Search

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment.Significance:CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy.This article is highlighted in the In This Issue feature, p. 101

Supplemental tables: (1) Subject characteristics. (2) Cytogenetic profiles and high-risk features. (3) Prior treatment exposures and refractoriness. (4) CAR T cell product characteristics. (5) Products that did not meet target dose. (6) Adverse events of grade 3-4. (7) Cytokine release syndrome and ICANS. (8). Maintenance therapy. Supplemental Figures: (1) Study schematic and subject disposition, (2) Correlates of manufacturing success, (3) Hematopoietic recovery, (4) Post-infusion T cell phenotypes, (5) Correlates of in vivo expansion and manufacturing success, (6) Late post-infusion CAR T cell re-expansion, (7) Soluble BCMA, (8) Late-onset clinical responses, (9) MM cell BCMA expression, (10) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA monotherapy patients, (11) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA + huCART19 combination therapy patients, (12) Sustained post-treatment SOX2-specific T-cell responses.

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment.Significance:CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy.This article is highlighted in the In This Issue feature, p. 101

Background and ObjectivesThe relationship between autologous hematopoietic stem cell transplant (aHSCT) for multiple myeloma (MM) and anti-GABAA receptor (GABAAR) encephalitis is unknown. We aimed to describe the clinical features, diagnostic process, and outcome of 3 cases of anti-GABAAR encephalitis in patients with a history of prior aHSCT for MM.MethodsA case series of 3 patients. Anti-GABAAR antibody was tested at the University of Pennsylvania Laboratory.ResultsThe patients were all male, aged 52 (case 1), 61 (case 2), and 62 (case 3) years at encephalitis symptom onset. The duration between completion of aHSCT and the onset of encephalitis was 43, 18, and 9 months, respectively. All 3 patients presented with new seizures and altered cognitive function. Other symptoms included headache and visual obscurations in cases 1 and 2 and intractable vertigo and mania in case 3. Brain MRI demonstrated nonenhancing multifocal T2-weighted/fluid-attenuated inversion recovery cortical and subcortical hyperintensities in all 3 patients. Cases 2 and 3 underwent brain biopsy before initiating immunomodulatory therapy, which demonstrated nonspecific encephalitis with astrogliosis in the white matter; these 2 patients were started on immunotherapy for the treatment of anti-GABAAR encephalitis after 22 days and 3 months, respectively, from the first presentation. Case 1 was started on empiric immunotherapy within 8 days of presentation without requiring brain biopsy, given characteristic MRI imaging. CSF analysis demonstrated the presence of anti-GABAAR antibodies in all 3 cases. Cases 1 and 3 also tested positive for anti-GABAAR antibodies in the serum (serum test was not performed in case 2). Cases 1 and 2 recovered to work full-time within 1 year. Case 3 reported occasional myoclonic-like movement.DiscussionWe highlight the importance of considering anti-GABAAR encephalitis in patients with seizures, multifocal nonenhancing brain lesions, and a history of aHSCT for MM. Awareness in recovered post-aHSCT patients with MM may be crucial because prompt recognition can avoid brain biopsy and delays in treatment. The rapid initiation of immunotherapy while awaiting autoantibody results will likely improve functional outcomes.

Contactin-associated protein-like 2 (Caspr2) is a neurexin-like protein that has been associated with numerous neurological conditions. However, the specific functional roles that Caspr2 plays in the central nervous system and their underlying mechanisms remain incompletely understood. Here, we report on a functional role for Caspr2 in the developing cerebellum. Using a combination of confocal microscopy, biochemical analyses, and behavioral testing, we show that loss of Caspr2 in the Cntnap2−/− knockout mouse results in impaired Purkinje cell dendritic development, altered intracellular signaling, and motor coordination deficits. We also find that Caspr2 is highly enriched at synaptic specializations in the cerebellum. Using a proteomics approach, we identify type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) as a specific synaptic interaction partner of the Caspr2 extracellular domain in the molecular layer of the developing cerebellum. The interaction of the Caspr2 extracellular domain with IP3R1 inhibits IP3R1-mediated changes in cellular morphology. Together, our work defines a mechanism by which Caspr2 controls the development and function of the cerebellum and advances our understanding of how Caspr2 dysfunction might lead to specific brain disorders.

Purpose Autoantibodies against glutamic acid decarboxylase 65 (GAD-65) have been identified in patients with chronic epilepsy. In this study, we ask (1) what is the frequency of GAD-65 antibodies in chronic epilepsy? (2) what is the frequency and type of epilepsy in individuals with GAD-65 antibodies? Methods For cohort 1, serum samples of patients with epilepsy (without type I diabetes) were obtained from our biobank. Samples were tested for GAD-65 antibodies using a cell-based assay and confirmed by immunohistochemistry. For cohort 2, patients with positive GAD-65 antibodies were identified and their medical records were reviewed for the presence and characteristics of epilepsy. Results Cohort 1 included 270 patients, of which 53% were women; median age was 47 years; median duration of epilepsy was 16 years. Epilepsy was focal in 87% (temporal lobe in 20%), and drug-resistant in 45%. GAD-65 antibodies were present in two out of 270 cases (0.7%) and zero controls. Cohort 2 consisted of 23 patients with known GAD-65 antibodies, of which ten had epilepsy (43%). Of these, 80% were women with a median age of 40 years and a median duration of epilepsy of 18 years. All ten patients had focal epilepsy, nine had temporal lobe epilepsy, and seven were drug resistant. Conclusions In patients with chronic epilepsy, the frequency of GAD-65 antibodies detected with our cell-based assay was substantially lower than previously reported with use of other methods. When present, GAD-65 antibodies are associated with drug-resistant temporal lobe epilepsy. GAD-65 positive epilepsy patients merit further investigation.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated, and clinically heterogeneous demyelinating disease affecting the nerve roots and peripheral nerves. We report a series of 4 patients who presented with early and progressive vision loss in the context of new-onset CIDP: 3 due to papilledema and 1 due to optic neuropathy without papilledema.This was a retrospective case series of 4 patients with vision loss as a presenting feature of CIDP evaluated at the Hospital of the University of Pennsylvania from January 2016 to August 2021. Demographic, clinical, diagnostic, and treatment data were collected via retrospective medical record review.Case 1 was a 51-year-old man with 2 months of progressive bilateral papilledema associated with reduced visual acuity (count fingers at 1 foot in each eye) and severely constricted visual fields. Case 2 was a 36-year-old man with 4 months of worsening headaches, reduced visual acuity (count fingers at 1 foot in each eye), severely constricted visual fields, and papilledema. Case 3 was a 39-year-old man with papilledema causing progressive vision loss (20/80 in both eyes), headaches, and relapsing limb sensorimotor deficits. Case 4 was a 19-year-old man with 3 months of progressive bilateral visual decline (20/400 in the right eye, 20/600 in the left eye), central scotoma, and optic disc pallor consistent with optic neuropathy without papilledema. All 4 patients met clinical and electrodiagnostic criteria of CIDP. Cases 3 and 4 each tested positive for serum neurofascin-155 IgG4 antibodies. All patients were managed with immunomodulatory therapy. Cases 1 and 2 also each required surgical intervention with bilateral optic nerve sheath fenestration and cerebrospinal fluid (CSF) shunting procedures.Vision loss from optic neuropathy with or without papilledema has rarely been reported in CIDP, and typically has been described in the context of longstanding disease. Our cases highlight how CIDP can present with early vision loss that may be profound and challenging to manage if diagnosis is delayed. CIDP should be considered in any patient with new progressive vision loss when associated with peripheral sensorimotor symptoms and elevated CSF protein. The small subgroup of CIDP patients with neurofascin-155 antibodies may be at particular risk of optic nerve involvement.

