ABSTRACT
Glioblastoma (GBM) remains an orphan cancer disease with poor outcome. Novel treatment strategies are needed. Immunotherapy has several modes of action. The addition of active specific immunotherapy with dendritic cell vaccines resulted in improved overall survival of patients. Integration of DC vaccination within the first-line combined treatment became a challenge, and immunogenic cell death immunotherapy during chemotherapy was introduced. We used a retrospective analysis using real world data to evaluate the complex combined treatment, which included individualized multimodal immunotherapy during and after standard of care, and which required adaptations during treatment, and found a further improvement of overall survival. We also discuss the use of real world data as evidence. Novel strategies to move the field of individualized multimodal immunotherapy forward for GBM patients are reviewed.
Subject(s)
Brain Neoplasms , Cancer Vaccines , Glioblastoma , Oncolytic Viruses , Humans , Glioblastoma/therapy , Oncolytic Viruses/genetics , Brain Neoplasms/therapy , Retrospective Studies , Cancer Vaccines/therapeutic use , Dendritic Cells/metabolismABSTRACT
The fundamental aim of healthcare is to improve overall health of the population by providing state-of-the-art healthcare for individuals at an affordable cost. The foundation for this system is largely referred to as "evidence-based medicine". Too often, evidence-based medicine is based solely on so-called "best research evidence", collected through randomized controlled trials while disregarding clinical expertise and patient expectations. As healthcare gravitates towards personalized and individualized medicine, such external clinical (research) evidence can inform, but never replace, individual clinical expertise. This applies in particular to orphan diseases, for which clinical trials are methodologically particularly problematic, and evidence derived from them is often questionable. Evidence-based medicine constitutes a complex process to allow doctors and patients to select the best possible solutions for each individual based on rapidly developing new therapeutic directions. This requires a revisit of the foundations of evidence-based medicine. A proposition as to how to manage evidence-based data in individualized immune-oncology is presented here.
ABSTRACT
Synergistic activity between maintenance temozolomide (TMZm) and individualized multimodal immunotherapy (IMI) during/after first-line treatment has been suggested to improve the overall survival (OS) of adults with IDH1 wild-type MGMT promoter-unmethylated (unmeth) GBM. We expand the data and include the OS of MGMT promoter-methylated (meth) adults with GBM. Unmeth (10 f, 18 m) and meth (12 f, 10 m) patients treated between 27 May 2015 and 1 January 2022 were analyzed retrospectively. There were no differences in age (median: 48 y) or Karnofsky performance index (median: 80). The IMI consisted of 5-day immunogenic cell death (ICD) therapies during TMZm: Newcastle disease virus (NDV) bolus injections and sessions of modulated electrohyperthermia (mEHT); subsequent active specific immunotherapy: dendritic cell (DC) vaccines plus modulatory immunotherapy; and maintenance ICD therapy. There were no differences in the number of vaccines (median: 2), total number of DCs (median: 25.6 × 106), number of NDV injections (median: 31), and number of mEHT sessions (median: 28) between both groups. The median OS of 28 unmeth patients was 22 m (2y-OS: 39%), confirming previous results. OS of 22 meth patients was significantly better (p = 0.0414) with 38 m (2y-OS: 81%). There were no major treatment-related adverse reactions. The addition of IMI during/after standard of care should be prospectively explored.
