Celiac disease is a common disease of the small intestine. There is only one effective treatment option: a gluten-free diet. In very rare cases, patients do not respond to a gluten-free diet and... Show moreCeliac disease is a common disease of the small intestine. There is only one effective treatment option: a gluten-free diet. In very rare cases, patients do not respond to a gluten-free diet and develop malignant cells in the small intestine. This is called refractory celiac disease type II (RCDII). RCDII is a severe disease and some RCDII patients pass away due to a lack of effective treatment strategies or due to the development of an even more aggressive form of lymphoma, namely enteropathy-associated T-cell lymphoma (EATL). In this thesis, we describe the current pharmacological approaches under development for the treatment of celiac disease. For RCDII, we describe the efficacy of a new targeted treatment modality: tofacitinib. Moreover, we describe the detailed characterization of the intestinal and peripheral immune system in patients with celiac disease and RCDII. For celiac disease, we explored the potential for plasma B cells acting as antigen-presenting cells in the small intestine. For RCDII, we describe the previously unappreciated heterogeneity of malignant cells in the small intestine. This could explain the variability in disease presentation and response to different treatment strategies. Additionally, we describe immune cells in the tumor microenvironment of RCDII, contributing to knowledge on putative anti- and pro-tumor responses in RCDII Show less
Treatment with neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the default treatment for muscle-invasive bladder cancer. However, with the encouraging results of immune... Show moreTreatment with neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the default treatment for muscle-invasive bladder cancer. However, with the encouraging results of immune checkpoint inhibitiors directed against PD-1/PD-L1 and CTLA-4 in recent years, the treatment landscape of bladder cancer is rapidly changing. In Chapter 2 we review the recent advancements in treatment with immune checkpoint inhibitors in bladder cancer and the relation with the tumor immune micro-environment. In Chapter 3 we aim to predict pathological response after neoadjuvant platinum-based chemotherapy based on the genomic biomarkers ERCC2, ERBB2, ATM, FANCC and RB1. In Chapter 4 we retrospectively investigate the effects of neoadjuvant platinum-based chemotherapy on the tumor-immune microenvironment in muscle-invasive bladder cancer patients. In Chapter 5 we describe the results of cohort 2 of the NABUCCO trial, where patients were randomized to receive either of two different dosing regimens of ipilimumab and nivolumab. In addition, we set out to predict pathological response and clinical outcome based on circulating tumor DNA in plasma and urine. In Chapter 6 we retrospectively assess the prostate tissue that was part of the radical cystoprostatectomy specimens from NABUCCO cohort 1. Show less
T-cell gene therapy is a relatively new immunotherapeutic strategy to treat cancer. Where immune checkpoint inhibition demonstrates promising results in cancer with a high mutational burden,... Show moreT-cell gene therapy is a relatively new immunotherapeutic strategy to treat cancer. Where immune checkpoint inhibition demonstrates promising results in cancer with a high mutational burden, cancers with a low mutational burden respond less well. For these cancers, T-cell gene therapy might be an attractive alternative. In this thesis, uveal melanoma and synovial sarcoma are described as favorable targets for T-cell gene therapy targeting PRAME. Furthermore, the immune tumor microenvironment of synovial sarcoma is studied in depth. Show less
Immunotherapy with immune checkpoint inhibitors (ICB) has greatly improved survival for advanced melanoma patients. This thesis examines strategies to further optimize these therapies. We found... Show moreImmunotherapy with immune checkpoint inhibitors (ICB) has greatly improved survival for advanced melanoma patients. This thesis examines strategies to further optimize these therapies. We found that neoadjuvant ICB in stage III melanoma offers advantages over adjuvant therapy, including enhanced immune activation and the ability to assess treatment response. The OpACIN study revealed that standard dosing of ipilimumab and nivolumab was too toxic, but the OpACIN-neo study demonstrated that a lower dose of ipilimumab reduced side effects while maintaining high response rates. Patients with a pathological response had excellent outcomes with the IFN-γ gene signature and tumor mutational burden identified as key biomarkers for response and survival. For BRAFV600-mutated melanoma, both targeted therapies (BRAF/MEK inhibitors) and ICB are effective. The IMPembra study found that short-term addition of dabrafenib and trametinib to pembrolizumab was feasible, and seems to improve progression-free survival. Anti-PD-1 monotherapy remains attractive for patients with favorable characteristics, but optimal treatment duration is unknown. In a cohort of patients who stopped treatment without progression or toxicity, median treatment duration was only 12 months, and the majority remained free of progression. Early increases in LDH or S100B can identify patients who may need additional therapy. The findings in this thesis contribute to the significant advances in the treatment of advanced melanoma and have the potential to reshape the standard of care for stage III melanoma. Show less