Background ADAM22 and ADAM23 are transmembrane proteins that bind the secreted synaptic protein LGI1 and associate with Kv1.1/Kv1.4 potassium channels. However, the roles of these proteins in regulated voltage-gated potassium currents are poorly understood. Methods Cultured cells were transfected to express ADAM22, ADAM23, and Kv1.1/Kv1.4. Voltage-gated potassium currents were measured by whole-cell patch-clamp. Immunostaining Kv1.1 with fluorescent antibodies and fluorescently tagged Kv1.1 subunits was used to measure the effects of ADAM proteins on cell-surface and total expression of Kv1.1 channels. LGI1-conditioned media was added to assess the effect on LGI1 on Kv1.1 currents. Results Cells transfected with Kv1.1/Kv1.4 showed voltage-gated potassium currents (Kv1.1 currents). ADAM23 was a powerful negative regulator of Kv1.1 currents and caused decreased surface expression of Kv1.1 subunits. This decrease in current was not mediated by clathrin-dependent endocytosis. LGI1-conditioned media did not affect the negative regulation of Kv1.1 currents by ADAM23. ADAM22 had no significant effect on Kv1.1 currents by itself, but in the presence of LGI1-conditioned media markedly potentiated Kv1.1 currents without changing channel activation kinetics. Conclusions ADAM22 and ADAM23 have opposite effects on Kv1.1 currents. The relative expression of these proteins, and the availability of LGI1 may shape the expression of Kv1.1 currents in different neuronal membrane domains.

ObjectiveTo construct a grading score that predicts neurologic function 1 year after diagnosis of anti-NMDA receptor (NMDAR) encephalitis.MethodsThree hundred eighty-two patients with detailed information and functional status at 1 year were studied. Factors associated with poor status (defined as modified Rankin Scale score ≥3) were identified and incorporated into a multivariate logistic regression model. This model was used to develop a 5-point prediction score, termed the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score.ResultsIntensive care unit admission (p < 0.001), treatment delay >4 weeks (p = 0.012), lack of clinical improvement within 4 weeks (p < 0.001), movement disorder (p = 0.001), central hypoventilation (p < 0.001), elevated CSF white blood cell count (p < 0.001), elevated CSF protein level (p = 0.027), and abnormal MRI (p = 0.002) were associated with 1-year functional status in univariate analysis. Intensive care unit admission, treatment delay >4 weeks, lack of clinical improvement within 4 weeks, abnormal MRI, and CSF white blood cell count >20 cells/μL were independent predictors for outcome in multivariate regression modeling. These 5 variables were assigned 1 point each to create the NEOS score. NEOS score strongly associated with the probability of poor functional status at 1 year (3% for 0 or 1 point to 69% for 4 or 5 points, p < 0.001).ConclusionsThe NEOS score accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.

Background and ObjectivesAnti-NMDA receptor encephalitis (anti-NMDARE) is one of the most common causes of encephalitis. It typically presents in adolescence and young adulthood, but little is known about its potential long-term consequences across the lifespan. Adaptive behavior describes an individual's ability to respond and adapt to environmental demands and unanticipated changes in daily routines. In this study, we evaluate the relationship between features from clinical presentation, including age, and long-term adaptive behavior in participants with anti-NMDARE.MethodsCross-sectional informant-reported data were collected between 2017 and 2019 from 41 individuals/caregivers of individuals with anti-NMDARE treated at 3 major academic hospitals. Neurologic disability was assessed by record review using the modified Rankin Scale (mRS). Functional outcomes were assessed using the validated Adaptive Behavior Assessment System, Third Edition (ABAS-3).ResultsThe mean age at the time of study enrollment was 23.4 years (SD 17.0 years), and the mean time from symptom onset to study enrollment was 4.0 years. Seventeen participants were aged 30 years. Mean ABAS-3 scores at study enrollment for all participants were in the average range (mean general adaptive composite standard score 92.5, SD 18.7). Individuals aged p < 0.05). Similar differences were seen in 3 of the individual subscales (functional academics, health and safety, and self-care). There were no significant differences in mRS scores between age groups (p > 0.05).DiscussionAlthough anti-NMDARE is associated with an overall favorable outcome, younger age at onset associates with worse long-term adaptive behavior despite no differences in neurologic disability. These findings suggest that the disease may have distinct consequences on the early developing brain. Future studies should evaluate behavioral recovery and quality of life after anti-NMDARE and identify additional factors associated with differential recovery.

