ABSTRACT
PURPOSE: The objective of this prospective, single-centre case series was to investigate feasibility, clinical outcomes, and neural correlates of non-invasive Neuromodulation-Induced Cortical Prehabilitation (NICP) before brain tumor surgery. Previous studies have shown that gross total resection is paramount to increase life expectancy but is counterbalanced by the need of preserving critical functional areas. NICP aims at expanding functional margins for extensive tumor resection without functional sequelae. Invasive NICP (intracranial neuromodulation) was effective but characterized by elevated costs and high rate of adverse events. Non-invasive NICP (transcranial neuromodulation) may represent a more feasible alternative. Nonetheless, up to this point, non-invasive NICP has been examined in only two case reports, yielding inconclusive findings. METHODS: Treatment sessions consisted of non-invasive neuromodulation, to transiently deactivate critical areas adjacent to the lesion, coupled with intensive functional training, to activate alternative nodes within the same functional network. Patients were evaluated pre-NICP, post-NICP, and at follow-up post-surgery. RESULTS: Ten patients performed the intervention. Feasibility criteria were met (retention, adherence, safety, and patient's satisfaction). Clinical outcomes showed overall stability and improvements in motor and executive function from pre- to post-NICP, and at follow-up. Relevant plasticity changes (increase in the distance between tumor and critical area) were observed when the neuromodulation target was guided by functional neuroimaging data. CONCLUSION: This is the first case series demonstrating feasibility of non-invasive NICP. Neural correlates indicate that neuroimaging-guided target selection may represent a valid strategy to leverage neuroplastic changes before neurosurgery. Further investigations are needed to confirm such preliminary findings.
ABSTRACT
Primary brain neoplasms are associated with elevated mortality and morbidity rates. Brain tumour surgery aims to achieve maximal tumour resection while minimizing damage to healthy brain tissue. Research on Neuromodulation Induced Cortical Prehabilitation (NICP) has highlighted the potential, before neurosurgery, of establishing new brain connections and transfer functional activity from one area of the brain to another. Nonetheless, the neural mechanisms underlying these processes, particularly in the context of space-occupying lesions, remain unclear. A patient with a left frontotemporoinsular tumour underwent a prehabilitation protocol providing 20 sessions of inhibitory non-invasive neuromodulation (rTMS and multichannel tDCS) over a language network coupled with intensive task training. Prehabilitation resulted in an increment of the distance between the tumour and the language network. Furthermore, enhanced functional connectivity within the language circuit was observed. The present innovative case-study exposed that inhibition of the functional network area surrounding the space-occupying lesion promotes a plastic change in the network's spatial organization, presumably through the establishment of novel functional pathways away from the lesion's site. While these outcomes are promising, prudence dictates the need for larger studies to confirm and generalize these findings.
ABSTRACT
BACKGROUND: One of the most frequent phenomena in the follow-up of glioblastoma is pseudoprogression, present in up to half of cases. The clinical usefulness of discriminating this phenomenon through magnetic resonance imaging and nuclear medicine has not yet been standardized; in this study, we used machine learning on multiparametric magnetic resonance imaging to explore discriminators of this phenomenon. METHODS: For the study, 30 patients diagnosed with IDH wild-type glioblastoma operated on at both study centers in 2011-2020 were selected; 15 patients corresponded to early tumor progression and 15 patients to pseudoprogression. Using unsupervised learning, the number of clusters and tumor segmentation was recorded using gap-stat and k-means method, adjusting to voxel adjacency. In a second phase, a class prediction was carried out with a multinomial logistic regression supervised learning method; the outcome variables were the percentage of assignment, class overrepresentation, and degree of voxel adjacency. RESULTS: Unsupervised learning of the tumor in its diagnosis shows up to 14 well-differentiated tumor areas. In the supervised learning phase, there is a higher percentage of assigned classes (P < 0.01), less overrepresentation of classes (P < 0.01), and greater adjacency (55% vs. 33%) in cases of true tumor progression compared with pseudoprogression. CONCLUSIONS: True tumor progression preserves the multidimensional characteristics of the basal tumor at the voxel and region of interest level, resulting in a characteristic differential pattern when supervised learning is used.
