IMMU-11. SELECTIVE ENRICHMENT OF SUPPRESSED IMMUNE CELLS IN THE TUMOR MICROENVIRONMENT CORRELATES WITH ESTABLISHMENT OF DISTINCT IMMUNOLOGIC NICHES IN HUMAN GLIOBLASTOMAS CONTACTING THE LATERAL VENTRICLE

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi94
Author(s):  
Todd Bartkowiak ◽  
Asa Brockman ◽  
Bret Mobley ◽  
Akshitkumar Mistry ◽  
Sierra Barone ◽  
...  
Keyword(s):  
T Cell ◽  
Lateral Ventricle ◽  
Odds Ratio ◽  
Clinical Trial Design ◽  
Standard Of Care ◽  
Therapeutic Benefit ◽  
Primary Glioblastoma ◽  
Selective Enrichment ◽  
Immune Biomarkers ◽  
Log Odds

Abstract Glioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit in GBM patients; however, no predictive immune features currently inform therapeutic stratification in GBM. We have shown that, independently of known prognosticators, radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse prognosis compared to patients with ventricle non-contacting GBM (NC-GBM). This study sought to characterize the GBM immune microenvironment and identify targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM. Primary glioblastoma specimens were resected in accordance with the Declaration of Helsinki (IRB #131870). Twelve patients presented with C-GBM and thirteen with NC-GBM. Machine learning tools applied to mass cytometry data characterized tumor-infiltrating immune populations and identified biomarkers correlating with C-GBM and patient survival. C-GBM tumors were enriched in blood-derived macrophages compared to NC-GBM (19 ± 8% vs. 6 ± 2%; p< 0.001) and depleted in lymphocytes (2.9 ± 1% vs. 7.6 ± 2%; p< 0.001) and tissue-resident microglia (1.8 ± 0.3% vs. 7 ± 3%; p< 0.001). Further, T cells in C-GBM co-expressed the checkpoint receptors PD-1 and TIGIT, suggesting acute T cell exhaustion. Multiplex immunohistochemistry (mxIHC) on matched FFPE tissue provided spatial context to risk-stratifying immune populations, and defined structured immunological niches within the TME. Macrophage-tumor niches were most common (36%), followed by T cell-microglia-tumor niches (26%). Within niches, T cell-T cell interactions were more prevalent (log odds ratio = 0.90) whereas T cell-macrophage interactions were less prevalent (log odds ratio = -1.61). These findings suggest that factors within the periventricular space may influence antitumor immunity within tumors, and identify clinically targetable immune biomarkers in glioblastoma. Notably, radiologic assessment of lateral ventricle contact by standard-of-care MRI may guide clinical trial design for immunotherapies in neuro-oncology.

scholarly journals 38 Spatial immune profiling of human glioblastoma tissue reveals the presence of aggregated lymphoid niches in the tumor microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A45-A45
Author(s):  
Todd Bartkowiak ◽  
Asa Brockman ◽  
Sierra Barone ◽  
Madeline Hayes ◽  
Caroline Roe ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Lateral Ventricle ◽  
Odds Ratio ◽  
Cell Interactions ◽  
Survival Prognosis ◽  
Random Chance ◽  
Immune Biomarkers ◽  
Log Odds ◽  
Lymphoid Aggregates

BackgroundGlioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit in GBM patients; however, no predictive immune features currently inform therapeutic stratification in GBM. We have shown that, independently of known prognosticators, radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse survival prognosis compared to patients with ventricle non-contacting GBM (NC-GBM). This study sought to characterize the GBM immune microenvironment and identify targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM.MethodsTwelve patients presented with pathologically confirmed primary, IDH wildtype C-GBM and thirteen with NC-GBM. Multiplex immunohistochemistry (mxIHC) was performed on formalin-fixed paraffin embedded (FFPE) tissue for each patient interrogating 8 predictive immune markers (CD3, CD4, CD8, FOXP3, CD68, IBA1, PD-1, and PD-L1). Machine learning tools characterized tumor-infiltrating immune populations and identified biomarkers correlating with C-GBM and patient survival. K-means clustering identified immunological neighborhoods within the tissue and a log odds ratio was used to quantify the likelihood of cell-cell interactions in the tissue.ResultsC-GBM tumors were enriched in monocyte-derived macrophages (MDM) compared to NC-GBM (19 ± 8% vs. 6 ± 2%; p<0.001) and depleted in lymphocytes (2.9 ± 1% vs. 7.6 ± 2%; p<0.001) and tissue-resident microglia (1.8 ± 0.3% vs. 7 ± 3%; p<0.001). Further, T cells in C-GBM co-expressed the checkpoint receptors PD-1, suggesting T cell exhaustion in the C-GBM tumor microenvironment. K-means clustering identified 10 immunological niches prevalent in GBM tissue. Macrophage-tumor niches were most common niche in the tissue accounting for 17.93% of all niches, followed by T cell-microglia-tumor niches (17.72%). Conversely, tumor-tumor niches were the least prevalent, accounting for only 2.51% of niches. Within niches, T cell-T cell interactions occurred more frequently than expected by random chance (log odds ratio = 0.90) whereas T cell-macrophage interactions occurred less frequently than expected by random chance (log odds ratio = -1.61). Pathological assessment of the tissue confirmed the presence of lymphoid aggregates in regions of myeloid exclusion in the tissue.ConclusionsThese findings suggest that factors within the periventricular space may influence antitumor immunity within GBM, and have identified clinically targetable immune biomarkers in glioblastoma. The prevalence of T cell niches in GBM tumors suggests the establishment tertiary lymphoid aggregates may be targetable to improve patient outcomes. Lastly, radiologic assessment of lateral ventricle contact by standard-of-care MRI may guide clinical trial design for immunotherapies in neuro-oncology.AcknowledgementsThis study was funded by NIH/NCI grant K00 CA212447 and supported by the Translational Pathology Shared Resource at Vanderbilt University (P30 CA068485).Ethics ApprovalPrimary glioblastoma tumors obtained in accordance with the Declaration of Helsinki and with institutional IRB approval (#131870) along with patient written informed consent.

scholarly journals PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emily Lee ◽  
Sarah Szvetecz ◽  
Ryan Polli ◽  
Angelo Grauel ◽  
Jayson Chen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
High Grade ◽  
Ovarian Cancers ◽  
Late Stage Diagnosis ◽  
Anti Tumor Activity

AbstractHigh-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

scholarly journals 208 E7777 (denileukin diftitox) enhances anti-tumor activity and significantly extends survival benefit of anti-PD-1 in syngeneic solid tumor models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A224-A225
Author(s):  
Mary Woodall-Jappe ◽  
A Raghav Chari ◽  
Anil Namboodiripad ◽  
Chandrasekhar Goda
Keyword(s):  
Overall Survival ◽  
Tumor Growth ◽  
Solid Tumor ◽  
Therapeutic Benefit ◽  
Tumor Models ◽  
Treg Depletion ◽  
Immune Biomarkers ◽  
Group 5 ◽  
Tumor Measurements ◽  
Anti Tumor Activity