CRISPR takes first steps in humans CRISPR-Cas9 is a revolutionary gene-editing technology that offers the potential to treat diseases such as cancer, but the effects of CRISPR in patients are currently unknown. Stadtmauer et al. report a phase 1 clinical trial to assess the safety and feasibility of CRISPR-Cas9 gene editing in three patients with advanced cancer (see the Perspective by Hamilton and Doudna). They removed immune cells called T lymphocytes from patients and used CRISPR-Cas9 to disrupt three genes ( TRAC, TRBC , and PDCD1 ) with the goal of improving antitumor immunity. A cancer-targeting transgene, NY-ESO-1, was also introduced to recognize tumors. The engineered cells were administered to patients and were well tolerated, with durable engraftment observed for the study duration. These encouraging observations pave the way for future trials to study CRISPR-engineered cancer immunotherapies. Science , this issue p. eaba7365 ; see also p. 976

Autoantibody encephalitis causes distinct clinical syndromes involving alterations in mentation, abnormal movements, seizures, psychiatric symptoms, sleep disruption, spasms, and neuromyotonia. The diagnoses can be confirmed by specific antibody tests, although some antibodies may be better detected in spinal fluid and others in serum. Each disorder conveys a risk of certain tumors which may inform diagnosis and be important for treatment. Autoantibodies to receptors and other neuronal membrane proteins are generally thought to be pathogenic and result in loss of function of the targets, so understanding the pharmacology of the receptors may inform our understanding of the syndromes. Patients may be profoundly ill but the syndromes usually respond to immune therapy, although there are differences in the types of immune therapy that are thought to be most effective for the various disorders.

It has been reported that embedded URLs and multimodal content (images, video, and sound recordings) in tweets are increasingly used to seduce users into a “wrong click,” leading to malware infection. In this paper, we predict whether a tweet is malicious or not by examining five classes of features: textual content including sentiment, paths emanating from a URL mentioned in the tweet, attributes associated with URLs, and multimodal content in the tweet. A fifth class of features first constructs a novel “tweet graph” and then defines features by analyzing “metapaths” contained in the tweet graph. Next, we propose a MALicious Tweets in Parallel ( ${\mathit {MALT^{P}}}$ ) collective classification algorithm that merges together tweet graphs, metapaths, and collective classification proposed previously in the literature. We conduct detailed experiments using two data sets—Warningbird (WB) and KBA. We show that our metapath-based approach outperforms past efforts at identifying malicious tweets and further show that metapath-based features in conjunction with Alexa ranks and features from KBA yield very high predictive accuracy—over 0.98 on KBA and over 0.94 on KBA, outperforming past work. More significantly, metapath features alone generate a predictive accuracy of 0.977 and 0.923, respectively, on the KBA and WB data sets, significantly outperforming the other methods in isolation. We conduct a further analysis to identify the most important features; surprisingly, our results show that the presence of multimodal content is not a major factor and that metapath-based features dominate in separating malicious from benign tweets.

B cell–depleting therapies have been shown to ameliorate symptoms in multiple sclerosis (MS) patients; however, the mechanism of action remains unclear. Following priming with Ag, B cells undergo secondary diversification of their BCR, including BCR class-switch recombination (CSR) and somatic hypermutation (SHM), with both processes requiring the enzyme activation-induced (cytidine) deaminase. We previously reported that activation-induced (cytidine) deaminase is required for full clinical manifestation of disease in an animal model of MS (experimental autoimmune encephalomyelitis; EAE) provoked by immunization with the extracellular domain of recombinant human myelin oligodendrocyte glycoprotein (hMOG). In this study, we investigated the role of CSR versus SHM in the pathogenesis of EAE. We found that passive transfer of class-switched anti-MOG IgG1 Abs into hMOG-primed Aicda−/− mice is sufficient to fully rescue EAE disease. In addition, we found that the nature of the Ag is an important determinant of EAE severity in Aicda−/− mice because the lack of a diversified BCR does not affect the induction of EAE when immunized with the extracellular domain of rat MOG. To discriminate the effect of either CSR or SHM, we induced EAE in uracil DNA glycosylase–deficient mice (Ung−/−) that exhibit a defect primarily in CSR. We observed that Ung−/− mice exhibit milder clinical disease compared with control mice, concomitant with a reduced amount of anti-MOG IgG1 class-switched Abs that preserved normal affinity. Collectively, these results indicate that CSR plays an important role in governing the incidence and severity of EAE induced with hMOG but not rat MOG.

Autoantibodies to Central nervous system (CNS) metabotropic receptors are associated with a growing family of autoimmune brain diseases, including encephalitis, basal ganglia encephalitis, Ophelia syndrome, and cerebellitis. The purpose of this review is to summarize the state of knowledge regarding the target receptors, the neurological autoimmune disorders, and the pathogenic mechanisms.Antibodies to the γ-aminobutyric acid B receptor are associate with limbic encephalitis and severe seizures, often with small cell lung cancers. Metabotropic glutamate receptor 5 (mGluR5) antibodies associate with Ophelia syndrome, a relatively mild form of encephalitis linked to Hodgkin lymphoma. mGluR1 antibodies associate with a form of cerebellar degeneration, and also Hodgkin lymphoma. Antibodies to Homer 3, a protein associated with mGluR1, have also been reported in two patients with cerebellar syndromes. Dopamine-2 receptor antibodies have been reported by one group in children with basal ganglia encephalitis and other disorders.CNS metabotropic receptor antibodies may exert direct inhibitory effects on their target receptors, but the evidence is more limited than with autoantibodies to ionotropic glutamate receptors. In the future, improved recognition of these patients may lead to better outcomes. Understanding the molecular mechanisms of the diseases may uncover novel treatment strategies.

BACKGROUND. CAR T cells are a promising therapy for hematologic malignancies. B cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS. We conducted a phase I study of autologous T cells lentivirally transduced with a fully human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts as follows: cohort 1, 1 × 108 to 5 × 108 CART-BCMA cells alone; cohort 2, cyclophosphamide (Cy) 1.5 g/m2 plus 1 × 107 to 5 × 107 CART-BCMA cells; cohort 3, Cy 1.5 g/m2 plus 1 × 108 to 5 × 108 CART-BCMA cells. No prespecified BCMA expression level was required. RESULTS. CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3–4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe cytokine release syndrome and encephalopathy. Responses (based on treated subjects) were seen in 4 of 9 (44%) in cohort 1, 1 of 5 (20%) in cohort 2, and 7 of 11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4/CD8 T cell ratio and frequency of CD45RO–CD27+CD8+ T cells in the premanufacturing leukapheresis product. CONCLUSION. CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily pretreated patients with MM. TRIAL REGISTRATION. {"type":"clinical-trial","attrs":{"text":"NCT02546167","term_id":"NCT02546167"}}NCT02546167. FUNDING. University of Pennsylvania-Novartis Alliance and NIH.

