4 is expressed by mesothelioma cells and mediates the anti-tumor activity of CSPG4-specific monoclonal antibodies (mAb). Immunohistochemical staining with mAb showed that CSPG4 was expressed on mesothelioma cells in 24 out of 40 MM biopsies with minimal expression on surrounding normal cells. Furthermore FACS analysis and western blots detected CSPG4 in all the 9 human MM cell lines tested and that the expression was induced on MM cells by their interactions with the extracellular matrix (ECM). To test the sensitivity of MM cells to the anti-tumor activity of CSPG4-specific mAb, 3 MM cell lines were incubated with mAb TP41.2 (final concentration 10ug/ml) for up to 72hrs. Cell proliferation was determined by MTT assay. Cells incubated with normal mouse IgG antibodies were used as controls. Addition of mAb TP41.2 to cells already attached to plates had no detectable effect on their proliferation. On the other hand incubation of MM cells with mAb TP41.2 before seeding in plates markedly inhibited their growth. The effect was time-dependent. These results were observed in all 3 cell lines and each cell lines was tested 3 times. The data suggest that CSPG4 promotes MM cell growth by mediating their interactions with ECM. This conclusion is corroborated by the growth of CSPG4-positive MM cells in serum-free medium in plates coated with collagen I, collagen IV or fibronectin. Furthermore CSPG4-specific mAb decreased the expression of the angiogenic growth factors VEGF and HEY1, as determined by RT-PCR, in MM cells. These results suggest that it may be worthwhile to test the hypothesis that CSPG4-specific mAb-based immunotherapy may represent a viable approach for the treatment of MM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2323.

Immunotherapy and radiation therapy for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a particularly aggressive thoracic malignancy with limited survival following combination chemotherapy. As a result, there has been increased interested in immunotherapy for mesothelioma, both in the first-line and salvage settings. Early investigations of interleukin-2 (IL-2) and interferon alfa-2a/b have been limited by modest response rates and toxicity, whereas cytokine gene therapy is currently being investigated and shows early promise. The most prominent class of immunotherapies to be trialed with mesothelioma in the past half-decade has been immune checkpoint inhibitors (CPI). Early results are encouraging, particularly for agents targeting the PD-1/PD-L1 pathways. With the increasing recognition of the immune potential of mesothelioma, interest in the immunomodulatory properties of radiation therapy has emerged. The combination of immunotherapy and radiation therapy may allow for complimentary immunologic effects that can enhance antitumor response. This article reviews the existing literature on the efficacy of immunotherapy for MPM, describes the rationale for combining immunotherapy with radiation therapy, and discusses early literature on this treatment combination.

48 Altering the tumor microenvironment to augment immunotherapy for mesothelioma

48 Altering the tumor microenvironment to augment immunotherapy for mesothelioma

Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses

Malignant mesothelioma is a cancer with dismal prognosis. The objective of the present study was to address the role of the immune system, tumour micro-environment and potential immunosuppression in mesothelioma. Expression profiles of 80 cytokines were determined in the supernatant of mesothelioma cell lines and the original patient's pleural effusion. Influx of immune effector cells was detected by immunohistochemistry. Angiogenin, vascular endothelial growth factor, transforming growth factor-beta, epithelial neutrophil-activating protein-78 and several other proteins involved in immune suppression, angiogenesis and plasma extravasation could be detected in both supernatant and pleural effusion. Surrounding stroma and/or infiltrating cells were the most likely source of hepatocyte growth factor, macrophage inflammatory protein (MIP)-1delta, MIP-3alpha, neutrophil-activating peptide-2, and pulmonary and activation-regulated chemokine that can cause leukocyte infiltration and activation. There was a massive influx of CD4+ and CD8+ T-lymphocytes and macrophages, but not of dendritic cells, in human mesothelioma biopsies. It was further demonstrated that human mesothelioma tissue contained significant amounts of Foxp3+CD4+CD25+ regulatory T-cells. When these CD25+ regulatory T-cells were depleted in an in vivo mouse model, survival increased. Mesothelioma is infiltrated by immune effector cells but also contains cytokines and regulatory T-cells that suppress an efficient immune response. Immunotherapy of mesothelioma might be more effective when combined with drugs that eliminate or control regulatory T-cells.