BackgroundRegulatory T cell (Tregs) inhibit activity of anti-tumor T cells, and have been shown to limit checkpoint inhibitor effectiveness. Depletion of Tregs seems desirable during immunotherapy, but chronic Treg depletion with antibody therapies can lead to serious autoimmune adverse events. Compared to antibodies, the fusion protein E7777 (IL-2/diphtheria toxin) has a relatively short half-life in circulation, which allows for transient and selective Treg depletion. The potential therapeutic benefit of combining E7777 with anti-PD-1 was tested in syngeneic solid tumor models.MethodsCT26 colon and H22 liver cancer tumors were implanted subcutaneously in immunocompetent BALB/c mice. E7777 (2.5 mcg/mouse, i.v.) was given on a Q7Dx3 schedule. Anti-murine PD-1 was given (100 mcg/mouse, i.v.) Q4Dx5. Groups of 16 mice received each agent as monotherapy or in combinations. Sequencing of combination administration was also varied: Group 4 started treatment on the same day; Group 5 received E7777 2 days prior to start of anti-PD-1; Group 6 received anti-PD-1 first. Tumor growth was compared across all groups. In survival studies, mice were treated for 3 weeks and observed with twice weekly tumor measurements. In other experiments, tumors, tumor-draining lymph nodes, and spleens were examined by IHC and by flow cytometry of immune cells from dissociated tissues at defined points, for immune biomarkers.ResultsFigure 1 shows additive benefit from the E7777 + anti-PD-1 combinations over either monotherapy. Most importantly, figure 2 and table 1 show significantly enhanced overall survival from a 3 week course of combinations compared to either agent alone (p<0.005) or to vehicle controls (p<0.000001). There was no clear distinction among different sequencing regimens. Benefit correlated with enhanced CD8:Treg ratios in tumors.Abstract 208 Figure 1Tumor growth in s.c. syngeneic solid tumors. N=16/groupAbstract 208 Figure 2Overall survival in s.c. syngeneic models. N=16/groupAbstract 208 Table 1Calculated median survivalConclusionsDepletion of Tregs by E7777 significantly increased anti-tumor activity and durably extended overall survival compared to treatment with anti-PD-1 alone in syngeneic solid tumor models. Clinical studies of a combination of the two agents are planned.Ethics ApprovalAll studies were conducted at Crown Bio, and were approved by the Crown Bio IACUC.

scholarly journals OP0173 IMMUNOMODULATION CO-THERAPY WITH PEGLOTICASE: DATABASE TRENDS 2014-2019

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 108.2-108
Author(s):  
B. Lamoreaux ◽  
M. Francis-Sedlak ◽  
K. Svensson ◽  
R. Holt
Keyword(s):  
Case Series ◽  
Standard Of Care ◽  
Response Rates ◽  
Therapeutic Benefit ◽  
Azathioprine Therapy ◽  
Claims Database ◽  
Immunomodulating Therapy ◽  
Therapeutic Benefits ◽  
To Receive ◽  
Medical Claims Database

Background:Pegloticase is a PEGylated biologic therapy for patients with uncontrolled gout who have not improved on or could not tolerate conventional urate-lowering therapies.1All biologics have the ability to engender anti-drug antibodies (ADAs) and it is known that some patients given pegloticase develop ADAs that cause them to stop treatment prior to recieving a complete course of therapy.2-3In other rheumatic autoimmune diseases, DMARDs such as methotrexate or azathioprine are used as standard of care to prevent the development of ADAs to biologics. These DMARDs often allow patients to remain on biologic therapies longer and recieve the full therapeutic benefits while minimizing adverse events.4While pegloticase has been used traditionally as monotherapy, recent case series have demonstrated the therapeutic benefit of immunomodulator co-administration, allowing more patients to receive a full course of pegloticase therapy.5-6Little has been published on how widespread this practice is and whether it has changed over time.Objectives:To examine medical claims database from 2014-2019 for trends in immunomodulating therapies being co-prescribed with pegloticase.Methods:An IQVIA claims database (November 2014 to October 2019) representing 1.3 billion claims, covering 30 million patients diagnosed with gout or CKD, was utilized to search for patients who had received pegloticase. Patients who had recieved pegloticase were classified as having been on an immunomodulating co-therapy if they were prescribed methotrexate or azathioprine within 60 days before or after initiation of their first pegloticase infusion.Results:We found relatively steady low rates of immunomodulation co-therapy with pegloticase from 2014 through 2018 ranging from 1% in 2016 to 4% in 2018 (Figure 1). In 2019 however, the proportion of pegloticase patients that were co-treated with methotrexate or azathioprine therapy increased to 15%. Most patients were started on immunomodulating therapy 20 days before to 10 days after initiation of pegloticase. Methotrexate was the more frequently used immunomodulaton co-therapy as compared to azathioprine.Conclusion:We found evidence of a relatively dramatic increasing initiation of immunomodulation therapy with pegloticase beginning soon after a November 2018 presentation of a case series which demonstrated improved response rates of pegloticase when co-administered with methotrexate. These data indicate that clinicians began to more frequently employ a strategy of DMARD co-treatment with pegloticase in 2019 to improve response rates to this important gout medicine.References:[1]Sundy JS, et al.JAMA2011;306:711-20.[2]Abeles AM.Arthritis Research & Therapy2014, 16:112[3]Strand V, et al.BioDrugs2017; 31:299–316.[4]Krieckaert CL, et al.Arthritis Res Ther2010;12:217.[5]Botson J and Peterson J.Ann Rheum Dis.2019; 78: A1289.[6]Bessen SY, et al.Semin Arthritis Rheum.2019;49:56-61.Disclosure of Interests:Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Megan Francis-Sedlak Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Karl Svensson Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Robert Holt Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics

An oncology clinical trial design with randomization adaptive to both short- and long-term responses

2017 ◽  
Vol 28 (7) ◽  
pp. 2015-2031 ◽  
Author(s):  
Hao Liu ◽  
Xiao Lin ◽  
Xuelin Huang
Keyword(s):  
Trial Design ◽  
Clinical Trial Design ◽  
Therapeutic Benefit ◽  
Survival Outcome ◽  
Operating Characteristics ◽  
Short Term ◽  
Term Survival ◽  
Long Term Survival ◽  
Term Response

In oncology clinical trials, both short-term response and long-term survival are important. We propose an urn-based adaptive randomization design to incorporate both of these two outcomes. While short-term response can update the randomization probability quickly to benefit the trial participants, long-term survival outcome can also change the randomization to favor the treatment arm with definitive therapeutic benefit. Using generalized Friedman’s urn, we derive an explicit formula for the limiting distribution of the number of subjects assigned to each arm. With prior or hypothetical knowledge on treatment effects, this formula can be used to guide the selection of parameters for the proposed design to achieve desirable patient number ratios between different treatment arms, and thus optimize the operating characteristics of the trial design. Simulation studies show that the proposed design successfully assign more patients to the treatment arms with either better short-term tumor response or long-term survival outcome or both.

Anti-CD20 mAb-Induced B Cell Apoptosis Generates T Cell Regulation of Experimental Myeloperoxidase ANCA-Associated Vasculitis

2021 ◽  
pp. ASN.2020060834
Author(s):  
Poh-Yi Gan ◽  
Jonathan Dick ◽  
Kim M. O’Sullivan ◽  
Virginie Oudin ◽  
Anne Cao Le ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Apoptosis ◽  
T Regulatory Cells ◽  
Ex Vivo ◽  
Therapeutic Benefit ◽  
Anca Associated Vasculitis ◽  
Splenic Macrophages ◽  
Humoral Autoimmunity ◽  
Anti Cd20

BackgroundMyeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease.MethodsMPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.ResultsAnti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell–mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb ex vivo–induced apoptotic splenocytes to unmanipulated mice attenuated autoimmunity and GN, whereas deletion of splenic marginal zone macrophages prevented anti-CD20 mAb-induced immunomodulation and treatment efficacy. Six days after administering anti-CD20 mAb to mice with murine anti-MPO GN, cell-mediated anti-MPO responses and GN were attenuated, and Tregs were enhanced, but ANCA levels were unchanged, suggesting humoral autoimmunity was redundant at this time point.ConclusionsCollectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20–induced apoptotic B cells.

scholarly journals Decline in prevalence and asymmetric distribution of human T cell lymphotropic virus 1 and 2 in blood donors, State of Minas Gerais, Brazil, 1993 to 2007