Synovial sarcoma is an aggressive soft-tissue cancer that shows limited responses to current immunotherapeutic approaches using immune checkpoint blockade or adoptive cell therapy. To improve... Show moreSynovial sarcoma is an aggressive soft-tissue cancer that shows limited responses to current immunotherapeutic approaches using immune checkpoint blockade or adoptive cell therapy. To improve immunotherapy for this cancer, understanding how the immune cells in the tumor microenvironment associate with histological subtype, disease progression and current therapies is vital. To evaluate the immune infiltrate in synovial sarcoma in relation to histological subtype, disease progression and in response to cytotoxic treatment, we performed immunodetection of T cells, CD68+ myeloid cells, endothelial cells and keratin on a series of 41 synovial sarcoma patients at various stages of disease. The immune composition of synovial sarcoma was dominated by CD68+ myeloid cells of which a substantial part was of the CD163+ immunosuppressive phenotype, which increased after chemotherapy or radiotherapy. Biphasic synovial sarcomas were more densely infiltrated by both T cells and myeloid cells than monophasic synovial sarcomas. In these tumors, the immune and endothelial cells were mostly located within the stromal like, spindle cell compartment and excluded from the epithelial compartment, greatly resembling the spatial organization of healthy epithelium such as in the colon. Together these data demonstrate that biphasic synovial sarcoma is immunologically different from monophasic synovial sarcoma and might be more susceptible to immunotherapies such as adoptive T-cell therapy. Finally, T-cell infiltration in primary synovial sarcoma was associated with prolonged overall survival of patients which suggests that intratumoral T cells may demonstrate anti-tumor activity. Show less
In this thesis, we aim at two aspects of leveraging liposomal formulations to enhance the efficacy of cancer chemotherapy and immunotherapy. Firstly, we employed liposomes to deliver multiple... Show moreIn this thesis, we aim at two aspects of leveraging liposomal formulations to enhance the efficacy of cancer chemotherapy and immunotherapy. Firstly, we employed liposomes to deliver multiple regiments simultaneously or subsequently to the target site, which successfully achieved a precise tumor control with a synergistic or addictive effects between chemotherapy and immunotherapy. Secondly, the liposomal formulation can reduce the severe side effects induced by either chemotherapy or/and immunotherapy while remaining pronounced immunomodulation on both the local and systemic immune system. Show less
Metastatic uveal melanoma (UM) represents a formidable challenge in oncology, characterized by limited treatment options and a poor prognosis. After successful treatment for the primary tumor, up... Show moreMetastatic uveal melanoma (UM) represents a formidable challenge in oncology, characterized by limited treatment options and a poor prognosis. After successful treatment for the primary tumor, up to 50% of patients will develop metastases, mainly to the liver. Percutaneous hepatic perfusion with Melphalan (M-PHP) is a minimally invasive treatment option for patients with liver-dominant metastatic disease and is discussed in this thesis. Firstly, part I provides an overview of the outcomes of UM patients diagnosed in the Netherlands over a period of thirty years (1989 – 2019). In part II, the results of M-PHP in three European centers are presented. Furthermore we describe a prospective analysis on the quality of life of patients who underwent M-PHP for metastatic UM. In the last part of the thesis the ongoing CHOPIN trial is introduced. In this trial a novel combination of M-PHP with systemic immunotherapy (ipilimumab and nivolumab) is applied. The results of the phase Ib part of the CHOPIN study are presented, showing that a combination of M-PHP with ipilimumab at 1mg/kg and nivolumab at 3mg/kg is safe and feasible in patients with hepatic metastases from UM. Show less
