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
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
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
Recent developments in oncology have led to a better molecular and cellular understanding of cancer, and the introduction of novel therapies. Conjunctival melanoma (CoM) is a rare but potentially... Show moreRecent developments in oncology have led to a better molecular and cellular understanding of cancer, and the introduction of novel therapies. Conjunctival melanoma (CoM) is a rare but potentially devastating disease. A better understanding of CoM, leading to the development of novel therapies, is urgently needed. CoM is characterized by mutations that have also been identified in cutaneous melanoma, e.g. in BRAF, NRAS and TERT. These mutations are distinct from the mutations found in uveal melanoma (UM), affecting genes such as GNAQ, GNA11, and BAP1. Targeted therapies that are successful in cutaneous melanoma may therefore be useful in CoM. A recent breakthrough in the treatment of patients with metastatic cutaneous melanoma was the development of immunotherapy. While immunotherapy is currently sparsely effective in intraocular tumours such as UM, the similarities between CoM and cutaneous melanoma (including in their immunological tumour micro environment) provide hope for the application of immunotherapy in CoM, and preliminary clinical data are indeed emerging to support this use. This review aims to provide a comprehensive overview of the current knowledge regarding CoM, with a focus on the genetic and immunologic understanding. We elaborate on the distinct position of CoM in contrast to other types of melanoma, and explain how new insights in the pathophysiology of this disease guide the development of new, personalized, treatments. Show less
BackgroundTo understand how to improve the effect of immune checkpoint inhibitors in uveal melanoma (UM), we need a better understanding of the expression of PD-1 and PD-L1, their relation with the... Show moreBackgroundTo understand how to improve the effect of immune checkpoint inhibitors in uveal melanoma (UM), we need a better understanding of the expression of PD-1 and PD-L1, their relation with the presence of tumor-infiltrating lymphocytes (TILs), and their prognostic relevance in UM patients. Materials and methodsExpression of PD-1 and PD-L1 was assessed in 71 UM tissue samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR), and further validated by western blotting. The effect of interferon gamma (IFN-gamma) on PD-1/PD-L1 expression was determined on four UM cell lines. ResultsImmunoreactivity of PD-1 was found in 30/71 cases and of PD-L1 in 44/71 UM samples. Tumor-infiltrating lymphocytes were found in 46% of UM tissues. PD-1 was expressed on TILs while tumor cells expressed PD-L1. UM with and without TILs showed expression of PD-1 in 69% and 18% cases, respectively (p=0.001). Similarly, PD-L1 was found in 75% of UM with TILs and in 50% of cases without TILs, respectively (p=0.03). DFS rate were lower in patients with TILs with expression of PD-1 and PD-L1, but the rate of DFS was higher with expression of PD-L1 in patients without TILs. After treatment of UM cell lines with IFN-gamma, PD-1 expression was induced in all UM cell lines whereas PD-L1 expression was found at a lower level in untreated cells, while expression also increased following treatment with IFN-gamma .ConclusionOur study suggests that increased infiltration with TILs promotes the aggressive behavior and suppresses the immune response of UM cells, thereby inhibiting immunotherapy. Show less
Immunotherapy has obtained a secure place in the treatment of metastatic non-small cell lung cancer (NSCLC) and has made a great impact on prognosis of responders. Unfortunately, not all NSCLC... Show moreImmunotherapy has obtained a secure place in the treatment of metastatic non-small cell lung cancer (NSCLC) and has made a great impact on prognosis of responders. Unfortunately, not all NSCLC patients derive benefit from this treatment. Several immune escape mechanisms have been postulated, explaining failure of tumor immune attack. A better understanding of these mechanisms helps us to seek treatment strategies to overcome resistance to immunotherapy. Radiotherapy has immunomodulatory qualities capable of enhancing the anticancer immune response by tackling a number of these tumor escape mechanisms. In this review, we focus on mechanisms of off-target effects of radiotherapy, the so-called abscopal effect, by describing the current role of immune checkpoint inhibitors (ICIs) in NSCLC, the possible reasons for its failures and evidence on how radiotherapy may be able to counteract these mechanisms. An oversight of pre-clinical and clinical data supporting augmentation of abscopal events by radiotherapy when combined with ICIs is presented. As much remains unclear regarding optimal dose, fractionation, target volume or timing of radiation therapy, future research will need to focus on implementing data from pre-clinical and translational findings in the development of new clinical trials in order to help optimizing the potential of the combination of immunotherapy with radiotherapy. Show less
Smit, H.J.M.; Aerts, J.; Heuvel, M. van den; Hiltermann, T.J.N.; Bahce, I.; Smit, E.F.; ... ; NVALT Immunotherapy Register 2020
