Introduction: Immunotherapy-induced pneumonitis (IIP) is a serious side-effect which requires accurate diagnosis and management with high-dose corticosteroids. The differ-ential diagnosis between... Show moreIntroduction: Immunotherapy-induced pneumonitis (IIP) is a serious side-effect which requires accurate diagnosis and management with high-dose corticosteroids. The differ-ential diagnosis between IIP and other types of pneumonitis (OTP) remains challenging due to similar radiological patterns. This study was aimed to develop a prediction model to differentiate IIP from OTP in patients with stage IV non-small cell lung cancer (NSCLC) who developed pneumonitis during immunotherapy. Methods: Consecutive patients with metastatic NSCLC treated with immunotherapy in six centres in the Netherlands and Belgium from 2017 to 2020 were reviewed and cause-specific pneumonitis events were identified. Seven regions of interest (segmented lungs and sphe-roidal/cubical regions surrounding the inflammation) were examined to extract the most pre-dictive radiomic features from the chest computed tomography images obtained at pneumonitis manifestation. Models were internally tested regarding discrimination, calibra-tion and decisional benefit. To evaluate the clinical application of the models, predicted labels were compared with the separate clinical and radiological judgements. Results: A total of 556 patients were reviewed; 31 patients (5.6%) developed IIP and 41 pa-tients developed OTP (7.4%). The line of immunotherapy was the only predictive factor in the clinical model (2nd versus 1st odds ratio Z 0.08, 95% confidence interval:0.01-0.77). The best radiomic model was achieved using a 75-mm spheroidal region of interest which showed an optimism-corrected area under the receiver operating characteristic curve of 0.83 (95% confidence interval:0.77-0.95) with negative and positive predictive values of 80% and 79%, respectively. Good calibration and net benefits were achieved for the radiomic model across the entire range of probabilities. A correct diagnosis was provided by the radiomic model in 10 out of 12 cases with non-conclusive radiological judgements. Conclusion: Radiomic biomarkers applied to computed tomography imaging may support cli-nicians making the differential diagnosis of pneumonitis in patients with NSCLC receiving immunotherapy, especially when the radiologic assessment is non-conclusive. 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Bulk, J. van den; Ploeg, M. van der; Ijsselsteijn, M.E.; Ruano, D.; Breggen, R. van der; Duhen, R.; ... ; Miranda, N.F.C.C. de 2023
Background Expression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8+ T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify... Show moreBackground Expression of CD103 and CD39 has been found to pinpoint tumor-reactive CD8+ T cells in a variety of solid cancers. We aimed to investigate whether these markers specifically identify neoantigen-specific T cells in colorectal cancers (CRCs) with low mutation burden.Experimental design Whole-exome and RNA sequencing of 11 mismatch repair-proficient (MMR-proficient) CRCs and corresponding healthy tissues were performed to determine the presence of putative neoantigens. In parallel, tumor-infiltrating lymphocytes (TILs) were cultured from the tumor fragments and, in parallel, CD8+ T cells were flow-sorted from their respective tumor digests based on single or combined expression of CD103 and CD39. Each subset was expanded and subsequently interrogated for neoantigen-directed reactivity with synthetic peptides. Neoantigen-directed reactivity was determined by flow cytometric analyses of T cell activation markers and ELISA-based detection of IFN-γ and granzyme B release. Additionally, imaging mass cytometry was applied to investigate the localization of CD103+CD39+ cytotoxic T cells in tumors.Results Neoantigen-directed reactivity was only encountered in bulk TIL populations and CD103+CD39+ (double positive, DP) CD8+ T cell subsets but never in double-negative or single-positive subsets. Neoantigen-reactivity detected in bulk TIL but not in DP CD8+ T cells could be attributed to CD4+ T cells. CD8+ T cells that were located in direct contact with cancer cells in tumor tissues were enriched for CD103 and CD39 expression.Conclusion Coexpression of CD103 and CD39 is characteristic of neoantigen-specific CD8+ T cells in MMR-proficient CRCs with low mutation burden. The exploitation of these subsets in the context of adoptive T cell transfer or engineered T cell receptor therapies is a promising avenue to extend the benefits of immunotherapy to an increasing number of CRC patients. Show less