ABSTRACT
The prognosis of IDH1 wild-type MGMT promoter-unmethylated GBM patients remains poor. Addition of Temozolomide (TMZ) to first-line local treatment shifted the median overall survival (OS) from 11.8 to 12.6 months. We retrospectively analyzed the value of individualized multimodal immunotherapy (IMI) to improve OS in these patients. All adults meeting the criteria and treated 06/2015-06/2021 were selected. Thirty-two patients (12f, 20m) had a median age of 47 y (range 18-69) and a KPI of 70 (50-100). Extent of resection was complete (11), Subject(s)
Brain Neoplasms
, Glioblastoma
, Adult
, Humans
, Temozolomide/therapeutic use
, Dacarbazine/therapeutic use
, DNA Modification Methylases/genetics
, DNA Modification Methylases/therapeutic use
, Glioblastoma/therapy
, Glioblastoma/drug therapy
, Antineoplastic Agents, Alkylating/therapeutic use
, DNA Repair Enzymes/genetics
, DNA Repair Enzymes/therapeutic use
, Retrospective Studies
, Brain Neoplasms/genetics
, Brain Neoplasms/therapy
, Tumor Suppressor Proteins/genetics
, DNA Methylation
, Immunotherapy
, Isocitrate Dehydrogenase/genetics
, Isocitrate Dehydrogenase/therapeutic use
ABSTRACT
INTRODUCTION: Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established. METHODS: CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled. RESULTS: For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%, respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histological grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%, respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent prognosticators. CONCLUSIONS: Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset of CPC can be cured without irradiation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Choroid Plexus Neoplasms , Randomized Controlled Trials as Topic , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma/drug therapy , Choroid Plexus Neoplasms/drug therapy , Etoposide/therapeutic use , Humans , Registries , Treatment Outcome , Vincristine/therapeutic useABSTRACT
Previously we showed that human monocytes isolated from peripheral blood display downregulation of several DNA repair proteins, including XRCC1, ligase III, PARP-1 and DNA-PKCS, resulting in a deficiency of DNA repair, while in macrophages derived from monocytes the repair protein expression and DNA repair is restored. To see whether this is a specific phenomenon of human monocytes and macrophages, we assessed the expression of these repair genes in mice. We also addressed the question at which differentiation step in bone marrow cells downregulation of DNA repair gene expression occurs. The study revealed that mouse monocytes, similar to human, lack the expression of XRCC1, ligase III, PARP-1 and DNA-PKCS. If mice were treated with total body irradiation, they showed significant apoptosis in bone marrow monocytes, but not in peritoneal macrophages. This was also observed after treatment with the methylating anticancer drug temozolomide, resulting in high death rate of monocytes, but not macrophages. Monocytes arise from hematopoietic stem cells. Even the early stem cell fraction (LT-HSC) expressed detectable amounts of XRCC1, which was transiently upregulated, achieving the highest expression level in CMP (common myeloid progenitor) and, during the subsequent differentiation process, downregulated up to a non-detectable level in monocytes. The immediate monocyte precursor GMP also expressed ligase III, PARP-1 and DNA-PKCS. All these repair genes lacking in monocytes were upregulated again in macrophages. The sensitivity of monocytes, macrophages and precursor cells roughly correlated with their XRCC1 expression level. Monocytes, but not macrophages, also displayed strong γH2AX focal staining, indicating the presence of non-repaired DNA double-strand breaks following total body irradiation. Overall, the data revealed that murine monocytes exhibit the same DNA repair-impaired phenotype and high sensitivity compared to macrophages as observed in human. Therefore, the repair deficiency previously described for human monocytes appears to be a general property of this cell type.
Subject(s)
DNA Damage , DNA Repair , Gamma Rays , Macrophages/metabolism , Monocytes/metabolism , Temozolomide/toxicity , Animals , Apoptosis , DNA/drug effects , DNA/metabolism , DNA/radiation effects , DNA Breaks, Double-Stranded , DNA Ligase ATP/genetics , DNA-Activated Protein Kinase/genetics , DNA-Binding Proteins/genetics , Female , Gene Expression Regulation , Histones/analysis , Histones/metabolism , Macrophages/drug effects , Macrophages/physiology , Macrophages/radiation effects , Mice , Mice, Inbred C57BL , Monocytes/drug effects , Monocytes/physiology , Monocytes/radiation effects , Poly (ADP-Ribose) Polymerase-1/genetics , Poly-ADP-Ribose Binding Proteins/genetics , Stem Cells/drug effects , Stem Cells/metabolism , Stem Cells/radiation effects , Temozolomide/pharmacology , X-ray Repair Cross Complementing Protein 1/geneticsABSTRACT
BACKGROUND: Histologically classified glioblastomas (GBM) can have different clinical behavior and response to therapy, for which molecular subclassifications have been proposed. We evaluated the relationship of epigenetic GBM subgroups with immune cell infiltrations, systemic immune changes during radiochemotherapy, and clinical outcome. METHODS: 450K genome-wide DNA methylation was assessed on tumor tissue from 93 patients with newly diagnosed GBM, treated with standard radiochemotherapy and experimental immunotherapy. Tumor infiltration of T cells, myeloid cells, and Programmed cell death protein 1 (PD-1) expression were evaluated. Circulating immune cell populations and selected cytokines were assessed on blood samples taken before and after radiochemotherapy. RESULTS: Forty-two tumors had a mesenchymal, 27 a receptor tyrosine kinase (RTK) II, 17 RTK I, and 7 an isocitrate dehydrogenase (IDH) DNA methylation pattern. Mesenchymal tumors had the highest amount of tumor-infiltrating CD3+ and CD8+ T cells and IDH tumors the lowest. There were no significant differences for CD68+ cells, FoxP3+ cells, and PD-1 expression between groups. Systemically, there was a relative increase of CD8+ T cells and CD8+ PD-1 expression and a relative decrease of CD4+ T cells after radiochemotherapy in all subgroups except IDH tumors. Overall survival was the longest in the IDH group (median 36 mo), intermediate in RTK II tumors (27 mo), and significantly lower in mesenchymal and RTK I groups (15.5 and 16 mo, respectively). CONCLUSIONS: Methylation based stratification of GBM is related to T-cell infiltration and survival, with IDH and mesenchymal tumors representing both ends of a spectrum. DNA methylation profiles could be useful in stratifying patients for immunotherapy trials.