Objective: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy... Show moreObjective: Phase III studies of checkpoint inhibitors changed the therapeutic landscape for lung cancer. In 2015 the Dutch Society of Chest Physicians (NVALT) introduced a national immunotherapy registry for patients with lung cancer; quality standards for hospitals were implemented. At population level we studied clinical benefit in daily practice and in patients who are underrepresented in phase III trials.Materials and Methods: From the initial introduction of checkpoint inhibitors in the Netherlands patients were centrally registered. Educational programs and quality control were provided under supervision of NVALT. The largest immunotherapy providing hospitals were compared to hospitals who provided less checkpoint inhibitors as marker of experience. Patients characteristics, treatment and side effects, response rate and survival were studied.Results: A total of 2676 patients were registered, 2302 with follow up data were evaluated. Between October 2015 and December 2017 a gradual increase from 12 to 30 qualified hospitals showed no major toxicity differences. Toxicity led to a hospital admission rate of 9.1 with an average duration of 10.4 days.Overall tumor response was 21.8 % and median overall survival 12.6 months. Overall survival was not significantly different for patients aged >= 75 years, those having brain metastases or selected auto-immune diseases before start checkpoint inhibitors compared to younger patients or those without, respectively. Survival outcomes were worse in patients with PS 2+, non-smokers, and patients who received any palliative radiotherapy (HR 2.1, 95 % CI 1.7-2.7; 1.3, 95 % CI 1.0-1.6 and 1.2, 95 % CI 1.1-1.4, respectively).Conclusions: Changes in the therapeutic landscape did not lead to major differences in quality of care between hospitals. Elderly patients, those with brain metastases or selected auto-immune disease underrepresented in clinical trials did not do worse on checkpoint inhibitors, except for those with PS 2+. Show less
Colorectal cancer can be categorized into two major molecular subtypes according to the status of their DNA proofreading and repair machinery. The DNA repair status of tumor cells plays a major... Show moreColorectal cancer can be categorized into two major molecular subtypes according to the status of their DNA proofreading and repair machinery. The DNA repair status of tumor cells plays a major role in shaping the immune landscape of tumors and in determining the clinical response of colorectal cancer patients to immune checkpoint blockade therapies. Colorectal cancers that develop in a context of DNA mismatch repair or polymerase proofreading deficiency are generally conspicuously infiltrated by effector memory T cells and are associated with an improved clinical prognosis relative to their replication repair-proficient counterpart. While mismatch repair-deficient colorectal cancers, and most likely POLE and POLD1-mutated cancers, are amenable to immune checkpoint blockade therapies, the promise of immunotherapy still remains unfulfilled for for the majority of colorectal cancer patients. This review focusses on the role of the immune system in the tumorigenesis and clinical behavior of colorectal cancer. Furthermore, we discuss how latest advances in the fields of genomics and oncoimmunology may pave the way to broaden the scope of immunotherapy for this disease. Show less
Malignant melanoma is an aggressive cancer associated with a poor prognosis in patients with metastatic disease. As in many other cancers, the incidence of melanoma rises with age; and combined... Show moreMalignant melanoma is an aggressive cancer associated with a poor prognosis in patients with metastatic disease. As in many other cancers, the incidence of melanoma rises with age; and combined with the longer life expectancy, this led to an increasing prevalence of melanoma in the older population. Recently, immune checkpoint inhibitors significantly improved the treatment of melanoma given their efficacy and tolerability profile. Two major classes of agents include the anti-cytotoxic T lymphocyte-associated protein 4 (CFLA-4) inhibitors, such as ipilimumab, and the anti-programmed death-ligand 1 (PD-1) inhibitors, such as nivolumab and pembrolizumab. Treatment of metastatic disease with immune checkpoint inhibitors demonstrated improved efficacy and better safety profiles compared to cytotoxic drugs and appears to be an attractive treatment option. Nevertheless, there is a need for tools designed to better predict which older patients will benefit from its use and who will experience toxicities related to the treatment. Current data do not show a major increase in toxicity rates in older patients. However, patients above 75 are often under-represented and those who are included are not representative of the general population of older patients, thereby also stressing the need for real-life data. Ongoing research is aiming at maximizing the potential treatment efficacy and developing novel immune-targeting modalities. Future studies should include older patients and assess geriatric domains in these older patients to better guide decision-making. This review discusses published clinical trials and where known, the efficacy and toxicity in older patients. Moreover, the clinical implications and future perspectives are discussed, with current recommendations for older patients, management of toxicities, and a proposal for an initial approach to the treatment of older patients with metastatic melanoma. (C) 2018 Elsevier Ltd. All rights reserved. Show less