In this thesis, we start with a general introduction in Chapter 1 to briefly present the state of PDT, immune therapies, and nanotechnology in the field of cancer. PDT is a well-established... Show moreIn this thesis, we start with a general introduction in Chapter 1 to briefly present the state of PDT, immune therapies, and nanotechnology in the field of cancer. PDT is a well-established approach in superficial cancer treatment. The aim of my Ph.D. research work has been to improve therapeutic responses in solid tumors by novel combinatorial strategies based on PDT and the utilization of nanotechnology. Insights and concepts in these works are expected to help to design personalized therapeutic interventions in cancer progression. In Chapter 2, we focused on the combination of PDT with a stimulator of interferon genes (STING) agonist: ADU-S100. We investigated the anti-tumor efficiency and survival time after this combined treatment in colon tumor mice models. We found that ADU-S100 post-PDT treatment could enhance PDT-induced inflammation and immune responses, which lead to abscopal effects in a distal untreated tumor. The combination also protected cured mice from tumor recurrence through memory T cell anti-tumor immune responses with high probability. In Chapter 3, we found that PDT in combination with viral core particles could prime systematic immune responses and serum antibody intensity to against colon cancer process in MC38 tumor-bearing mice. In Chapter 4, we reviewed the current challenges facing the combination of PDT and multiple cancer treatment options based on current published literature. We highlighted the opportunities of nanoparticle-based PDT in cancer therapies. In Chapter 5, we investigated how hydrogel-supported near-infrared (NIR) -PDT with improved therapy potential in tumor-bearing mice by combining it with immune checkpoint inhibitors. In addition to the improved tumor growth inhibitory effects and prolonged survival time, immune mechanisms were also studied. We found that hydrogel-supported NIR-PDT by multi-stimulation could induce a higher level of lymphocytes in the circulating blood and increased lymphocytes infiltration into tumor site. A general discussion of overall data observed in this work, and clinical and research prospects related to this thesis are provided in Chapter 6. Show less
The immune system plays a dual role in cancer development. Besides the potential to eliminate cancer cells, immunoregulatory mechanisms exist that counteract anti-tumor immunity.Research in this... Show moreThe immune system plays a dual role in cancer development. Besides the potential to eliminate cancer cells, immunoregulatory mechanisms exist that counteract anti-tumor immunity.Research in this thesis focusses on the role of regulatory T cells (Tregs), a type of adaptive immune cell that plays a major role in tumor-associated immunosuppression. Specifically, the role of Tregs was investigated during the development of primary- and metastatic breast cancer, and in the context of novel immunotherapeutics. This was done by using advanced genetically engineered mouse models that recapitulate human breast cancer.The results in this thesis describe that breast tumors are, already early in their development, able to mobilise Tregs in the tumor-draining lymph nodes, thereby creating a local immunosuppressive niche leading to increased lymph node metastasis. In addition, it was found that the immunotherapeutic treatments anti-PD1 and anti-CTLA4 inadvertently activate Tregs, resulting in a diminished efficacy of this treatment in mice bearing breast tumors. Finally, we describe a mechanism by which intratumoral macrophages are critical promote the intratumoral accumulation of Tregs in breast tumors.Insights from this thesis may eventually contribute to the development of therapeutic applications that are aimed at overcoming immunoregulatory mechanisms in breast cancer. Show less
Purpose To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma ... Show morePurpose To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma (mUM) patients (NCT04283890), primary objective was defining a safe treatment dose of IPI/NIVO plus M-PHP. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03). Secondary objective was response rate, PFS and OS.Materials and Methods Patients between 18-75 years with confirmed measurable hepatic mUM according to RECIST 1.1 and WHO performance score 0-1 were included. Intravenous IPI was applied at 1 mg/kg while NIVO dose was increased from 1 mg/kg in cohort 1 to 3 mg/kg in cohort 2. Transarterial melphalan dose for M-PHP was 3 mg/kg (maximum of 220 mg) in both cohorts. Treatment duration was 12 weeks, consisting of four 3-weekly courses IPI/NIVO and two 6-weekly M-PHPs.Results Seven patients were included with a median age of 63.6 years (range 50-74). Both dose levels were well tolerated without dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 patients in cohort 1 and in 3/4 patients in cohort 2, including Systemic Inflammatory Response Syndrome (SIRS), febrile neutropenia and cholecystitis. Grade I/II immune-related AEs occurred in all patients, including myositis, hypothyroidism, hepatitis and dermatitis. There were no dose-limiting toxicities. The safe IPI/NIVO dose was defined as IPI 1 mg/kg and NIVO 3 mg/kg. There was 1 complete response, 5 partial responses and 1 stable disease (3 ongoing responses with a median FU of 29.1 months).Conclusion Combining M-PHP with IPI/NIVO was safe in this small cohort of patients with mUM at a dose of IPI 1 mg/kg and NIVO 3 mg/kg. Show less