Subject(s)
Brain Neoplasms , Glioblastoma , Multiparametric Magnetic Resonance Imaging , Humans , Glioblastoma/diagnostic imaging , Glioblastoma/surgery , Glioblastoma/pathology , Unsupervised Machine Learning , Principal Component Analysis , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Brain Neoplasms/pathology , Magnetic Resonance Imaging/methods , Disease ProgressionABSTRACT
T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.
Subject(s)
Antibodies, Bispecific , Brain Neoplasms , Glioblastoma , Animals , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Cell Line, Tumor , Cytokines , ErbB Receptors/metabolism , Glioblastoma/drug therapy , Glioblastoma/genetics , Humans , Receptors, Antigen, T-Cell/genetics , T-Lymphocytes/metabolismABSTRACT
The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. SIGNIFICANCE: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.
Subject(s)
Brain Neoplasms , Melanoma , Brain/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mitogen-Activated Protein Kinase Kinases , Mutation , Neoplasm Recurrence, Local/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-rafABSTRACT
The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice.
ABSTRACT
Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.
Subject(s)
Brain Neoplasms/immunology , Cerebrospinal Fluid/immunology , Leukocytes , Tumor Microenvironment/immunology , Adenocarcinoma of Lung , Brain/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , CD8-Positive T-Lymphocytes/immunology , Humans , Immune Checkpoint Inhibitors , Lung Neoplasms , PrognosisABSTRACT
The levels of cell free circulating tumor DNA (ctDNA) in plasma correlated with treatment response and outcome in systemic lymphomas. Notably, in brain tumors, the levels of ctDNA in the cerebrospinal fluid (CSF) are higher than in plasma. Nevertheless, their role in central nervous system (CNS) lymphomas remains elusive. We evaluated the CSF and plasma from 19 patients: 6 restricted CNS lymphomas, 1 systemic and CNS lymphoma, and 12 systemic lymphomas. We performed whole exome sequencing or targeted sequencing to identify somatic mutations of the primary tumor, then variant-specific droplet digital PCR was designed for each mutation. At time of enrolment, we found ctDNA in the CSF of all patients with restricted CNS lymphoma but not in patients with systemic lymphoma without CNS involvement. Conversely, plasma ctDNA was detected in only 2/6 patients with restricted CNS lymphoma with lower variant allele frequencies than CSF ctDNA. Moreover, we detected CSF ctDNA in 1 patient with CNS lymphoma in complete remission and in 1 patient with systemic lymphoma, 3 and 8 months before CNS relapse was confirmed; indicating CSF ctDNA might detect CNS relapse earlier than conventional methods. Finally, in 2 cases with CNS lymphoma, CSF ctDNA was still detected after treatment even though a complete decrease in CSF tumor cells was observed by flow cytometry (FC), indicating CSF ctDNA better detected residual disease than FC. In conclusion, CSF ctDNA can better detect CNS lesions than plasma ctDNA and FC. In addition, CSF ctDNA predicted CNS relapse in CNS and systemic lymphomas.
Subject(s)
Circulating Tumor DNA , Lymphoma, B-Cell , Biomarkers, Tumor/genetics , Central Nervous System , Circulating Tumor DNA/genetics , Humans , Neoplasm Recurrence, LocalABSTRACT
PURPOSE OF REVIEW: The molecular characterization of central nervous system (CNS) malignancies is crucial for obtaining the correct diagnosis and prognosis, and to guide the optimal therapeutic approach. However, obtaining surgical specimens can be challenging because of the anatomical location of the tumour and may limit the correct characterization of these malignancies. Recently, it has been shown that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) can be used as a liquid biopsy to characterize and monitor CNS malignancies and here we review its implications and advances. RECENT FINDINGS: In the last 5 years, several groups including ours have shown that ctDNA is highly present in the CSF, in larger amounts than in plasma, and that ctDNA can be sequenced to provide information about the diagnosis and prognosis of brain malignancies. Furthermore, the analysis of CSF ctDNA has allowed the selection of optimal therapeutic approaches monitoring response to treatment and tracking tumour evolution, providing crucial information about the molecular changes during tumour progression. SUMMARY: Here, we review the recent discoveries and data relative to CSF ctDNA and discuss how CSF ctDNA can be used as a liquid biopsy to facilitate and complement the clinical management of patients with CNS malignancies.