Immune checkpoint inhibitors (ICIs) are highly efficacious for treating many solid tumor types. Because of their immune-activating mechanism of action, ICIs can trigger various immune-mediated toxicities. We present three cases: i) a woman with anti-Ri brainstem encephalitis; ii) a man with anti-Hu sensory neuronopathy; and iii) a woman with suspected combined anti-Hu and anti-NMDA paraneoplastic syndromes associated with the initiation of the ICIs pembrolizumab and nivolumab. These cases suggest that ICIs can induce both humoral and cell-mediated paraneoplastic neurologic syndromes. Identifying biomarkers that predict risk of developing ICI-associated paraneoplastic syndromes and the development of efficacious treatment strategies for neurologic ICI-toxicities are critical unmet needs.

ObjectiveTo report 2 patients with anti–myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis who were initially misdiagnosed with small vessel primary CNS vasculitis.MethodsReview of symptoms, MRI and neuropathologic features, and response to treatment. MOG antibodies were determined in serum and CSF using a cell-based assay.ResultsSymptoms included fever, headache, and progressive mental status changes and focal neurologic deficits. CSF studies revealed lymphocytic pleocytosis, and both patients had abnormal brain MRIs. Brain biopsy samples showed prominent lymphocytic infiltration of the wall of small vessels; these findings initially suggested small vessel CNS vasculitis, and both patients were treated accordingly. Although 1 patient had a relapsing-remitting course not responsive to cyclophosphamide, the other one (also treated with cyclophosphamide) did not relapse. Retrospective assessment of serum and CSF demonstrated MOG antibodies in both cases, and review of biopsy specimens showed absence of fibrinoid necrosis (a pathologic requirement for small vessel CNS vasculitis).ConclusionsAnti–MOG-associated encephalitis can be mistaken for small vessel CNS vasculitis. This is important because the diagnosis of anti–MOG-associated encephalitis does not require brain biopsy and can be established with a serologic test.

Martinez-Hernandez et al.1 systematically explored the co-occurrence of anti-NMDAR with other cell surface neuronal antibodies or glial antibodies (MOG, AQP4). Anti-NMDAR encephalitis is an autoimmune brain disease characterized by psychosis, memory loss, dystonia, catatonia, seizures, and coma.2 Ovarian teratoma triggers about half of cases but other tumors are rare. Anti-NMDAR encephalitis is usually not associated with other types of brain autoimmunity. However, a small group of patients may have co-existing neuromyelitis optica, MOG antibody syndrome, or additional CNS synaptic antibodies.3,4

Objective:We investigated a series of patients with LGI1 antibody (Ab)–related cognitive deterioration to determine the clinical presentation, long-term outcome, and LGI1 Ab evolution.Methods:We retrospectively analyzed the clinical information of 76 patients with LGI1 Ab–related cognitive deterioration. Presenting syndromes were classified as limbic encephalitis (LE), non-LE, or encephalopathy (normal MRI and no CSF pleocytosis). Frequency of relapses and clinical outcome were assessed in 48 patients with prolonged follow-up (median 39 months, range 18–200).Results:Sixty-three patients (83%) developed LE, 3 (4%) non-LE, and 10 (13%) encephalopathy. All patients received steroids, IV immunoglobulins (Ig), or both. At 2 years, 17 (35%; 95% CI 21%–49%) fully recovered, 17 (35%) became functionally independent but not at baseline or were unable to return to work, 11 (23%) required assistance because of moderate or severe cognitive deficits, and 3 (6%) died. Predictors of bad outcome included no response to initial immunotherapy (odds ratio 23.0, 95% CI 2.4–215.6, p = 0.006) and clinical relapses (odds ratio 10.2, 95% CI 1.0–100.1, p = 0.047) that occurred in 13 patients (27%). In all patients, the LGI1 Abs were IgG4 and usually detectable in both serum and CSF (only CSF, 8%). Abs remained positive in serum of 4 of 16 patients with long-term follow-up; 3 of these 4 patients fully recovered and none showed class switch to IgG1.Conclusions:Up to 13% of patients with LGI1 Abs develop cognitive impairment without criteria of encephalitis. After immunotherapy, only 35% of patients return to their baseline cognitive function. Serum LGI1 Abs may remain detectable after full clinical recovery.

Importance: Symptoms of stiff-person syndrome (SPS), stiff-limb syndrome (SLS), or progressive encephalomyelitis with rigidity, myoclonus, or other symptoms (SPS-plus) can occur with several autoantibodies, but the relative frequency of each antibody, syndrome specificity, and prognostic implications are unclear. Objective: To report the clinical and immunologic findings of a large cohort of patients with stiff-person spectrum disorder (SPSD), including SPS, SLS, and SPS-plus. Design, Setting, and Patients: This study retrospectively examined a case series (January 1, 1998, through December 31, 2014) of immunologic investigations performed in a neuroimmunology referral center. The study included 121 patients with clinical features of SPSD. Data analysis was performed from July 1, 2015, through November 1, 2015. Main Outcomes and Measures: Analysis of clinical-immunologic associations, including autoantibodies to 8 proteins expressed in inhibitory synapses. Results: The median age of the patients was 51 years (interquartile range, 40-61 years), and 75 (62.0%) were female. Fifty (41.3%) had SPS, 37 (30.6%) had SPS-plus, 24 (19.8%) had SLS, and 10 (8.3%) had SPS or SLS overlapping with ataxia, epilepsy, or encephalitis. Fifty-two patients (43.0%) had glutamic acid decarboxylase (GAD65) antibodies (2 with γ-aminobutyric acid-A [GABA-A] receptor antibodies), 24 (19.8%) had α1-subunit of the glycine receptor (GlyR) antibodies (2 with GAD65 antibodies), 5 (4.1%) had other antibodies, and 40 (33.1%) tested negative for antibodies. None had gephyrin or glycine transporter antibodies. Among the main immunologic groups (GAD65 antibodies, GlyR antibodies, and antibody negative), those with GAD65 antibodies were more likely to be female (45 [86.5%] of 52, 8 [36.4%] of 22, and 18 [45.0%] of 40, respectively; P

Adeno-associated virus-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations affecting the CNS. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that, despite a global increase in progranulin, overexpression resulted in dramatic and selective hippocampal toxicity and degeneration affecting neurons and glia. Hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid similarly resulted in T cell infiltration, as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression prior to progressing to the clinic.