Background: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune... Show moreBackground: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. Methods: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (& GE; 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (& GE; 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade & GE; 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. Discussion: Transplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its effectiveness. Show less
Upconversion nanoparticles (UCNPs) represent a group of NPs that can convert near-infrared (NIR) light into ultraviolet and visible light, thus possess deep tissue penetration power with less... Show moreUpconversion nanoparticles (UCNPs) represent a group of NPs that can convert near-infrared (NIR) light into ultraviolet and visible light, thus possess deep tissue penetration power with less background fluorescence noise interference, and do not induce damage to biological tissues. Due to their unique optical properties and possibility for surface modification, UCNPs can be exploited for concomitant antigen delivery into dendritic cells (DCs) and monitoring by molecular imaging. In this study, we focus on the development of a nano-delivery platform targeting DCs for immunotherapy and simultaneous imaging. OVA 254-267 (OVA24) peptide antigen, harboring a CD8 T cell epitope, and Pam3CysSerLys4 (Pam3CSK4) adjuvant were chemically linked to the surface of UCNPs by amide condensation to stimulate DC maturation and antigen presentation. The OVA24-Pam3CSK4-UCNPs were thoroughly characterized and showed a homogeneous morphology and surface electronegativity, which promoted a good dispersion of the NPs. In vitro experiments demonstrated that OVA24-Pam3CSK4-UCNPs induced a strong immune response, including DC maturation, T cell activation, and proliferation, as well as interferon gamma (IFN-gamma) production. In vivo, highly sensitive upconversion luminescence (UCL) imaging of OVA24-Pam3CSK4-UCNPs allowed tracking of UCNPs from the periphery to lymph nodes. In summary, OVA24-Pam3CSK4-UCNPs represent an effective tool for DC-based immunotherapy. Show less
T cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T... Show moreT cell exhaustion is a state of T cell hypofunction arising during persistent viral infections and cancer. Recent advances in the field of immunology uncover the roles of cytokines in regulating T cell responses. Using LCMV Clone-13 as a model of persistent viral infection, this thesis investigates the roles of IL-27 and IFN-I in regulating T cells during infection. In addition, the thesis explores the potential of JAK inhibitor in rescuing T cell exhaustion during persistent viral infection and cancer. Show less
Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying... Show moreSingle-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete-and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41-100% of all patients and 0-11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities. Show less
Gemcitabine was examined as switch maintenance therapy after standard first line chemotherapy in the NVALT19 trial, which provided the first conformation of gemcitabine activity in malignant... Show moreGemcitabine was examined as switch maintenance therapy after standard first line chemotherapy in the NVALT19 trial, which provided the first conformation of gemcitabine activity in malignant mesothelioma (MM). We describe additional analyses to confirm the prognostic value of CYFRA 21-1 and examine the prognostic value of CYFRA 21-1 in MM patients treated with gemcitabine. We also searched how gemcitabine could improve antitumor immune responses by positively modulating the immune system.In this thesis we describe a cohort of 107 malignant mesothelioma patients treated with nivolumab in the Netherlands. The real- world data of single agent PD-1 blocking were disappointing compared to previous reported single arm phase II trials. To examine clinical and peripheral blood biomarkers univariable and multivariable analyses were performed.As malignant peritoneal mesothelioma is even rarer then pleural mesothelioma, we hypothesized that centralization of care for peritoneal mesothelioma could benefit patients as they would likely receive treatment more often.Prognosis has a significant influence on the treatment preferences of patients, but prognosis of individual MM patients is variable and is hard to predict. We presented the MESOPRO score for patient with MM which are about the start with any systemic treatment. Show less
Lau, S.P.; Land, F.R. van 't; Burg, S.H. van der; Homs, M.Y.V.; Lolkema, M.P.; Aerts, J.G.J.V.; Eijck, C.H.J. van 2022
Introduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy... Show moreIntroduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses. Methods and analysis In this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses. Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Show less
