Pre-treatment systemic inflammation response index and systemic immune inflammation in patients with primary central nerve system lymphoma as a useful prognostic indicator.

PURPOSE: The systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) are based on neutrophil, monocyte, platelet, and lymphocyte counts. The SIRI and SII are used to predict the survival of patients with malignant tumors. It is well known that the inflammatory immune response is closely related to cancer occurrence and progression. In the present study, we evaluated the potential prognostic significance of SIRI and SII in patients with primary central nervous system lymphoma (PCNSL). METHODS: Fifty-eight consecutive patients were enrolled in this study between November 2006 and May 2022. Among the 58 patients, 47 patients with sufficient blood test data and follow-up were analyzed. The patients with steroid intake at the time point of the blood test and higher C-reactive protein were excluded. RESULTS: The median follow-up and survival times were 31 and 36 months, respectively. The optimal cutoff SIRI value was based on the receiver operating characteristic curve (ROC) for overall survival (OS) and stratified patients into low (< 1.43 × 109/L, n = 22) and high (≥ 1.43 × 109/L, n = 25) SIRI groups. The optimal cutoff SII value based on the ROC for OS stratified patients into low (< 694.9, n = 28) and high (≥ 694.9, n = 19) SII groups. A low SIRI value was associated with longer OS (p = 0.006). Furthermore, a low SII value was associated with longer OS (p = 0.044). The prognostic factors associated with prolonged survival in univariate analysis using the Cox proportional hazard model were age < 65 years, low SIRI, and low SII. The multivariate analysis demonstrated that age < 65 years and low SIRI independently predicted longer OS. CONCLUSION: Simple, less expensive, and routinely ordered preoperative blood count assessments such as SIRI and SII predict the OS of patients with PCNSL. This study demonstrated that PCNSL is associated with pre-treatment systemic immune-inflammation states.

Targeting the tumor microenvironment in primary central nervous system lymphoma: Implications for prognosis.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma, and there is limited research on its tumor microenvironment (TME). Nevertheless, more and more studies have evidence that TME has essential effects on tumor cell proliferation, immune escape, and drug resistance. Thus, it is critical to elucidate the role of TME in PCNSL. The understanding of the PCNSL TME is gradually unfolding, including factors that distinguish it from systemic diffuse large B-cell lymphoma (DLBCL). The TME in PCNSL exhibits both transcriptional and spatial intratumor heterogeneity. Cellular interactions between tumor cells and stroma cells reveal immune evasion signaling. The comparative analysis between PCNSL and DLBCL suggests that PCNSL is more likely to be an immunologically deficient tumor. In PCNSL, T cell exhaustion and downregulation of macrophage immune function are accompanied by suppressive microenvironmental factors such as M2 polarized macrophages, endothelin B receptor, HLA depletion, PD-L1, and TIM-3. MMP-9, Integrin-ß1, and ICAM-1/LFA-1 play crucial roles in transendothelial migration towards the CNS, while CXCL13/CXCR5, CD44, MAG, and IL-8 are essential for brain parenchymal invasion. Further, macrophages, YKL-40, CD31, CD105, PD-1/PD-L1 axis, osteopontin, galectin-3, aggregative perivascular tumor cells, and HLA deletion may contribute to poor outcomes in patients with PCNSL. This article reviews the effect of various components of TME on the progression and prognosis of PCNSL patients to identify novel therapeutic targets.

Intrathecal IgM synthesis as a diagnostic marker in patients with suspected CNS lymphoma.