International audience; The SCN1A gene encodes for the voltage-dependent Nav1.1 Na+ channel, an isoform mainly expressed in GABAergic neurons that is the target of hundreds of epileptogenic mutations. More recently, it has been shown that the SCN1A gene is also the target of mutations responsible for familial hemiplegic migraine (FHM-3), a rare autosomal dominant subtype of migraine with aura. Studies of these mutations indicate that they induce gain of function of the channel. Surprisingly, the mutation L1649Q responsible for pure FHM-3 showed a complete loss of function, but, when partially rescued it induced an overall gain of function because of modification of the gating properties of the mutant channel. Here, we report the characterization of the L1670W SCN1A mutation that has been previously identified in a Chinese family with pure FHM-3, and that we have identified also in a Caucasian American family with pure FHM-3. Notably, one patient in our family had severe neurological deterioration after brain radiation for cancer treatment. Functional analysis of L1670W reveals that the mutation is responsible for folding/trafficking defects and, when they are rescued by incubation at lower temperature or by expression in neurons, modifications of the gating properties lead to an overall gain of function. Therefore, L1670W is the second mutation responsible for FHM-3 with this pathophysiological mechanism, showing that it may be a recurrent mechanism for Nav1.1 hemiplegic migraine mutations.

Anti–tumor necrosis factor alpha (TNF-α) therapies have been a significant advance in the treatment of autoimmune and rheumatologic diseases. Early preclinical and clinical studies of anti–TNF-α therapies emphasized infection and malignancy as serious adverse events associated with these agents.1 However, subsequent clinical experience has increasingly recognized a rare and seemingly paradoxical risk of autoimmunity with agents targeting the TNF-α pathway, most notably psoriatic eruptions,2 but also autoimmune processes associated with autoantibody production, including systemic vasculitis and lupus erythematosus.3,4 The development of neurologic diseases in association with anti–TNF-α therapy has been documented in case series and small prospective studies,5 with the most commonly reported associations being demyelinating diseases of the CNS and peripheral nervous systems. Here, we report a patient who developed anti–NMDA receptor (NMDAR) encephalitis while being treated with adalimumab for Crohn disease.

B cell-depleting therapies have been shown to ameliorate symptoms in multiple sclerosis (MS) patients; however, the mechanism of action remains unclear. Following priming with Ag, B cells undergo secondary diversification of their BCR, including BCR class-switch recombination (CSR) and somatic hypermutation (SHM), with both processes requiring the enzyme activation-induced (cytidine) deaminase. We previously reported that activation-induced (cytidine) deaminase is required for full clinical manifestation of disease in an animal model of MS (experimental autoimmune encephalomyelitis; EAE) provoked by immunization with the extracellular domain of recombinant human myelin oligodendrocyte glycoprotein (hMOG). In this study, we investigated the role of CSR versus SHM in the pathogenesis of EAE. We found that passive transfer of class-switched anti-MOG IgG1 Abs into hMOG-primed

Adeno-associated virus (AAV)-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations, and use of AAV vectors for treatment of diseases of the CNS is increasing. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL), and two recent studies using focal intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse FTD models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that despite a global increase in progranulin throughout many brain regions, overexpression of GRN resulted in dramatic and selective hippocampal toxicity and degeneration affecting both neurons and glia. Histologically, hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing, suggesting an inflammatory component to the ensuing neuronal loss. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid (CSF) similarly resulted in T cell infiltration as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response following GRN gene delivery. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression in relevant animal models prior to progressing to the clinic.Significance StatementGene therapies using adeno-associated viral (AAV) vectors show great promise for many human diseases, including diseases that affect the central nervous system (CNS). Frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL) are neurodegenerative diseases resulting from loss of one or both copies of the gene encoding progranulin (GRN), and gene replacement has been proposed for these currently untreatable disorders. Here, we used two different AAV vectors to induce widespread brain GRN expression in mice lacking the gene, as well as in wild-type mice. Unexpectedly, GRN overexpression resulted in T cell infiltration, followed by marked hippocampal neurodegeneration. Our results call into question the safety of GRN overexpression in the CNS, with wider implications for development of CNS gene therapies.

Autoimmune encephalitis causes subacute deficits of memory and cognition, often followed by suppressed level of consciousness or coma. A careful history and examination may show early clues to particular autoimmune causes, such as neuromyotonia, hyperekplexia, psychosis, dystonia, or the presence of particular tumors. Ancillary testing with MRI and EEG may be helpful for excluding other causes, managing seizures, and, rarely, for identifying characteristic findings. Appropriate autoantibody testing can confirm specific diagnoses, although this is often done in parallel with exclusion of infectious and other causes. Autoimmune encephalitis may be divided into several groups of diseases: those with pathogenic antibodies to cell surface proteins, those with antibodies to intracellular synaptic proteins, T-cell diseases associated with antibodies to intracellular antigens, and those associated with other autoimmune disorders. Many forms of autoimmune encephalitis are paraneoplastic, and each of these conveys a distinct risk profile for various tumors. Tumor screening and, if necessary, treatment is essential to proper management. Most forms of autoimmune encephalitis respond to immune therapies, although powerful immune suppression for weeks or months may be needed in difficult cases. Autoimmune encephalitis may relapse, so follow-up care is important.

BACKGROUND The role of brain biopsy in patients with cryptogenic neurological disease is uncertain. OBJECTIVE To determine the risks and benefits of diagnostic brain biopsy for nonneoplastic indications in immunocompetent patients. METHODS Appropriate studies were identified by searching electronic databases. RESULTS We screened 3645 abstracts and included 20 studies with a total of 831 patients. Indications for biopsy were: (1a) severe neurological disease of unknown etiology in adults (n = 7) and (1b) in children (n = 2); (2) suspected primary angiitis of the central nervous system (PACNS) (n = 3); (3) chronic meningitis of unknown cause (n = 3); (4) atypical dementia (n = 4); and (5) nonneoplastic disease (n = 1). Diagnostic success rates calculated for subgroups were 51.3% (34.5-68.1) for 1a, 53.8% (42.9-64.5) for 1b, 74.7% (64.0-84.1) for 2, 30.3% (17.2-45.4) for 3, and 60.8% (41.2-78.8) for 4. Clinical impact rates were 30.5% (13.6-50.6) for 1a (n = 6), 67.1% (42.8-87.3) for 1b (n = 2), 8.3% (2.3-20.0) for 3 (n = 1), and 14.2% (6.5-24.3) for 4 (n = 2). Lymphoma (n = 32) and Creutzfeldt-Jakob disease (n = 30) were the most common diagnoses on the final histopathology reports of positive brain biopsies in 1a. In 1b, encephalitis (n = 7), PACNS (n = 6), and demyelination (n = 6) were the most common. The odds ratio for achieving a diagnostic biopsy when there was a radiological target was 3.70 (P = .014, 95% confidence interval, 1.31-10.42). CONCLUSION Brain biopsy in cryptogenic neurological disease was associated with the highest diagnostic yield in patients with suspected PACNS. The greatest clinical impact was seen in children with cryptogenic neurological disease. The presence of a radiological target was associated with a higher diagnostic yield.