Lau, S.P.; Land, F.R. van 't; Burg, S.H. van der; Homs, M.Y.V.; Lolkema, M.P.; Aerts, J.G.J.V.; Eijck, C.H.J. van 2022
Introduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy... Show moreIntroduction The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses.Methods and analysis In this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses.Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Show less
Background Transcription factor Wilms' tumor gene 1 (WT1) is an ideal tumor target based on its expression in a wide range of tumors, low-level expression in normal tissues and promoting role in... Show moreBackground Transcription factor Wilms' tumor gene 1 (WT1) is an ideal tumor target based on its expression in a wide range of tumors, low-level expression in normal tissues and promoting role in cancer progression. In clinical trials, WT1 is targeted using peptide-based or dendritic cell-based vaccines and T-cell receptor (TCR)-based therapies. Antitumor reactivities were reported, but T-cell reactivity is hampered by self-tolerance to WT1 and limited number of WT1 peptides, which were thus far selected based on HLA peptide binding algorithms. Methods In this study, we have overcome both limitations by searching in the allogeneic T-cell repertoire of healthy donors for high-avidity WT1-specific T cells, specific for WT1 peptides derived from the HLA class I associated ligandome of primary leukemia and ovarian carcinoma samples. Results Using broad panels of malignant cells and healthy cell subsets, T-cell clones were selected that demonstrated potent and specific anti-WT1 T-cell reactivity against five of the eight newly identified WT1 peptides. Notably, T-cell clones for WT1 peptides previously used in clinical trials lacked reactivity against tumor cells, suggesting limited processing and presentation of these peptides. The TCR sequences of four T-cell clones were analyzed and TCR gene transfer into CD8+ T cells installed antitumor reactivity against WT1-expressing solid tumor cell lines, primary acute myeloid leukemia (AML) blasts, and ovarian carcinoma patient samples. Conclusions Our approach resulted in a set of naturally expressed WT1 peptides and four TCRs that are promising candidates for TCR gene transfer strategies in patients with WT1-expressing tumors, including AML and ovarian carcinoma. Show less
Gezgin, G.; Visser, M.; Ruano, D.; Santegoets, S.J.; Miranda, N.F.C.C. de; Velden, P.A. van der; ... ; Jager, M.J. 2022
PurposeTo evaluate whether expanded tumor-infiltrating lymphocytes (TILs) can be obtained from primary uveal melanoma (UM) for potential use as adjuvant treatment in patients at risk of developing ...Show morePurposeTo evaluate whether expanded tumor-infiltrating lymphocytes (TILs) can be obtained from primary uveal melanoma (UM) for potential use as adjuvant treatment in patients at risk of developing metastatic disease.DesignExperimental research study.ParticipantsFreshly obtained primary UM from 30 patients.MethodsThree different methods were used to expand TILs: (1) direct culture from small fragments of fresh tumor tissue, (2) single-cell tissue preparation by enzymatic digestion and subsequent enrichment of mononuclear cells, and (3) selection of CD3+ T cells using magnetic beads. Surface expression of costimulatory and inhibitory T-cell markers and T-cell reactivity against autologous tumor cells was assessed. Clinical, histopathologic, genetic, and immunologic characteristics of the tumors were compared with the capacity to expand TILs and with their reactivity against autologous tumor cells.Main Outcome MeasuresThe feasibility of expanding TILs from primary UM, testing their reactivity to autologous UM cells, and evaluating the impact of an immunomodulatory environment.ResultsDirect culture of tumor parts led to successful TIL culture in 4 of 22 tumors (18%), enrichment of mononuclear cells gave rise to TILs in 5 of 12 tumors (42%), while preselection of CD3+ T cells with magnetic beads resulted in TIL expansion in 17 of 25 tumors (68%). In 8 of 17 tumors (47%), the TIL cultures comprised UM-reactive T cells. The presence of UM-reactive T cells among TILs was not related to clinical, histologic, genetic, or immunological tumor characteristics. Interestingly, RNA-Seq analysis showed that approximately half of the UM tumors displayed an increased expression of immunomodulatory molecules related to T-cell suppression, such as galectin 3, programmed death-ligand 1, cytotoxic T-lymphocyte-associated protein 4, indoleamine 2,3-dioxygenase 1, and lymphocyte activating 3, potentially explaining why T cells require optimal removal of tumor components for expansion.ConclusionsThe need to separate TILs from their tumor microenvironment for their successful expansion and the presence of UM-reactive T cells among TILs suggests that these UM-reactive T cells are strongly suppressed in vivo and that UM is immunogenic. These findings indicate that adoptive TIL therapy could be an option as an adjuvant treatment in primary UM patients at high risk of developing metastatic disease. Show less