Subject(s)
Central Nervous System Neoplasms/diagnosis , Circulating Tumor DNA/cerebrospinal fluid , Biomarkers, Tumor/cerebrospinal fluid , Central Nervous System Neoplasms/cerebrospinal fluid , Humans , Liquid Biopsy , PrognosisABSTRACT
The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.
Subject(s)
Brain Neoplasms/cerebrospinal fluid , Circulating Tumor DNA/cerebrospinal fluid , Medulloblastoma/cerebrospinal fluid , Biomarkers, Tumor/cerebrospinal fluid , Biomarkers, Tumor/genetics , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Circulating Tumor DNA/genetics , DNA, Neoplasm/cerebrospinal fluid , DNA, Neoplasm/genetics , Genomics , Humans , Medulloblastoma/diagnosis , Medulloblastoma/geneticsABSTRACT
BACKGROUND: Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. METHODS: Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. RESULTS: Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. CONCLUSIONS: These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Central Nervous System Neoplasms/mortality , Karyopherins/antagonists & inhibitors , Lymphoma, Non-Hodgkin/mortality , Macrophages/immunology , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Tumor Microenvironment/immunology , Adenine/administration & dosage , Adenine/analogs & derivatives , Animals , Apoptosis , Cell Proliferation , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/immunology , Central Nervous System Neoplasms/pathology , Drug Resistance, Neoplasm , Drug Synergism , Female , Humans , Hydrazines/administration & dosage , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/immunology , Lymphoma, Non-Hodgkin/pathology , Mice , Mice, Nude , Piperidines/administration & dosage , Survival Rate , Triazoles/administration & dosage , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Exportin 1 ProteinABSTRACT
INTRODUCTION: Tumor-associated status epilepticus (TASE) follows a relatively benign course compared with SE in the general population. Little, however, is known about associated prognostic factors. METHODS: We conducted a prospective, observational study of all cases of TASE treated at a tertiary hospital in Barcelona, Spain between May 2011 and May 2019. We collected data on tumor and SE characteristics and baseline functional status and analyzed associations with outcomes at discharge and 1-year follow-up. RESULTS: Eighty-two patients were studied; 58.5% (nâ¯=â¯48) had an aggressive tumor (glioblastoma or brain metastasis). Fifty-one patients (62.2%) had a favorable outcome at discharge compared with just 30 patients (25.8%) at 1-year follow-up. Fourteen patients (17.1%) died during hospitalization. Lateralized period discharges (LPDs) on the baseline electroencephalography (EEG), presence of metastasis, and SE severity were significantly associated with a worse outcome at discharge. The independent predictors of poor prognosis at 1-year follow-up were SE duration of at least 21â¯h, an aggressive brain tumor, and a nonsurgical treatment before SE onset. Lateralized period discharges, super-refractory SE, and an aggressive tumor type were independently associated with increased mortality. CONCLUSIONS: Status epilepticus duration is the main modifiable factor associated with poor prognosis at 1-year follow-up. Accordingly, patients with TASE, like those with SE of any etiology, should receive early, aggressive treatment.
Subject(s)
Brain Neoplasms/diagnostic imaging , Brain Neoplasms/mortality , Hospitalization/trends , Status Epilepticus/diagnostic imaging , Status Epilepticus/mortality , Tertiary Care Centers/trends , Adult , Aged , Brain Neoplasms/physiopathology , Cohort Studies , Electroencephalography/trends , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Spain/epidemiology , Status Epilepticus/physiopathology , Survival Rate/trendsABSTRACT
BACKGROUND: Myxopapillary ependimoma (MPE) is a benign slow-growing tumor, and it has been designated histologically as a Grade I neoplasm according to the 2016 World Health Organization classification. Despite the benign character, dissemination and metastasis have occasionally been reported. The retrograde dissemination to other levels of the neuraxis is extremely rare, being more frequent to the intracranial compartment. CASE DESCRIPTION: We hereby present a case of medullary metastasis of cauda equina MPE, with a history of having undergone a subtotal resection and postoperative adjuvant radiotherapy. The patient presents complaints of night dorsal pain attributable to intradural metastasis twenty-one years after the first surgical intervention. CONCLUSION: The case reported highlights the importance of long follow-up in patients with MPE, since the possibility of secondary seeding to distant craniospinal sites or local spinal sites after surgery, and radiotherapy should be considered in metastatic disease.