Paraneoplastic neurologic syndromes target specific areas of the nervous system with pathogenic autoantibodies or T-cell responses. Each syndrome conveys a risk of particular tumors. Expanded paraneoplastic antibody testing has led to improved diagnosis but created challenges involving appropriate interpretation of test results.Peripheral nervous system paraneoplastic disorders such as myasthenia gravis and Lambert-Eaton myasthenic syndrome involve pathogenic autoantibodies. Recently, the pathogenic mechanisms and antigens of these disorders have been further elucidated. Paraneoplastic syndromes associated with onconeuronal antibodies, such as anti-Hu, have strong cancer associations and limited response to treatment. Autoimmunity to central nervous system membrane proteins, such as the N-methyl-D-aspartate (NMDA) receptor or leucine-rich, glioma inactivated 1 (LGI1), defines an expanding group of disorders with better prognosis and more variable cancer associations. In these diseases, the autoantibodies are either proven to be or are potentially pathogenic. An animal model of anti-NMDA receptor encephalitis will allow novel treatments to be developed. Autoantibodies to intracellular synaptic antigens, such as glutamic acid decarboxylase 65 (GAD65), are associated with diverse disorders such as stiff person syndrome, and the pathophysiology of these diseases is unclear.Paraneoplastic disorders have diverse clinical manifestations, including weakness, sensory neuronopathy, encephalitis, epilepsy, and psychosis. Proper use of antibody testing may assist with diagnosis. Treatment may require immunotherapy and tumor treatment.

To determine the pathogenic mechanisms of autoantibodies to the cell adhesion molecule Caspr2 in acquired neuromyotonia and autoimmune encephalitis.Caspr2-positive samples were confirmed using a cell-based assay, and their IgG subtypes were determined by enzyme-linked immunosorbent assay and cell-based assay. A solid phase binding assay quantified the binding of Caspr2 to contactin-2 in the presence of Caspr2 autoantibodies. Living cultures of primary rat hippocampal neurons were incubated with Caspr2-positive or control sera, and the distribution of Caspr2-positive immunofluorescent puncta and total surface Caspr2 was quantified. HEK cells transfected to express Caspr2 were incubated with Caspr2-positive or control samples, and cell-surface biotinylation and Western blot were used to assess total, internalized, and surface levels of Caspr2.We confirmed 6 samples with strong Caspr2 reactivity. IgG4 Caspr2 antibodies were present in all 6 cases. Caspr2 interacted with another cell adhesion molecule, contactin-2, with nanomolar affinity in the solid phase assay, and Caspr2 autoantibodies inhibited this interaction. Caspr2 autoantibodies did not affect the surface expression of Caspr2 in rat primary hippocampal neurons or transfected HEK cells.Caspr2 autoantibodies inhibit the interaction of Caspr2 with contactin-2 but do not cause internalization of Caspr2. Functional blocking of cell adhesion molecule interactions represents a potential mechanism with therapeutic implications for IgG4 autoantibodies to cell adhesion molecules in neurological diseases. Ann Neurol 2018;83:40-51.

Objective To measure the frequency, persistence, isoform specificity, and clinical correlates of neurofascin antibodies in patients with peripheral neuropathies. Methods We studied cohorts of patients with Guillain-Barre syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 59), genetic neuropathy (n = 111), and idiopathic neuropathy (n = 43) for immunoglobulin (Ig) G and IgM responses to 3 neurofascin (NF) isoforms (NF140, NF155, and NF186) using cell-based assays. Results Neurofascin antibodies were more common in patients with GBS/CIDP (14%, 8 of 59) compared to genetic neuropathy controls (3%, 3 of 111, p = 0.01). Seven percent (3 of 43) of patients with idiopathic neuropathy also had neurofascin antibodies. NF155 IgG4 antibodies were associated with CIDP refractory to IV immunoglobulin but responsive to rituximab, and some of these patients had an acute onset resembling GBS. NF186 IgG and IgM to either isoform were less specific. A severe form of CIDP, approaching a locked-in state, was seen in a patient with antibodies recognizing all 3 neurofascin isoforms. Conclusions Neurofascin antibodies were 4 times more frequent in autoimmune neuropathy samples compared to genetic neuropathy controls. Persistent IgG4 responses to NF155 correlated with severe CIDP resistant to usual treatments but responsive to rituximab. IgG4 antibodies against the common domains shared by glial and axonal isoforms may portend a particularly severe but treatable neuropathy. The prognostic implications of neurofascin antibodies in a subset of idiopathic neuropathy patients and transient IgM responses in GBS require further investigation.

Thymic malignancy is often associated with paraneoplastic neurological diseases (PNDs) and recognition of these disorders is important for physicians who treat these patients. The most common thymoma-associated PNDs are myasthenia gravis (MG), acquired neuromyotonia (Isaacs' syndrome), encephalitis, Morvan's syndrome, and myositis. Diagnosis of these disorders is complex but often aided by testing for specific autoantibodies, including those to the acetylcholine receptor for MG and to contactin-associated protein-like 2, protein of the voltage-gated potassium channel complex, in patients with acquired neuromyotonia, Morvan's syndrome, or encephalitis. Patients who manifest these disorders should be screened for thymoma at diagnosis, and worsening of these PNDs may be associated with recurrent thymoma. These disorders can cause profound disability but usually respond to immunotherapy, and often improve with thymoma treatment. Close cooperation among a team of specialists is required to take proper care of these patients.