Antibodies, the cardinal effector molecules of the immune system, are being leveraged to enormous success as biotherapeutic drugs. Adaptive immune responses consist of epitope-diverse polyclonal... Show moreAntibodies, the cardinal effector molecules of the immune system, are being leveraged to enormous success as biotherapeutic drugs. Adaptive immune responses consist of epitope-diverse polyclonal antibody mixtures that are capable of neutralizing their targets via binding interference and by mediating humoral and cellular effector functions. A mechanistic theme fundamental to virtually all aspects of antibody biology, including antibody-antigen binding, clonal selection and effector functions, is the utilization of avidity to drive and tune functional responses. Manipulating antibody avidity has since emerged as an important design principle for enhancing or engineering novel properties in antibody biotherapeutics. In the context of ‘classical’ effector functions, complement-dependent cytotoxicity (CDC) can be improved by single point mutations in the IgG Fc domain that increase intermolecular Fc-Fc interactions upon binding to membrane-bound targets, thereby facilitating enhanced IgG hexamer formation and C1q binding. Such engineering approaches illustrate the relevance of promoting avidity interactions such as antibody clustering to enhance effector functions. The aim of this thesis was to explore the role of antibody avidity interactions, and more specifically the importance of ‘ordered clustering’, in antibody mechanisms of action and to apply the knowledge obtained in designing novel and improved antibody-based therapeutics Show less
The TME has increasingly been recognized as an important player in tumor progression and metastasis and a possible target for therapy. The TME consists of multiple cell types secreting growth... Show moreThe TME has increasingly been recognized as an important player in tumor progression and metastasis and a possible target for therapy. The TME consists of multiple cell types secreting growth factors and cytokines that exert either pro- or anti-tumor effects. This thesis mainly focuses on studies of the TME, especially the effects of Endoglin, on several cell types within the TME, including endothelial cells, fibroblasts, and immune cells.The TME has increasingly been recognized as an important player in tumor progression and metastasis and a possible target for therapy. The TME consists of multiple cell types secreting growth factors and cytokines that exert either pro- or anti-tumor effects. This thesis mainly focusses on studies of the TME, especially the effects of Endoglin, on several cell types within the TME, including endothelial cells, fibroblasts, and immune cells. This thesis aims to unravel the role of Endoglin as a possible target on various cell types within the TME of solid tumors. Endoglin is known for its role during angiogenesis, however, an increasing number of studies have shown the importance of Endoglin expression on several other cell types (e.g., immune cells, CAFs, tumor cells). Show less
Background: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint... Show moreBackground: Recent reports suggest the limited efficacy of immune checkpoints inhibitors in advanced acral melanoma (AM). This study aims to investigate the clinical outcomes of immune checkpoint inhibitors in patients with stage III and IV AM and compare them to cutaneous melanoma (CM). Methods: We included patients with advanced AM and CM treated with first-line anti -programmed cell death (PD)-1 monotherapy or ipilimumab-nivolumab registered in the prospective nationwide Dutch Melanoma Treatment Registry. Objective response rates, progression free survival (PFS) and overall survival (OS) were calculated. A Cox proportional hazard model was used to assess the prognostic factors with PFS and OS. Results: In total, 2058 patients (88 AM and 1970 CM) with advanced melanoma were included. First-line objective response rates were 34% for AM versus 54% for CM in the advanced anti-PD-1 cohort and 33% for AM versus 53% for CM in the advanced ipilimumab-nivolumab cohort. The Median PFS was significantly shorter for anti-PD-1 treated AM patients (3.1 months; 95%CI: 2.8-5.6) than patients with CM (10.1 months; 95%CI: 8.5-12.2) (P < 0.001). In patients with advanced melanoma, AM was significantly associated with a higher risk of progression (HRadj 1.63; 95%CI: 1.26-2.11 ; P < 0.001) and death (HRadj 1.54; 95%CI: 1.15-2.06; P Z 0.004) than CM. Conclusions: This study shows lower effectiveness of anti-PD-1 monotherapy and ipilimumab-nivolumab in AM, with lower response rates, PFS and OS than CM. This group of patients should be prioritised in the development of alternative treatment strategies. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Lau, S.P.; Klaase, L.; Vink, M.; Dumas, J.; Bezemer, K.; Krimpen, A. van; ... ; Eijck, C.H.J. van 2022