With the arrival of effective systemic therapies, the treatment of metastasized melanoma and Merkel cell carcinoma has evolved rapidly in recent years. In this thesis we have studied the role of... Show moreWith the arrival of effective systemic therapies, the treatment of metastasized melanoma and Merkel cell carcinoma has evolved rapidly in recent years. In this thesis we have studied the role of surgery in the era of immunotherapy, as well as two new combination therapies for stage III melanoma. We found that lymph node dissections for stage III melanoma can be performed safely after treatment with neoadjuvant systemic therapy. Furthermore, we present the results of the phase II NIVEC trial, investigating the combination of nivolumab with T-VEC treatment for stage III melanoma. In addition, the phase I of the Nivo-ILP trial is presented here, testing the safety of combining nivolumab with an isolated limb perfusion for stage III melanoma.The second part of this thesis studies the more rare but aggressive skin cancer called Merkel cell carcinoma. We have investigated the use of different types of imaging for optimal staging of this cancer type, as well as two histopathological parameters as prognostic value for survival. In the last chapter of this thesis, we show that the duration of immunotherapy treatment for metastasized Merkel cell carcinoma can safely be reduced. Show less
The role of a cardio-oncologist has expanded significantly due to the broadened definition of cardiovascular toxicity, now encompassing a wide range of cardiovascular issues beyond the traditional... Show moreThe role of a cardio-oncologist has expanded significantly due to the broadened definition of cardiovascular toxicity, now encompassing a wide range of cardiovascular issues beyond the traditional focus on left ventricular dysfunction and heart failure. This complexity is further compounded by the continuous discovery of new associations between modern cancer therapies and cardiovascular complications. While ideally, all cancer patients would be thoroughly screened and monitored for cardiovascular toxicity, this approach is impractical, resource-intensive, and often lacks strong evidence-based guidelines. Therefore, identifying patients at increased risk for cardiovascular toxicity is essential to optimize monitoring and maximize patient benefit without unnecessary strain. The aim of this thesis is twofold. First, it seeks to identify novel predictors for the spectrum of cardiovascular toxicity resulting from both conventional and modern anticancer therapeutics. Second, it aims to explore innovative methods for harnessing the vast amount of data within the electronic health records of cancer patients, utilizing natural language processing, artificial intelligence, and automations. Show less
In this thesis we identified TCRs for the treatment of B-cell and plasma cell malignancies. In our approach we identified TCRs specific to peptides from B-cell lineage antigens, that are expressed... Show moreIn this thesis we identified TCRs for the treatment of B-cell and plasma cell malignancies. In our approach we identified TCRs specific to peptides from B-cell lineage antigens, that are expressed in B-cell malignancies, presented in various HLA alleles. These epitopes, being self-peptides, are not immunogenic in an HLA-matched setting. To overcome this, we isolated T-cell clones across HLA-barriers using donors lacking the target HLA-alleles. We used peptide-HLA multimers for isolation, followed by comprehensive potency and safety tests to select T cells with precise antigen recognition. The TCRs of selected T-cell clones were sequenced, inserted into retroviral vectors, and introduced into third-party T cells. These T cells were then evaluated for their specificity and ability to target and eliminate B-cell malignancies expressing the antigen in vitro and in in vivo xenograft models. Throughout the thesis we described multiple TCRs with potential clinical applicability for B-cell and plasma cell malignancies. In chapter 2, TCRs are described that target peptides from FCRL5 in HLA-A1, VPREB3 in HLA-A24, and BOB1 in HLA-B35. In chapter 3, TCRs target peptides from the Jchain presented in HLA-A1, -A3, -A11 and -A24. In chapter 4, TCRs target peptides from IgA in HLA-B7 and IgG in HLA-A2. Show less
Yeghaian, M.; Bucho, T.M.T.; Bruin, M. de; Schmitz, A.; Bodalal, Z.; Smit, E.F.; ... ; Trebeschi, S. 2024