Antibodies to glutamic acid decarboxylase (GAD) have been associated with a host of neurological disorders including stiff person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. Whether anti-GAD antibodies have an etiological role in these neurological disorders or simply serve as disease markers is unclear. Here, we report a case of a patient with recurrent seizures, poorly responsive to conventional treatment, associated with anti-GAD antibodies. The patient was experiencing near daily seizures at the time of presentation and had marked improvement while receiving immunosuppressive therapy and therapeutic plasma exchange (TPE). We go on to show that the patient had a substantial reduction of her GAD autoantibody burden following this therapy. Using immunostaining, we further demonstrate a progressive loss of GAD reactivity in the patient's sera to neurons and GAD-expressing HELA cells with successive TPEs. Hence, these data support the concept of an immune-mediated pathogenic component to these autoantibody-associated neurological syndromes.

The Kv7 (KCNQ) family of voltage-gated K(+) channels regulates cellular excitability. The functional role of Kv7.2 has been hampered by the lack of a viable Kcnq2-null animal model. In this study, we generated homozygous Kcnq2-null sensory neurons using the Cre-Lox system; in these mice, Kv7.2 expression is absent in the peripheral sensory neurons, whereas the expression of other molecular components of nodes (including Kv7.3), paranodes, and juxtaparanodes is not altered. The conditional Kcnq2-null animals exhibit normal motor performance but have increased thermal hyperalgesia and mechanical allodynia. Whole-cell patch recording technique demonstrates that Kcnq2-null sensory neurons have increased excitability and reduced spike frequency adaptation. Taken together, our results suggest that the loss of Kv7.2 activity increases the excitability of primary sensory neurons.

BACKGROUND: Anti-BCMA CAR T cells are effective in relapsed/refractory multiple myeloma (RRMM), but most patients eventually progress. Extensive prior therapy and high disease burden in RRMM pts may compromise CAR T cell safety, feasibility, and efficacy, and rare BCMA-neg/CD19+ MM cells with enhanced clonogenic potential may mediate relapse after anti-BCMA CARs. We therefore initiated a trial of anti-BCMA CAR T cells (CART-BCMA) as consolidation of response to prior MM therapy, including high-risk (HR) pts responding to first-line therapy, and combined CART-BCMA with anti-CD19 CAR T cells (CTL119). Both CART-BCMA and CTL119 are 4-1BB/CD3z-based CARs transduced via lentiviral vector. CART-BCMA was previously reported (Cohen et al JCI 2019) and exhibited 64% response rate at 5x108 cell dose following cyclophosphamide (cy) alone as lymphodepleting chemo in RRMM. CTL119 is a humanized version of tisagenlecleucel. METHODS: To assess safety/feasibility of CART-BCMA + CTL119, Phase A (PhA) is evaluating the combination in pts responding (≥MR) to ≥3rd line therapy (or ≥2nd line if exposed to all major agents). After early PhA results showed no excessive toxicity, Phase B (PhB) began enrolling HR pts (R-ISS 3, complex karyotype, PC leukemia, or RESULTS: 6/7 enrolled PhA pts were infused; 1 pt died due to CNS progression before infusion. 4/4 enrolled PhB pts were infused (2 CART-BCMA alone, 2 CART-BCMA + CTL119). See table for age & prior # therapies; 9/10 had HR cytogenetics or were R-ISS 3. Regarding mfg feasibility, 2 PhA pts (05, 07) failed to meet full target doses; all 4 PhB pts achieved full dose. Two subjects (01, 03) had the 3rd (60%) dose held due to early fevers. CRS was gr 0-2 by ASTCT criteria and was observed in pts with both high and low disease burden (table). No neurologic toxicity was observed. Gr 3-4 toxicities were mainly hematologic; 3/6 PhA pts had either ANC CONCLUSIONS: Preliminary results support safety and high initial response-rate of CART-BCMA + CTL119 after cy/flu in MM. In pts with low disease burden responding to prior therapy, including first-line therapy, CAR T cells expanded in vivo and generated clinical responses with low-grade CRS and no neurotoxicity. Preliminarily, hematologic toxicity and feasibility of maint seem more favorable in first-line setting. Addition of CTL119 did not clearly prevent progression after CART-BCMA in the PhA population (3-9 prior lines); data from PhB with randomization +/- CTL119 are immature. Accrual is ongoing, and updated results will be presented at the meeting. Table. Disclosures Garfall: Surface Oncology: Consultancy; Novartis: Patents & Royalties: inventor on patents related to tisagenlecleucel (CTL019) and CART-BCMA, Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Honoraria, Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding. Lacey:Novartis: Research Funding; Tmunity: Research Funding; Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers. Tian:Novartis: Research Funding. Hwang:Novartis: Research Funding; Tmunity: Research Funding. Vogl:Active Biotech: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Lancaster:novartis: Research Funding. Nelson:Novartis: Research Funding. Ferthio:Novartis: Research Funding. Fesnak:Novartis: Research Funding. Melenhorst:National Institutes of Health: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Incyte: Research Funding; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding, Speakers Bureau; Stand Up to Cancer: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Genentech: Speakers Bureau. Young:novartis: Research Funding. Levine:Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Cure Genetics: Consultancy; Novartis: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership; CRC Oncology: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees. Brogdon:Novartis: Employment. Isaacs:Novartis: Employment. June:Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties; Novartis: Research Funding. Milone:Novartis: Patents & Royalties, Research Funding. Stadtmauer:Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy.