For CNS lymphomas (CNSL), there is a high need for minimally invasive and easily obtainable diagnostic markers. Intrathecal IgM synthesis can easily be determined in routine CSF diagnostics. The aim of this study was to systematically investigate the diagnostic potential of intrathecal IgM synthesis in primary and secondary CNSL (PCNSL and SCNSL). In this retrospective study, patients with a biopsy-proven diagnosis of PCNSL or SCNSL were compared with patients with other neurological diseases in whom CNSL was initially the primary radiological differential diagnosis based on MRI. Sensitivity and specificity of intrathecal IgM synthesis were calculated using receiver operating characteristic curves. Seventy patients with CNSL were included (49 PCNSL and 21 SCNSL) and compared to 70 control patients. The sensitivity and specificity for the diagnosis of CNSL were 49% and 87%, respectively, for the entire patient population and 66% and 91% after selection for cases with tumor access to the CSF system and isolated intrathecal IgM synthesis. In cases with MRI-based radiological suspicion of CNSL, intrathecal IgM synthesis has good specificity but limited sensitivity. Because of its low-threshold availability, analysis of intrathecal IgM synthesis has the potential to lead to higher diagnostic accuracy, especially in resource-limited settings, and deserves further study.

Enhancing brain entry and therapeutic activity of chimeric antigen receptor T cells with intra-arterial NEO100 in a mouse model of CNS lymphoma.

OBJECTIVE: Malignancies of the CNS are difficult to treat because the blood-brain barrier (BBB) prevents most therapeutics from reaching the intracranial lesions at sufficiently high concentrations. This also applies to chimeric antigen receptor (CAR) T cells, for which systemic delivery is inferior to direct intratumoral or intraventricular injection of the cells. The authors previously reported on a novel approach to safely and reversibly open the BBB of mice by applying intra-arterial (IA) injections of NEO100, a pharmaceutical-grade version of the natural monoterpene perillyl alcohol. The authors hypothesized that this method would enable enhanced brain entry and therapeutic activity of intravenously delivered CAR T cells, which the authors tested in a mouse model of CNS lymphoma. METHODS: Human Raji lymphoma cells were implanted into the brains of immune-deficient mice. After tumor uptake was confirmed with bioluminescent imaging, 0.3% NEO100 was injected intra-arterially, which was followed by intravenous (IV) delivery of CD19-targeted CAR T cells. After this single intervention, tumor growth was monitored with imaging, long-term survival of mice was recorded, and select mice were euthanized to analyze the distribution of CAR T cells in brain tissue. RESULTS: Intravenously injected CAR T cells could be readily detected in brain tumor areas after IA injection of NEO100 but not after IA injection of the vehicle (without NEO100). Although all untreated control animals died within 3 weeks, all mice that received IA NEO100 followed by IV CAR T cells survived and thrived for 200 days, when the experiment was terminated. Of the mice that received IV CAR T cells without prior IA NEO100, 3 died within 3 weeks and 2 survived long-term. CONCLUSIONS: BBB opening by IA NEO100 facilitates brain entry of intravenously delivered CD19 CAR T cells. The long-term survival of all mice with CNS lymphoma, along with the disappearance of the tumor as determined with imaging, suggests that this one-time therapeutic intervention was curative. BBB opening by IA NEO100 may offer a novel option to increase brain access by CAR T cells.

Amphiphysin-IgG autoimmune sciatic neuropathy and facial neuropathy related to primary central nervous system lymphoma: A case report.

We reported a 61-year-old man presented with 10-month progressing left sciatic neuropathy and 10-day right facial neuropathy. Serum amphiphysin-IgG was positive. 18F-FDG PET/CT of the whole body showed no signs of malignancy. Treatment with plasma exchange and oral prednisone relieved the symptoms. Nine months later, right hemiparesis and seizure of right limbs developed. 18F-FDG and 18F-PBR06 (18 kDa translocator protein, TSPO) radioligand PET/MRI of the whole body revealed intense uptake in the intracranial lesions. Intracranial lymphoma was diagnosed by stereotactic needle brain biopsy. Mononeuropathies could be paraneoplastic syndromes. TSPO shows high uptake in intracranial lymphoma on 18F-PBR06 PET images.

Transcriptome and methylome analysis of CNS germ cell tumor finds its cell-of-origin in embryogenesis and reveals shared similarities with testicular counterparts.