Background: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming.... Show moreBackground: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming. We previously demonstrated the potency of allogeneic lysatedendritic cell (DC) vaccination in a preclinical model. Here we translate this concept to patients.Methods: In this phase I study, patients with resected PDAC were included when they demonstrated no radiologic signs of recurrence after standard-of-care treatment. Allogeneic tumour lysate-loaded autologous monocyte-derived DCs were injected at weeks 0, 2, 4 and at months 3 and 6. Objectives are feasibility, safety and immunogenicity of allogeneic tumour-DCs. The presence of tumour antigens shared between the vaccine and patient tumours was investigated. Immunological analyses were performed on peripheral blood, skin and tumour.Results: Ten patients were included. DC production and administration were successful. All patients experienced a grade 1 injection-site and infusion-related reaction. Two patients experienced a grade 2 fever and 1 patient experienced a grade 3 dyspnoea. No vaccine-related serious adverse events were observed. Shared tumour antigens were found between the vaccine and patient tumours. All evaluated patients displayed a vaccine-induced response indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T-cells. In addition, treatment-induced T-c ell reactivity to autologous tumour of study patients was detected. Seven out of ten patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15-32 months).Conclusion: Allogeneic tumour lysate-DC treatment is feasible, safe and induces immune reactivity to PDAC expressed antigens. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Ocular melanoma is a rare disease that originates from melanocytes in the eye. It is the most prevalent primary ocular malignancy in adults, and has a high metastatic rate. Two important questions... Show moreOcular melanoma is a rare disease that originates from melanocytes in the eye. It is the most prevalent primary ocular malignancy in adults, and has a high metastatic rate. Two important questions for good patient care are: 1) How to differentiate between (benign) nevi, and (malignant) melanoma?, and 2) How to treat this tumor best, particularly in cases with metastases?This thesis addresses two types of ocular melanoma: melanoma of the internal parts of the eye (uveal melanoma) and melanoma of the mucous membrane covering the eye (conjunctival melanoma). This thesis combines patient-related projects with projects from the lab.With new imaging techniques we demonstrate that oxygen values differ in eyes with melanoma compared to other eyes including those with a nevus. We use OCT-angiography to depict tumour vessels non-invasively in conjunctival and iris lesions. These two techniques may be used in the future to differentiate lesions, and to monitor patients after treatment.With studies in the lab we show that new drugs (immunotherapy) that are recently used in cutaneous melanoma, can also be used to treat conjunctival melanoma. We show that vascular growth in uveal melanoma is related to other (genetic and immunologic) characteristics, providing new clues for therapy. Show less
Objective: In CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient... Show moreObjective: In CheckMate 743 (NCT02899299), nivolumab + ipilimumab significantly prolonged overall survival in patients with unresectable malignant pleural mesothelioma (MPM). We present patient-reported outcomes (PROs). Materials and Methods: Patients (N = 605) were randomized to nivolumab + ipilimumab or chemotherapy. Changes in disease-related symptom burden and health-related quality of life (HRQoL) were evaluated descriptively using the Lung Cancer Symptom Scale (LCSS)-Mesothelioma (Meso) average symptom burden index (ASBI), LCSS-Meso 3-item global index (3-IGI), 3-level EuroQol 5-dimensional (EQ-5D-3L) visual analog score (VAS), and EQ-5D-3L utility index. PROs were assessed at baseline and every 2 (nivolumab + ipilimumab) or 3 weeks (chemotherapy) through 12 weeks, every 6 weeks through 12 months, every 12 weeks thereafter, and at specified follow-ups. Mixed-effect model repeated measures (MMRM) and time to deterioration analyses were conducted. Results: Completion rates were generally > 80%. LCSS-Meso ASBI mean changes from baseline trended to improve over time with nivolumab + ipilimumab and deteriorate with chemotherapy, but did not meet clinically important difference thresholds [& PLUSMN;10 score change]. EQ-5D-3L VAS mean scores improved over time with nivolumab + ipilimumab; by week 60, patients had scores consistent with United Kingdom normal population values. MMRM analyses favored nivolumab + ipilimumab for all individual symptoms except cough. Nivolumab + ipilimumab delayed time to definitive deterioration in HRQoL (hazard ratio 0.52 [95% confidence interval 0.36-0.74]) and showed a trend in symptom delay versus chemotherapy. Conclusions: Nivolumab + ipilimumab decreased the risk of deterioration in disease-related symptoms and HRQoL versus chemotherapy and maintained QoL in patients with unresectable MPM. Show less