Subject(s)
Brain Neoplasms , Glioblastoma , Brain Neoplasms/genetics , Brain Neoplasms/therapy , DNA Methylation , Glioblastoma/genetics , Glioblastoma/therapy , Humans , Isocitrate Dehydrogenase/genetics , Promoter Regions, GeneticABSTRACT
Immunotherapies represent a promising strategy for glioblastoma multiforme (GBM) treatment. Different immunotherapies include the use of checkpoint inhibitors, adoptive cell therapies such as chimeric antigen receptor (CAR) T cells, and vaccines such as dendritic cell vaccines. Antibodies have also been used as toxin or radioactive particle delivery vehicles to eliminate target cells in the treatment of GBM. Oncolytic viral therapy and other immunogenic cell death-inducing treatments bridge the antitumor strategy with immunization and installation of immune control over the disease. These strategies should be included in the standard treatment protocol for GBM. Some immunotherapies are individualized in terms of the medicinal product, the immune target, and the immune tumor-host contact. Current individualized immunotherapy strategies focus on combinations of approaches. Standardization appears to be impossible in the face of complex controlled trial designs. To define appropriate control groups, stratification according to the Recursive Partitioning Analysis classification, MGMT promotor methylation, epigenetic GBM sub-typing, tumor microenvironment, systemic immune functioning before and after radiochemotherapy, and the need for/type of symptom-relieving drugs is required. Moreover, maintenance of a fixed treatment protocol for a dynamic, deadly cancer disease in a permanently changing tumor-host immune context might be inappropriate. This complexity is illustrated using our own data on individualized multimodal immunotherapies for GBM. Individualized medicines, including multimodal immunotherapies, are a rational and optimal yet also flexible approach to induce long-term tumor control. However, innovative methods are needed to assess the efficacy of complex individualized treatments and implement them more quickly into the general health system.
ABSTRACT
INTRODUCTION: Prospective double-blind placebo-controlled randomized clinical trials (RCTs) are considered standard for the proof of the efficacy of oncologic therapies. Molecular methods have provided new insights into tumor biology and led to the development of targeted therapies. Due to the increasing complexity of molecular tumor characteristics and of the individuality of specific anti-tumor immune reactivity, RCTs are unfortunately only of limited use. AREAS COVERED: The historical methods of drug research and approval and the related practices of reimbursement by statutory and private health insurance companies are being questioned. New, innovative methods for the documentation of evidence in personalized medicine will be addressed. Possible perspectives and new approaches are discussed, in particular with regard to glioblastoma. EXPERT OPINION: Highly specialized translational oncology groups like the IOZK can contribute to medical progress and quick transfer 'from bench to bedside.' Their contribution should be acknowledged and taken into account more strongly in the development of guidelines and the reimbursement of therapy costs. Methodological plurality should be encouraged.
Subject(s)
Molecular Targeted Therapy , Neoplasms/pathology , Randomized Controlled Trials as Topic/methods , Antineoplastic Agents/administration & dosage , Glioblastoma/immunology , Glioblastoma/pathology , Glioblastoma/therapy , Guidelines as Topic , Humans , Neoplasms/immunology , Neoplasms/therapy , Precision Medicine/methods , Reimbursement Mechanisms , Translational Research, Biomedical/organization & administrationABSTRACT
At times of personalized and individualized medicine the concept of randomized- controlled clinical trials (RCTs) is being questioned. This review article explains principles of evidence-based medicine in oncology and shows an example of how evidence can be generated independently from RCTs. Personalized medicine involves molecular analysis of tumor properties and targeted therapy with small molecule inhibitors. Individualized medicine involves the whole patient (tumor and host) in the context of immunotherapy. The example is called Individualized Multimodal Immunotherapy (IMI). It is based on the individuality of immunological tumor-host interactions and on the concept of immunogenic tumor cell death (ICD) induced by an oncolytic virus. The evidence is generated by systematic data collection and analysis. The outcome is then shared with the scientific and medical community. The priority of big pharma studies is commercial benefit. Methods used to achieve this are described and have damaged the image of RCT studies in general. A critical discussion is recommended between all partners of the medical health system with regard to the conduct of RCTs by big pharma companies. Several clinics and institutions in Europe try to become more independent from pharma industry and to develop their own modern cancer therapeutics. Medical associations should include references to such studies from personalized and individualized medicine in their guidelines.