BACKGROUND: CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. METHODS: We used a combined transcriptomic and methylomic approach in 84 cases and conducted an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs. RESULTS: Genome-wide transcriptome analysis in CNS GCTs indicated that germinoma had a transcriptomic profile representative of primitive cells during early embryogenesis with high meiosis/mitosis potentials, while nongerminomatous GCTs (NGGCTs) had differentiated phenotypes oriented toward tissue formation and organogenesis. Co-analysis with the transcriptome of human embryonic cells revealed that germinomas had expression profiles similar to those of primordial germ cells, while the expression profiles of NGGCTs were similar to those of embryonic stem cells. Some germinoma cases were characterized by extensive immune-cell infiltration and high expression of cancer-testis antigens. NGGCTs had significantly higher immune-cell infiltration, characterized by immune-suppression phenotype. CNS and testicular GCTs (TGCTs) had similar mutational profiles; TGCTs showed enhanced copy number alterations. Methylation analysis clustered germinoma/seminoma and nongerminoma/nonseminoma separately. Germinoma and seminoma were co-categorized based on the degree of the tumor microenvironment balance. CONCLUSIONS: These results suggested that the pathophysiology of GCTs was less dependent on their site of origin and more dependent on the state of differentiation as well as on the tumor microenvironment balance. This study revealed distinct biological properties of GCTs, which will hopefully lead to future treatment development.

Cytokine Release Syndrome after Treatment of Anti-CD19 CAR-T Therapy with IL-6 Knocking Down in Patients with Central Nervous System B-cell Acute Lymphocytic Leukemia.

OBJECTIVE: To investigate the cytokine release syndrome (CRS) condition for central nervous system B-cell acute lymphocytic leukemia (CNS B-ALL) patients after CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) infusion. METHODS: This prospective observational research included a total of 12 cases of patients with CNS B-ALL from March 2017 to February 2020. ssCART-19 infusions (5×106 cells/kg) were given to patients for 3 consecutive days. After infusion, the temperature of all patients was detected constantly and the CRS was carefully monitored within 1 month after treatment. The serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, CRP and IL-17A were tested by enzyme-linked immunosorbent assay (ELISA) within 10 days after infusion. RESULTS: All 12 CNS B-ALL patients showed CRS with 100% incidence rate, with 3 cases (25.00%) of CRS stage I and 9 cases (75.00%) with CRS stage II. No CRS stage III~V was observed. The overall response rate was 91.67% (11/12), with 10 patients (83.33%) showed CR and 1 case (8.33%) of PR. In 9 patients with CRS stage II, the temperature increased persistently, ranging from 4 days to 14 days after infusion, and decreased gradually after 14 days of nursing treatment. The hyperthermia condition started from 1 day after infusion and returned to baseline at the following 2-10 days of nursing treatment. The levels of the inflammatory factors increased markedly after ssCAR-T19s infusion for 2-3 days compared to the baseline, and gradually returned to the baseline after treatment. After 10 days of infusion, all inflammatory factors returned to normal levels. CONCLUSION: ssCART-19s infusion induced short-term slight CRS with increased temperature and inflammatory factors, and no severe CRS was observed.

ANXA2 is correlated with the molecular features and clinical prognosis of glioma, and acts as a potential marker of immunosuppression.

Recent studies have shown that ANXA2 is important in the development of many cancers, while its role in glioma-related immune response remains unclear. We aimed to comprehensively investigate its biological characteristics and clinical value in glioma. We analyzed 699 glioma samples from The Cancer Genome Atlas as training cohort and 325 samples from the Chinese Glioma Genome Atlas as validation cohort. All the statistical analyses and figures were generated with R. ANXA2 was overexpressed significantly in high-grade glioma, isocitrate dehydrogenase wild-type and mesenchymal-subtype glioma. ANXA2 was a special indicator of mesenchymal subtype. The survival analysis showed that highly-expressed ANXA2 was related to worse survival status as an independent factor of poor prognosis. Further gene ontology analysis showed that ANXA2 was mainly involved in immune response and inflammatory activities of glioma. Subsequent correlation analysis showed that ANXA2 was positively correlated with HCK, LCK, MHC II, STAT1 and interferon but negatively with IgG. Meanwhile, ANXA2 was positively related to the infiltration of tumor-related macrophages, regulatory T cells and myeloid-derived suppressor cells. Our study revealed that ANXA2 is a biomarker closely related to the malignant phenotype and poor prognosis of glioma, and plays an important role in immune response, inflammatory activity and immunosuppression.