2010 ◽  
Vol 43 (6) ◽  
pp. 615-619 ◽  
Author(s):  
Maria Regina Dias-Bastos ◽  
Cláudia Di Lorenzo Oliveira ◽  
Anna Bárbara de Freitas Carneiro-Proietti
Keyword(s):  
T Cell ◽  
Odds Ratio ◽  
Blood Donors ◽  
Elisa Test ◽  
Minas Gerais ◽  
Asymmetric Distribution ◽  
Donor Pool ◽  
Human T Cell ◽  
Low Prevalence ◽  
Positive Results

INTRODUCTION: Human T cell lymphotropic virus types 1 and 2 (HTLV-1/2) are endemic in Brazil and are screened for in transfusion services since 1993. This study evaluated the evolution of the prevalence of HTLV-1 and 2 in blood donors of the Hemominas Foundation from 1993 to 2007, and its geographical distribution in State of Minas Gerais, Brazil. METHODS: The Hemominas Foundation is a centralized blood center in Minas Gerais, Brazil. The sources of data were the Hemominas Foundation Technical Bulletin and files from the centralized serological laboratory. Donors were tested in the period using enzyme linked immuno sorbent assays (ELISA), followed by Western blot, when repeatedly reactive. The data were analyzed by EPIINFO 6.2 and TABWIN 3.5 softwares. RESULTS: The average seroprevalence in the period 1993-2007 was 0.1%. A steady decline occurred from 0.4% in 1993 to below 0.1% in 2002 and later, with a transient peak of 0.5% in 1994. HTLV reactivity distribution was asymmetrical in the state, with regions of higher prevalence, interspersed with low prevalence areas. Comparison of positive and negative donors verified that increasing age was proportional to virus positivity. Odds ratio for age ranged from 1.43 (30 to 39 years-old) to 3.09 (50 to 65 years-old). Women had a greater chance of being positive (OR-1.64), as previously described. CONCLUSIONS: Possible explanations for HTLV-1/2 prevalence decline are the exclusion of positive donors from the donor pool, an increase in repeat donors and ELISA test improvement, with reduction in the number of false positive results.

scholarly journals On sufficient variable screening using log odds ratio filter

2022 ◽  
Vol 16 (1) ◽  
Author(s):  
Baoying Yang ◽  
Wenbo Wu ◽  
Xiangrong Yin
Keyword(s):  
Odds Ratio ◽  
Variable Screening ◽  
Log Odds

Innowacyjna metoda prowadzenia ITI za pomocą preparatu czynnika VIII z frakcją Fc u pacjentów z hemofilią A z obecnością inhibitora czynnika VIII – przegląd literaturowy

2018 ◽  
Vol 22 (3) ◽  
Author(s):  
Maciej Trzaska ◽  
Marek Karwacki ◽  
Paweł Łaguna ◽  
Michał Matysiak
Keyword(s):  
Factor Viii ◽  
Tolerance Induction ◽  
Standard Of Care ◽  
Preliminary Evidence ◽  
Immunological Tolerance ◽  
Therapeutic Benefit ◽  
High Titre ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
First Time

Eradication of factor VIII inhibitors using Immune tolerance induction (ITI) treatment is the standard of care for severe haemophilia A patients presenting with factor VIII inhibitors, but is not always effective. A description of the potential immunological tolerance effect of the IgG Fc domain of recombinant factor VIII Fc fusion protein (rFVIIIFc), as well as published experience with rFVIIIFc for ITI in patients with severe haemophilia A and high-titre inhibitors. Review of published literature describing cases of ITI with rFVIIIFc in patients with severe haemophilia A and high-titre inhibitors between November 2015 and June 2018. Four publications has been found. Of 56 patients with haemophilia A who presented with FVIII inhibitors, 28 achieved a negative Bethesda titre (< 0.6) after ITI treatment using rFVIIIFc. Additional patients continued on rFVIIIFc ITI at the time of publication, while a few were reported to have switched to bypass therapy alone or other factors . For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events were reported. Based on literature review, preliminary evidence of FVIIIFc use in high risk, first-time ITI suggests rapid time to tolerization. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI. These findings give hope but highlight the need for further evaluation in ongoing clinical trials.

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