ABSTRACT
Background: The prognosis of children with diffuse intrinsic pontine glioma (DIPG) remains dismal despite radio- and chemotherapy or molecular-targeted therapy. Immunotherapy is a powerful and promising approach for improving the overall survival (OS) of children with DIPG. Methods: A retrospective analysis for feasibility, immune responsiveness, and OS was performed on 41 children treated in compassionate use with multimodal therapy consisting of Newcastle disease virus, hyperthermia, and autologous dendritic cell vaccines as part of an individualized combinatorial treatment approach for DIPG patients. Results: Patients were treated at diagnosis (n = 28) or at the time of progression (n = 13). In the case of 16 patients, histone H3K27M mutation was confirmed by analysis of biopsy (n = 9) or liquid biopsy (n = 9) specimens. PDL1 mRNA expression was detected in circulating tumor cells of ten patients at diagnosis. Multimodal immunotherapy was feasible as scheduled, until progression, in all patients without major toxicity. When immunotherapy was part of primary treatment, median PFS and OS were 8.4 m and 14.4 m from the time of diagnosis, respectively, with a 2-year OS of 10.7%. When immunotherapy was given at the time of progression, median PFS and OS were 6.5 m and 9.1 m, respectively. A longer OS was associated with a Th1 shift and rise in PanTum Detect test scores. Conclusions: Multimodal immunotherapy is feasible without major toxicity, and warrants further investigation as part of a combinatorial treatment approach for children diagnosed with DIPG.
ABSTRACT
Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
Subject(s)
Immunogenic Cell Death/genetics , Molecular Biology/methods , Consensus , Guidelines as Topic , HumansABSTRACT
BACKGROUND/AIM: The need for more effective treatment modalities that can improve the clinical outcome of patients with glioblastoma multiforme remains imperative. Dendritic cell vaccination is a fast-developing treatment modality, currently under exploration. Functional immune cell subpopulations may play a role in the final outcome. MATERIALS AND METHODS: Data from 101 patients drawn from the HGG-2010 trial, including baseline patient characteristics and fluorescence-activated cell sorting of immune cell subpopulations, were analyzed by statistical and machine-learning methods. RESULTS: The analysis revealed strong correlations between immune profiles and overall survival, when the extent of resection and the vaccination schedule were used as stratification variables. CONCLUSION: A systematic, in silico workflow detecting strong and statistically significant correlations between overall survival and immune profile-derived quantities obtained at the start of dendritic cell vaccination was devised. The derived correlations could serve as a basis for the identification of prognostic markers discriminating between potential long- and short-term survivors of patients with glioblastoma multiforme.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Brain Neoplasms/immunology , Brain Neoplasms/therapy , Dendritic Cells/immunology , Glioblastoma/immunology , Glioblastoma/therapy , Temozolomide/therapeutic use , Adult , Aged , Combined Modality Therapy , Female , Flow Cytometry , Humans , Immunotherapy , Leukapheresis , Male , Middle Aged , Phenotype , Treatment Outcome , VaccinationABSTRACT
Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological characteristics have been identified, and these characteristics are increasingly used to facilitate accurate diagnoses and therapeutic recommendations. Future treatments will be further tailored to specific molecular subtypes of disease, specific tumour predisposition syndromes, and other biological criteria. Successful biomaterial collection is a key requirement for the application of contemporary methodologies for the validation of candidate prognostic factors, the discovery of new biomarkers, the establishment of appropriate preclinical research models for targeted agents, a quicker clinical implementation of precision medicine, and for other therapeutic uses (eg, for immunotherapies). However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours in most centres. Practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.
Subject(s)
Biological Specimen Banks/standards , Biomarkers, Tumor , Central Nervous System Neoplasms , Medical Oncology/standards , Translational Research, Biomedical/methods , Biological Specimen Banks/ethics , Biological Specimen Banks/organization & administration , Child , Female , Humans , Male , Medical Oncology/organization & administration , Medical Oncology/trends , Translational Research, Biomedical/organization & administration , Translational Research, Biomedical/standardsABSTRACT
Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether 'targeting' in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas.