PurposeIn this study, we aimed to evaluate the potential of routine blood markers, serum tumour markers and their combination in predicting RECIST-defined progression in patients with stage IV non... Show morePurposeIn this study, we aimed to evaluate the potential of routine blood markers, serum tumour markers and their combination in predicting RECIST-defined progression in patients with stage IV non-small cell lung cancer (NSCLC) undergoing treatment with immune checkpoint inhibitors.MethodsWe employed time-varying statistical models and machine learning classifiers in a Monte Carlo cross-validation approach to investigate the association between RECIST-defined progression and blood markers, serum tumour markers and their combination, in a retrospective cohort of 164 patients with NSCLC.ResultsThe performance of the routine blood markers in the prediction of progression free survival was moderate. Serum tumour markers and their combination with routine blood markers generally improved performance compared to routine blood markers alone. Elevated levels of C-reactive protein (CRP) and alkaline phosphatase (ALP) ranked as the top predictive routine blood markers, and CYFRA 21.1 was consistently among the most predictive serum tumour markers. Using these classifiers to predict overall survival yielded moderate to high performance, even when cases of death-defined progression were excluded. Performance varied across the treatment journey.ConclusionRoutine blood tests, especially when combined with serum tumour markers, show moderate predictive value of RECIST-defined progression in NSCLC patients receiving immune checkpoint inhibitors. The relationship between overall survival and RECIST-defined progression may be influenced by confounding factors. Show less
Poelgeest, M.I.E. van; Kortekaas, K.E.; Doorn, H.C. van; Oonk, M.; Nijman, H.W.; Boere, I.; ... ; Burg, S.H. van der 2024
Background Vulvar squamous cell carcinoma (VSCC) is a rare cancer for which the cornerstone of treatment is surgery with high complication rates. The unmet need is a less radical and more effective... Show moreBackground Vulvar squamous cell carcinoma (VSCC) is a rare cancer for which the cornerstone of treatment is surgery with high complication rates. The unmet need is a less radical and more effective treatment for VSCC.Primary Objectives To investigate the impact of mono-immunotherapy pembrolizumab as neoadjuvant treatment for primary resectable VSCC patients.Study Hypothesis Some primary VSCC patients display a specific immune profile which is associated with better survival. In other tumors, this profile is associated with a better response to programmed cell death protein 1 (PD-1) checkpoint blockade which may reinvigorate tumor-specific T cells. This potentially results in a reduced tumor load and less radical surgery and/or adjuvant treatment in patients with this immune profile.Trial Design This is an investigator-initiated, prospective, single arm, multicenter, phase II clinical trial.Inclusion Criteria Patients with VSCC clinical stage International Federation of Gynecology and Obstetrics (FIGO) I-III (2021) eligible for primary surgery, with at least one measurable lesion of at least one dimension ≥10 mm in the largest diameter, are included in this study.Main Exclusion Criteria Patients not suitable for surgery and/or previously treated with immunomodulatory agents, and/or who suffer from comorbidities that may interfere with PD-1 blockade, are excluded from the study.Endpoints The clinical efficacy of neoadjuvant pembrolizumab in VSCC is measured by an objective change in tumor size according to the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) and documented by calipers using standardized digital photography with a reference ruler. In addition, the activation, proliferation, and migration of T cells in the tumor will be studied. The secondary endpoints are pathological complete responses at the time of surgery, feasibility, and safety. Show less
Lung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of... Show moreLung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of immunotherapy in 2015, this survival has increased significantly, with the first results showing a survival of even a few years. However, the response rate is relatively low, the treatment is expensive and the (low percentage of) side effects are severe. Therefore a biomarker is needed to predict which patients would benefit of immunotherapy.This thesis is about the search for a new biomarker. With the use of the RNA of platelets, proteins, tumor markers in blood and a an electronic nose for exhaled breath, we tried to find a non-invasive biomarker for the prediction of response on immunotherapy and for the (future) use in clinical practice, some of which are promising. Show less
Radiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined... Show moreRadiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined in clinical studies, although their success has been limited. We used mouse tumor models to understand how radiotherapy induces T cell priming and subsequent anti-tumor immunity. In a model resembling lymphocyte-depleted cancer, we identified obstacles to systemic radiotherapy-induced T cell responses and proposed interventions to overcome them. Additionally, we explored strategies to counter local T cell suppression in the tumor microenvironment. In poorly immunogenic tumors, radiotherapy can provoke a T cell response, but this is counteracted by the generation of immunosuppressive Tregs. Combining radiotherapy with checkpoint immunotherapy, despite its success in humans, unexpectedly amplified the Treg response, further hindering cytotoxic T-cell activity. Our findings suggest this immunotherapy may not benefit these cancers. We discovered that molecules like CD80 and CD86, capable of stimulating T cells via the CD28 receptor, have distinct roles in promoting cytotoxic and Treg cells. Blocking CD86 enhanced cytotoxic T cell responses post-radiotherapy, leading to tumor rejection. Our study elucidates how tumor characteristics shape T-cell responses, how radiotherapy can evoke both favorable and unfavorable responses, and how targeted antibody immunotherapy can influence this interplay. Show less
Mucosal melanomas (MM) are malignant tumours arising from melanocytes located at the mucosal lining of the head and neck region or the respiratory, gastrointestinal, anorectal, or genital tract.... Show moreMucosal melanomas (MM) are malignant tumours arising from melanocytes located at the mucosal lining of the head and neck region or the respiratory, gastrointestinal, anorectal, or genital tract. Due to the low incidence the disease is still poorly understood and management is mostly based on guidelines of cutaneous melanoma (CM). Survival of patients with MM is poor and regardless of stage is worse than that of CM. This is explained by the advanced stage at diagnosis and high recurrence rates of MM. Moreover, whilst immunotherapeutic agents have revolutionized the therapeutic landscape in CM, in MM, the efficacy is low and survival has not improved since the introduction of these therapies.The MM located at the vulva (VMM) account for 60% of the female genital tract MM and together with the head and neck region are the most common locations of MM. In line with the MM located at all other locations, prognosis is poor. Whilst the majority of the patients is diagnosed with local disease, the aggressive course of disease is demonstrated by the high recurrence rates with short time to recurrence with a median overall survival of 33 months. To improve outcomes in MM, there is a critical need for clinical trials specifically designed for this disease and international collaboration. Show less
Cancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high... Show moreCancer immunotherapy has experienced remarkable advances in the last decades. Striking clinical responses have been achieved for several solid cancers, particularly cancer types with a high mutation burden, which placed tumour-mutated antigens (neoantigens) centre stage as targets of tumour immunity and cancer immunotherapy. Neoantigens can be presented in complex with HLA molecules on the tumour cell surface, where T cells with the correct specificity can recognize the neoantigen as ‘non-self’ which will trigger killing of the tumour cell by the T cell. In theory, cancers with a low/moderate mutation burden that present neoantigens in complex with HLA class molecules could still be eligible for T cell-mediated immunotherapy. This thesis, describes the finding that neoantigen-specific T cells are present in mismatch-repair proficient (MMR-p) colorectal cancer patients, a low mutation burden cancer type. Moreover, CD39 and CD103 were found as cell surface markers that pinpoint the T cell population that contains the neoantigen-specific T cells. In addition, subsequent metastasis of a melanoma patient cohort were studied and revealed that also at advanced, late-stage disease, neoantigen-directed T cell therapy is, in theory, still applicable. Taken together, the studies reveal potential for the development of neoantigen-directed cancer immunotherapy for a broader patient population. Show less
This thesis focuses on the outcome to immunotherapy in locoregional and metastatic urothelial cancer and biomarkers in the tumor-immune microenvironment that may inform outcome, ultimately... Show moreThis thesis focuses on the outcome to immunotherapy in locoregional and metastatic urothelial cancer and biomarkers in the tumor-immune microenvironment that may inform outcome, ultimately enhancing cancer immunotherapy. Firstly, we discuss the outcome of urothelial cancer patients treated with checkpoint immunotherapy in the metastatic (Part I) and preoperative setting (Part II). Next, we focus on the UC tumor immune microenvironment (Part III), as this may facilitate the discovery and development of novel cancer immunotherapy as well as predictive biomarkers for immunotherapy response in UC. A comprehensive framework based on tumor- and host-specific parameters to better understand immunotherapy response in UC is also provided (Part III). Show less
Nagy, N.A.; Lozano Vigario, F.; Sparrius, R.; Capel, T.M.M. van; Ree, R. van; Tas, S.W.; ... ; Jong, E.C. de 2023
To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