Modulation of the Complement System by Neoplastic Disease of the Central Nervous System.

The complement system is a highly conserved component of innate immunity that is involved in recognizing and responding to pathogens. The system serves as a bridge between innate and adaptive immunity, and modulation of the complement system can affect the entire host immune response to a foreign insult. Neoplastic diseases have been shown to engage the complement system in order to evade the immune system, gain a selective growth advantage, and co-opt the surrounding environment for tumor proliferation. Historically, the central nervous system has been considered to be an immune-privileged environment, but it is now clear that there are active roles for both innate and adaptive immunity within the central nervous system. Much of the research on the role of immunological modulation of neoplastic disease within the central nervous system has focused on adaptive immunity, even though innate immunity still plays a critical role in the natural history of central nervous system neoplasms. Here, we review the modulation of the complement system by a variety of neoplastic diseases of the central nervous system. We also discuss gaps in the current body of knowledge and comment on future directions for investigation.

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. METHODS: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. RESULTS: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. CONCLUSIONS: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.

CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials.

BACKGROUND: CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia. METHODS: In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity. FINDINGS: Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata. INTERPRETATION: Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia. FUNDING: Children's Hospital of Philadelphia Frontier Program.

Combined tumor-associated macrophages biomarker predicting extremely poor outcome of patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive and rare malignancy with poor prognosis. However, there are no reliable prognostic biomarkers for PCNSL in clinical practice. Here, we aimed to identify a reliable prognostic biomarker for predicting the survival of PCNSL patients. In this study, multiplex immunofluorescence and digital imaging analysis were used to characterize tumor-associated macrophages (TAMs) immunophenotypes and the expression of programmed cell death ligand 1 on TAMs, with regard to prognosis from diagnostic tumor tissue samples of 59 PCNSL patients. We found that the M2-to-M1 ratio was a more reliable prognostic biomarker for PCNSL than M1-like or M2-like macrophage infiltration. In addition, the combination of programmed death-ligand 1 (PD-L1) expression on TAMs and the M2-to-M1 ratio in PCNSL demonstrated improved performance in prognostic discrimination than PD-L1-positive TAMs or M2-to-M1 ratio. To validate the prognostic significance of the combined TAMs associated biomarkers, they were integrated into the International Extranodal Lymphoma Study Group (IELSG) index and termed as IELSG-M index. Kaplan-Meier plots showed that the IELSG-M index could discriminate patients into low-, intermediate- or high-risk subgroups, better than IELSG, in terms of prognosis. The areas under the receiver operating characteristic curves of IELSG-M was 0.844 for overall survival; superior to the IELSG model (0.580). Taken together, this study's findings showed that the combination of PD-L1 on TAMs and the M2-to-M1 ratio could be strong prognostic predictive biomarkers for PCNSL and the IELSG-M index had improved prognostic significance than the IELSG index.

Sequential CD19/22 CAR T-cell immunotherapy following autologous stem cell transplantation for central nervous system lymphoma.

Chimeric antigen receptor (CAR) T-cell immunotherapy following autologous stem cell transplantation (ASCT) is a promising method for refractory or relapsed multiple myeloma, but explicit data for central nervous system lymphoma (CNSL) are lacking. Here, we treated 13 CNSL patients with ASCT sequential CD19/22 CAR T-cell infusion and simultaneously evaluated the clinical efficacy and toxicity. The 13 CNSL patients analyzed included four primary CNSL and nine secondary CNSL patients. Patients 1 and 10, who had complete remission status before enrollment, maintained clinical efficacy without recurrence. Nine of the remaining 11 patients responded to our protocol with a median durable time of 14.03 months, and the overall response and complete remission rate were 81.81% and 54.55%, respectively. No patient suffered grades 3-4 cytokine-release syndrome (CRS), and only patient 10 experienced severe immune effector cell-associated neurotoxicity syndrome (ICANS). In addition, increases in serum ferritin and interleukin-6 levels were often accompanied by CRS and ICANS. After a median follow-up time of 14.20 months, the estimated 1-year progression-free survival and overall survival rates were 74.59% and 82.50%, respectively. Sequential CD19/22 CAR T-cell immunotherapy following ASCT as a novel method for CNSL appears to have encouraging long-term efficacy with relatively manageable side effects.