ABSTRACT
Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Further, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples, and the membranal HLA of GBM tumors of 10 of these patients' tumor samples. Tumor samples were fresh-frozen immediately after surgery and the plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the individual patients, whereas low correlations were observed between these HLA peptidomes and the tumors' proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.
Subject(s)
Antigens, Neoplasm/blood , Brain Neoplasms/blood , Glioblastoma/blood , Histocompatibility Antigens Class I/blood , Peptides/blood , Proteome/metabolism , Alleles , Biomarkers, Tumor/blood , Brain Neoplasms/surgery , Glioblastoma/surgery , HumansABSTRACT
Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Chemokine CXCL9/metabolism , Leukemia Inhibitory Factor/immunology , Macrophages/immunology , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Animals , Antibodies, Neutralizing/pharmacology , CD8-Positive T-Lymphocytes/metabolism , Chemokine CCL2/metabolism , Epigenesis, Genetic , Humans , Immunologic Memory , Leukemia Inhibitory Factor/antagonists & inhibitors , Leukemia Inhibitory Factor/metabolism , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Macrophages/metabolism , Mice, Inbred C57BL , Mice, SCID , Neoplasm Transplantation , Neoplasms/immunology , Neoplasms/pathology , Programmed Cell Death 1 Receptor/immunology , Tumor Microenvironment/immunologyABSTRACT
The additional author support information was erroneously omitted from the Supplementary Information. This has been corrected online.
ABSTRACT
Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30-50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens-that is, both unmutated antigens and neoepitopes-may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-L-lysine carboxymethylcellulose) and granulocyte-macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.
Subject(s)
Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Glioblastoma/diagnosis , Glioblastoma/therapy , Precision Medicine/methods , Adult , Aged , Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Female , Glioblastoma/immunology , HLA-A Antigens/immunology , Humans , Immunologic Memory/immunology , Male , Middle Aged , T-Lymphocytes, Helper-Inducer/immunology , Treatment OutcomeABSTRACT
Se presenta un caso de aneurisma gigante no traumático de la arteria meníngea media en un paciente de 59años con antecedentes de trasplante hepático, cirrosis hepática y hepatocarcinoma, enfermedad renal crónica, HTA y bronquitis crónica que ingresó por presentar crisis tónico-clónica. La TC y la RM mostraron una lesión sugestiva de metástasis sin descartar un tumor de tipo glial. Fue intervenido mediante una craneotomía FT izquierda. Durante la cirugía se produjo una hemorragia arterial. La muestra histológica orientó hacia un origen aneurismático que se confirmó con ARM y angiografía. Una segunda intervención permitió la extirpación de un aneurisma gigante de la arteria meníngea media parcialmente trombosado. Los aneurismas de la arteria meníngea media son raros y en general presentan un antecedente traumático. No se ha encontrado en la literatura médica ningún caso de aneurisma gigante
A case of a non-traumatic giant aneurysm of the middle meningeal artery is presented in a 59-year-old patient with a history of liver transplantation, liver cirrhosis and hepatocarcinoma, chronic renal disease, hypertension and chronic bronchitis who presented with tonic-clonic seizures. CT and MRI showed a lesion suggestive of metastasis without ruling out a glial type tumor. He was operated through a left FT craniotomy. During the surgery there was an arterial hemorrhage. The histological sample oriented toward an aneurysmal origin that was confirmed with ARM and angiography. A second intervention allowed the removal of a giant middle meningeal aneurysm partially thrombosed. Aneurysms of the middle meningeal artery are rare and generally present a traumatic history. No case of giant aneurysm has been found in the medical literature
Subject(s)
Humans , Male , Middle Aged , Aneurysm/diagnostic imaging , Aneurysm/surgery , Middle Cerebral Artery/diagnostic imaging , Middle Cerebral Artery/surgery , Cerebral AngiographyABSTRACT
Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Furthermore, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples, and the membranal HLA of GBM tumors of 10 of these patients' tumor samples. Tumor samples were fresh-frozen immediately after surgery and the plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the individual patients, whereas low correlations were observed between these HLA peptidomes and the tumors' proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.