Background: Autologous T cells genetically modified with a lentiviral vector to express affinity-enhanced T cell receptors (TCR) or chimeric antigen receptors have shown great promise for the treatment of cancer. NY-ESO-1 is a cancer testis antigen with little normal tissue expression but with aberrant expression in MM, sarcomas, and melanomas. An HLA-A201 restricted TCR recognizing the NY-ESO-1/LAGE-1 157-165 epitope (SLLMWITQC) kills NY-ESO positive cell lines and has been used to treat 25 patients with MM after ASCT with expansion, persistence, antigen-directed functionality and long-term safety and antitumor activity (Nat Med 2015, Blood Adv 2019). We hypothesized removal of the genes encoding the endogenous TCR, TCRα (TRAC) and TCRβ (TRBC), would enhance NY-ESO TCR expression and reduce TCR mispairing and with removal of PD-1 (PDCD1) would enhance activity and persistence. We previously demonstrated CRISPR/Cas9 and TCRα, TCRβ and PDCD1 targeting gRNAs could be successfully introduced via electroporation in preclinical models to disrupt gene expression (Clin Cancer Res 2017). We therefore began a phase 1 pilot clinical trial for pts with advanced MM and sarcoma of NY-ESO-1 TCR-expressing T cells with CRISPR/Cas9 TCRα, TCRβ and PDCD1 edited genes to assess safety, feasibility and activity (NCT03399448). Methods: Adults with HLA-A*0201 and expressing NY-ESO-1 and/or LAGE-1 antigen with advanced MM, synovial sarcoma, and myxoid/round cell liposarcoma (MRCL) with adequate performance and organ function and, for MM relapsed or refractory to at least 3 prior regimens and, for MRCL, proven metastatic disease or surgically inoperable local recurrence, were enrolled. Autologous T cells were transfected with Cas9 protein complexed with single guide RNAs against TRAC, TRBC and PDCD1 and subsequently transduced to express NY-ESO-1-specific TCR at the University of Pennsylvania. Frequency of NYCE T cells in final product was measured by flow cytometric dextramer analysis. Once cells were successfully manufactured and released, pts received fludarabine 30mg/m2 and cyclophosphamide 300mg/m2 daily on day -4,-3,-2. On Day 0 pts received a single infusion of thawed NYCE T cells as an out-patient. Pts were monitored closely for the first 28 days, monthly till 6 mo and then followed every 3 mo for adverse events, antitumor response and survival, NYCE T cell expansion, persistence, trafficking, phenotype and function, and immunogenicity. An assessment after accrual of the first 3 subjects in this ongoing trial was planned and is reported here. Results: 3 pts, 2 with MM and 1 with MRCL, have received NYCE T cells. Pt 1 is a 67 y/o F with IgG kappa MM with lytic bone lesions, and a +17q after 8 lines of therapy including 3 ASCTs, lenalidomide, pomalidomide, bortezomib, carfilzomib, daratumumab, and panobinostat. Pt 2 is a 65 y/o M with a recurrent MRCL manifested by abdominal and pelvic involvement after neo-adjuvant doxorubicin, multiple resections and radiation treatments with progression at time of enrollment. Pt 3 is a 62 y/o F with kappa light chain MM with lytic bone lesions and plasmacytomas and a +1q after 7 lines of therapy including lenalidomide, pomalidomide, bortezomib, carfilzomib, daratumumab, 2 ASCTs and an immunoconjugate . Manufacturing for these pts resulted in satisfactory products with 89.4 to 96% viability, transduction efficiency by qPCR of 0.04 to 0.2 copies/cell , residual Cas9 concentration 0 to 0.37 ng/ml, dextramer 0.4 to 1.8% NY-ESO-1 expression. TRAC, TRBC, and PDCD1 disruption efficiency was 44.3 to 49.4, 3.61 to 15.7 and 15.6 to 20.2% respectively. Pts tolerated treatment well without neurotoxicity or CRS. By day +60 pt 1 progressed by IMWG. Pt 2 received 1 U PRBC. By day +90 he remained with stable disease by serial CT scans. Pt 3 is too early to evaluate. Serial qPCR for copies of lentiviral transcripts in peripheral blood and tumor biopsies for pts 1+2 showed in vivo expansion, stable persistence and tumor targeting (Figure). Conclusion: Early results of a phase 1 trial of NYCE T cells infused in 3 pts with advanced MM and MRCL show safety and feasibility and viable, expanding, and persisting CRISPR/Cas9 gene edited T cells that trafficked to tumor. The persistence of the NYCE T cells suggests that immunogenicity from multiplexed gene-editing using Cas9 is minimal under these conditions. Further characterization of phenotype and function of these cells and clinical outcomes will be presented. Figure Disclosures Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding. Lacey:Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers; Tmunity: Research Funding; Novartis: Research Funding. Melenhorst:Incyte: Research Funding; Novartis: Research Funding, Speakers Bureau; Parker Institute for Cancer Immunotherapy: Research Funding; Genentech: Speakers Bureau; Stand Up to Cancer: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; National Institutes of Health: Research Funding. Fraietta:Tmunity: Research Funding; Cabaletta: Research Funding; LEK Consulting: Consultancy. Mangan:amgen: Speakers Bureau; takeda: Speakers Bureau; celgene: Speakers Bureau; janssen: Speakers Bureau. Lancaster:novartis: Research Funding. Suhoski:novartis: Research Funding. Fesnak:Novartis: Research Funding. Young:novartis: Research Funding. Chew:tmunity: Other: Scientific Founder, Research Funding; novartis: Research Funding. Zhao:Tmunity: Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Research Funding. Hwang:Novartis: Research Funding; Tmunity: Research Funding. Hexner:novartis: Research Funding. June:Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties.

In this issue of N2 , the paper by O'Connor et al.1 reports the clinical, immunologic, and radiographic features of a series of patients with anti-γ-aminobutyric acid type A (GABAA) receptor encephalitis. Anti-GABAA receptor encephalitis is characterized by cognitive disruption, severe seizures, and characteristic brain lesions.2 The disease affects a very broad age range and both sexes. In the current study, as in prior reports, most patients responded favorably to immune therapy, although the optimal approach is still not clear. The series does provide a cautionary note regarding a patient with delayed diagnosis who had poor outcome. The present report further confirms the risk of thymoma, among other malignancies, although cases occurring after herpes virus infection have also been reported.3

Objective: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder. Methods: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients9 informed consent. Results: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses. Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.

Summary Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

Delta/Notch-like EGF-related receptor (DNER) has been reported to act as a Notch ligand, despite lacking a Delta/Serrate/Lag (DSL) binding domain common to all other known ligands. The established Notch ligand Delta-like 1 (DLL1), but not DNER, activated Notch1 in a luciferase assay, prevented the differentiation of myoblasts through Notch signaling, and bound Notch-fc in a cell-based assay. DNER is not a Notch ligand and its true function remains unknown.

Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. The disorder predominantly affects children and young adults, occurs with or without tumour association, and responds to treatment but can relapse. The presence of a tumour (usually an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older than 18 years, and slightly more predominant in black women than it is in white women. Patients treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) respond faster to treatment and less frequently need second-line immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who receive similar initial immunotherapy. More than 75% of all patients have substantial recovery that occurs in inverse order of symptom development and is associated with a decline of antibody titres. Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation. On the basis of models of pharmacological or genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.

We describe a patient with both Neurofibromatosis type 1 and Charcot-Marie-Tooth disease type 1B. While one might expect an overwhelming tumor burden due to the combination of these two disorders, the two mutations did not appear to interact.