Efficacy and Safety of Axicabtagene Ciloleucel and Tisagenlecleucel Administration in Lymphoma Patients With Secondary CNS Involvement: A Systematic Review.

Background: The efficacy and safety of chimeric antigen receptor T (CAR-T) cell therapy in the treatment of non-Hodgkin's lymphoma has already been demonstrated. However, patients with a history of/active secondary central nervous system (CNS) lymphoma were excluded from the licensing trials conducted on two widely used CAR-T cell products, Axicabtagene ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel). Hence, the objective of the present review was to assess whether secondary CNS lymphoma patients would derive a benefit from Axi-cel or Tisa-cel therapy, while maintaining controllable safety. Method: Two reviewers searched PubMed, Embase, Web of Science, and Cochrane library independently in order to identify all records associated with Axi-cel and Tisa-cel published prior to February 15, 2021. Studies that included secondary CNS lymphoma patients treated with Axi-cel and Tisa-cel and reported or could be inferred efficacy and safety endpoints of secondary CNS lymphoma patients were included. A tool designed specifically to evaluate the risk of bias in case series and reports and the ROBINS-I tool applied for cohort studies were used. Results: Ten studies involving forty-four patients were included. Of these, seven were case reports or series. The other three reports were cohort studies involving twenty-five patients. Current evidence indicates that secondary CNS lymphoma patients could achieve long-term remission following Axi-cel and Tisa-cel treatment. Compared with the non-CNS cohort, however, progression-free survival and overall survival tended to be shorter. This was possibly due to the relatively small size of the CNS cohort. The incidence and grades of adverse effects in secondary CNS lymphoma patients resembled those in the non-CNS cohort. No incidences of CAR-T cell-related deaths were reported. Nevertheless, the small sample size introduced a high risk of bias and prevented the identification of specific patients who could benefit more from CAR-T cell therapy. Conclusion: Secondary CNS lymphoma patients could seem to benefit from both Axi-cel and Tisa-cel treatment, with controllable risks. Thus, CAR-T cell therapy has potential as a candidate treatment for lymphoma patients with CNS involvement. Further prospective studies with larger samples and longer follow-up periods are warranted and recommended.

Innovative and Promising Strategies to Enhance Effectiveness of Immunotherapy for CNS Tumors: Where Are We?

Although there are several immunotherapy approaches for the treatment of Central Nervous System (CNS) tumors under evaluation, currently none of these approaches have received approval from the regulatory agencies. CNS tumors, especially glioblastomas, are tumors characterized by highly immunosuppressive tumor microenvironment, limiting the possibility of effectively eliciting an immune response. Moreover, the peculiar anatomic location of these tumors poses relevant challenges in terms of safety, since uncontrolled hyper inflammation could lead to cerebral edema and cranial hypertension. The most promising strategies of immunotherapy in neuro-oncology consist of the use of autologous T cells redirected against tumor cells through chimeric antigen receptor (CAR) constructs or genetically modified T-cell receptors. Trials based on native or genetically engineered oncolytic viruses and on vaccination with tumor-associated antigen peptides are also under evaluation. Despite some sporadic complete remissions achieved in clinical trials, the outcome of patients with CNS tumors treated with different immunotherapeutic approaches remains poor. Based on the lessons learned from these unsatisfactory experiences, novel immune-therapy approaches aimed at overcoming the profound immunosuppressive microenvironment of these diseases are bringing new hope to reach the cure for CNS tumors.

Nanoparticles for Enhanced Adoptive T Cell Therapies and Future Perspectives for CNS Tumors.