Subject(s)
Brain Neoplasms/immunology , Brain Neoplasms/therapy , Dendritic Cells/immunology , Glioblastoma/immunology , Glioblastoma/therapy , Immunotherapy , Animals , Brain/drug effects , Brain/immunology , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Cell Line, Tumor , Combined Modality Therapy , Dendritic Cells/cytology , Female , Glioblastoma/drug therapy , Glioblastoma/pathology , Humans , Immune Tolerance/drug effects , Mice , Mice, Inbred C57BL , Survival Analysis , T-Lymphocytes/immunology , Temozolomide/pharmacology , Temozolomide/therapeutic useABSTRACT
Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Glioma/drug therapy , Lymphocytes, Tumor-Infiltrating/pathology , Programmed Cell Death 1 Receptor/genetics , Animals , Disease Models, Animal , Flow Cytometry , Gene Expression Regulation, Neoplastic/drug effects , Glioma/genetics , Glioma/immunology , Glioma/pathology , Humans , Lymphocytes, Tumor-Infiltrating/drug effects , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Tumor Microenvironment/genetics , Tumor Microenvironment/immunologyABSTRACT
In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages' polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.
Subject(s)
Drug Therapy/methods , Galectin 1/genetics , Gene Knockdown Techniques , Glioblastoma/therapy , Immunotherapy/methods , RNA, Small Interfering/administration & dosage , Tumor Microenvironment/physiology , Administration, Intranasal , Animals , Disease Models, Animal , Mice , Treatment Outcome , Tumor Microenvironment/drug effectsABSTRACT
BACKGROUND AIMS: Atypical rhabdoid/teratoid tumors (AT/RT) are the most common brain tumors in infants and associated with a dismal prognosis. Although intensification of first-line therapy has resulted in improvement of overall survival, novel treatment strategies are needed. Because immunotherapy has resulted in remarkable results in several adult tumor entities, incorporation of immunotherapy into AT/RT treatment offers a novel alternative. METHODS: We retrospectively analyzed data from 7 AT/RT patients from five countries treated within the HGG-Immuno Consortium. Two patients were ≤1 year and 4 patients were ≤2 years of age at diagnosis. All received immunotherapy with autologous, tumor-lysate-loaded dendritic cells (DCs) on a compassionate use basis using a schedule of three to four weekly DC vaccinations with up to 2 × 10(7) DCs per vaccine, followed by three lysate boosts each 1 month apart. RESULTS: Monocyte collections (median age at apheresis 31.5, range 20-143 months) and vaccinations were uneventful without any severe adverse event related to the vaccine, demonstrating feasibility and safety in this very young age group. Two children received immunotherapy during their primary and the remaining five during second- or third-line therapy. Three of seven patients survived long term with a follow-up of 143, 138 and 46 months, with at least two of them harboring somatic mutations. One long-term survivor was vaccinated during primary treatment and the other two after first or second relapse/progression. Two analyzed patients showed positive CD8(+) T-cell responses after vaccination. DISCUSSION: Our data demonstrate that anti-tumor immunotherapy with autologous DCs is feasible and safe in young children with ATRTs and that this approach warrants further investigation in controlled clinical trials.
Subject(s)
Brain Neoplasms/therapy , Cancer Vaccines/therapeutic use , Immunotherapy/methods , Rhabdoid Tumor/therapy , Brain Neoplasms/immunology , Child , Child, Preschool , Compassionate Use Trials , Dendritic Cells/immunology , Dendritic Cells/transplantation , Female , Humans , Infant , Male , Monitoring, Immunologic/methods , Prognosis , Retrospective Studies , Rhabdoid Tumor/immunology , Surveys and Questionnaires , Treatment OutcomeABSTRACT
: MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8+ cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was-even after major histocompatibility complex class I upregulation-insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8-CD69+ T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed-lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune-modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs. SIGNIFICANCE: Because multipotent adult progenitor cells (MAPCs) are among the noteworthy adult mesenchymal stem cell populations for immune therapy and have the advantage over mesenchymal stem cells (MSCs) of large-scale manufacturing and banking potential and thus prompt availability, it is important to understand how MAPCs interact with immune cells to validate their widespread therapeutic applicability. Cytotoxic immune effector cells play a crucial role in immune homeostasis and in the pathogenesis of some autoimmune diseases. This study assessed for the first time the in vitro influence of a clinical-grade human MAPC product (MultiStem) on the cytotoxic function of CD8+ T cells (CTLs) by evaluating the immunogenicity of MAPCs and the susceptibility of MAPCs toward CTL-mediated lysis and by analyzing the mechanism of MAPC-mediated modulation of CTL functionality. These results may represent a highly relevant contribution to the current knowledge and, in combination with the results of future phase II/III trials using MultiStem, could lead to an intriguing continuation of stem cell-based research for immunotherapy.