Adoptive T cell therapy has emerged as a revolutionary immunotherapy for treating cancer. Despite immense promise and clinical success in some hematologic malignancies, limitations remain that thwart its efficacy in solid tumors. Particularly in tumors of the central nervous system (CNS), T cell therapy is often restricted by the difficulty in intratumoral delivery across anatomical niches, suboptimal T cell specificity or activation, and intratumoral T cell dysfunction due to immunosuppressive tumor microenvironments (TMEs). Nanoparticles may offer several advantages to overcome these limitations of T cell therapy, as they can be designed to robustly and specifically activate T cells ex vivo prior to adoptive transfer, to encapsulate T cell stimulating agents for co-localized stimulation, and to be conjugated onto T cells for added functionality. This perspective highlights recent preclinical advances in using nanoparticles to enhance T cell therapy, and discusses the potential applicability and constraints of nanoparticle-enhanced T cells as a new platform for treating CNS tumors.

Evaluating Infectious, Neoplastic, Immunological, and Degenerative Diseases of the Central Nervous System with Cerebrospinal Fluid-Based Next-Generation Sequencing.

Cerebrospinal fluid (CSF) is a clear and paucicellular fluid that circulates within the ventricular system and the subarachnoid space of the central nervous system (CNS), and diverse CNS disorders can impact its composition, volume, and flow. As conventional CSF testing suffers from suboptimal sensitivity, this review aimed to evaluate the role of next-generation sequencing (NGS) in the work-up of infectious, neoplastic, neuroimmunological, and neurodegenerative CNS diseases. Metagenomic NGS showed improved sensitivity-compared to traditional methods-to detect bacterial, viral, parasitic, and fungal infections, while the overall performance was maximized in some studies when all diagnostic modalities were used. In patients with primary CNS cancer, NGS findings in the CSF were largely concordant with the molecular signatures derived from tissue-based molecular analysis; of interest, additional mutations were identified in the CSF in some glioma studies, reflecting intratumoral heterogeneity. In patients with metastasis to the CNS, NGS facilitated diagnosis, prognosis, therapeutic management, and monitoring, exhibiting higher sensitivity than neuroimaging, cytology, and plasma-based molecular analysis. Although evidence is still rudimentary, NGS could enhance the diagnosis and pathogenetic understanding of multiple sclerosis in addition to Alzheimer and Parkinson disease. To conclude, NGS has shown potential to aid the research, facilitate the diagnostic approach, and improve the management outcomes of all the aforementioned CNS diseases. However, to establish its role in clinical practice, the clinical validity and utility of each NGS protocol should be determined. Lastly, as most evidence has been derived from small and retrospective studies, results from randomized control trials could be of significant value.

Emerging insights into origin and pathobiology of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive cancer typically confined to the brain, eyes, leptomeninges and spinal cord, without evidence of systemic involvement. PCNSL remains a challenge for scientists and clinicians due to insufficient biological knowledge, a lack of appropriate animal models and validated diagnostic biomarkers. We summarize recent findings on genomic, transcriptomic and epigenetic alterations identified in PCNSL. These findings help to define pathobiology of the disease and delineate defects in B cell differentiation. Evidence from genomic and transcriptomic studies helps to separate PCNSL from other hematological malignancies, improves diagnostics and reveals new therapeutic targets for treatment. Discovery of the CNS lymphatic system may be instrumental in better understanding the origin of the disease. We critically assess the attempts to model PCNSL in rodents, and conclude that there is a lack of a genetic/transgenic model that adequately mimics pathogenesis of the disease. Contribution of the tumor microenvironment in tumorigenesis and aggressiveness of PCNSL remains understudied. Assessing heterogeneity of immune infiltrates, cytokine profiling and molecular markers, may improve diagnostics and put forward new therapeutic strategies.

The immune contexture of primary central nervous system diffuse large B cell lymphoma associates with patient survival and specific cell signaling.

Rationale: Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We hence investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Methods: Analysis of PCNSL transcriptomes (sequencing, n = 20; microarrays, n = 34). Integrated correlation analysis and signaling pathway topology enabled us to infer intercellular interactions. Immunohistopathology and digital imaging were used to validate bioinformatic results. Results: Transcriptomics revealed three immune subtypes: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, e.g., IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/ß-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, i.e., CTLA-4/CD86 and TIM-3/LAGLS9. TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Conclusion: Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.