scholarly journals 528 Correlation of baseline circulating Vg9Vd2 T cell counts and pharmacodynamic activity of ICT01 in cancer patients: preliminary results from EVICTION and a novel patient enrichment strategy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A558-A558
Author(s):  
Emmanuel Valentin ◽  
Aude de Gassart ◽  
Patrick Brune ◽  
Clément Ghigo ◽  
Sophie Agaugué ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Count ◽  
T Cell Activation ◽  
Immune Cell ◽  
Selection Criterion ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Cell Counts ◽  
Tumor Biopsies

BackgroundICT01, a novel, anti-BTN3A immunotherapeutic mAb for activating g9d2T cells, is currently evaluated in a Phase 1/2a clinical trial in patients with advanced-stage, relapsed/refractory cancer (NCT04243499, EVICTION). ICT01 indirectly activates g9d2 T cells that secrete inflammatory cytokines and migrate into tumors to coordinate antitumor immune responses. Therefore, the baseline number of g9d2 T effector cells constitutes a biomarker of interest and a potential selection criterion for target patients.MethodsFull immunophenotyping (cell counts and activation state) was performed by flow cytometry on fresh blood collected pre- and on-treatment. Serum cytokines were monitored at baseline and post-treatment. Tumor biopsies were harvested at baseline and on Day 28, and multiplex IHC coupled with digital pathology was used to quantify g9d2T cell, CD8 T cell, NK cell, and T reg infiltration and activation stateResultsBaseline circulating g9d2 T cell count was highly variable in solid tumor patients enrolled in the monotherapy arm of EVICTION (median 6918 cell/mL, n=26). Melanoma and colorectal patients displayed respectively the highest (median 42277 cell/mL, n=3) and the lowest (median 3040 cell/mL, n=9) baseline number. During the dose escalation phase, g9d2 T cell activation (CD69+) and migration from the blood was observed 30 min post-ICT01 administration. Serum cytokine levels showed variability within ICT01 dose cohorts. IFNg, TNFa, IL-6 and IL-8 levels post-ICT01 dosing were ICT01 dose dependent and clearly related to baseline number of circulating g9d2 T cells. Activation of peripheral blood NK cells, granulocytes and CD8 T cells was observed post-dosing at ICT01 doses ≥7 mg, which was significantly correlated with baseline g9d2 T cell counts, but not with other immune subsets (Spearman r=0.51, 0.47 and 0.65 for CD69+NK, CD69+CD8 and PD-L1+granulocytes respectively, p<0.05, n=19). Baseline circulating g9d2 T cell count was positively correlated with gdTCR+ T cell density in baseline tumor biopsies (Spearman r=0.76, p=0.0086, n=11). Finally, a trend was observed between baseline g9d2 T cell counts and overall tumor immune cell infiltration and activation post-ICT01 treatment, with 4 patients (out of 13 with available biopsy pairs) with g9d2 T cell counts above the median displaying the highest tumor immune cell infiltration and activation.ConclusionsThese results suggest the utility of measuring baseline g9d2 T cells as part of the patient selection process for ICT01 clinical trials. Patient enrichment based on this biomarker will be tested in EVICTION expansion arms where a minimum baseline threshold of g9d2 T cells counts will be one of the eligibility criteria.Trial RegistrationNCT04243499Ethics ApprovalThe study has obtained Competent Authority and Ethics Committee approvals. Informed consent forms were obtained from all enrolled patients.

scholarly journals Enhanced CD4+ and CD8+ T cell infiltrate within convex hull defined pancreatic islet borders as autoimmune diabetes progresses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexander J. Dwyer ◽  
Jacob M. Ritz ◽  
Jason S. Mitchell ◽  
Tijana Martinov ◽  
Mohannad Alkhatib ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Convex Hull ◽  
Pancreatic Islets ◽  
Immune Cell ◽  
Nod Mice ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Analytical Strategy ◽  
Islet Mass

AbstractThe notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.

Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14532-e14532
Author(s):  
Joerg Wischhusen ◽  
Markus Haake ◽  
Neha Vashist ◽  
Sabrina Genßler ◽  
Kilian Wistuba-Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Serum Levels ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
T Cell Infiltration ◽  
Melanoma Patients

e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8+ T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for HPV+ OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.

scholarly journals 918 Doxycycline regulatable ß-catenin demonstrates inducible immune evasion in a melanoma GEM model

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A963-A963
Author(s):  
Alexandra Cabanov ◽  
Stefani Spranger ◽  
Thomas Gajewski ◽  
Alexandra Cabanov ◽  
Elen Torres-Mejia
Keyword(s):  
T Cells ◽  
Drinking Water ◽  
T Cell ◽  
Immune Cell ◽  
Active Form ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Rapid Reduction

BackgroundLack of response to checkpoint blockade immunotherapy has been linked to a deficiency of immune cell infiltration within the tumor microenvironment (TME). One demonstrated mechanism sufficient for the non-T cell inflamed TME is tumor cell-intrinsic activation of the β-catenin signaling pathway. Using genetically engineered mouse models (GEMMs), tumors constitutively expressing active β-catenin lack a robust endogenous T cell infiltrate and fail to respond to immunotherapies. In support of these mouse studies, human melanoma metastases with increased active β-catenin signaling exhibit decreased numbers of tumor infiltrating Batf3-driven cDC1 and CD3+ T cells. However, whether temporal activation and inactivation of β-catenin within the same developing tumor would alter immune cell infiltration is not known.MethodsA model was created in which tamoxifen-regulated Cre-recombinase mediates BRAFV600E oncogene activation and PTEN tumor suppressor gene deletion as well as expression of a doxycycline regulatable reverse transactivator. Upon administration of doxycycline via the drinking water to these animals, a non-degradable form of nuclear β-catenin becomes expressed. Immunofluorescence assays were performed assessing the β-catenin expression status in the tumor cells as well as immune cell infiltration within the TME. Additionally, immunotherapy efficacy experiments were performed.ResultsWe observed that administration of doxycycline to these animals drove expression of an active form of nuclear β-catenin. Activation of nuclear β-catenin resulted in a 2-fold decrease in the overall CD3+ T cells infiltration into the TME. Moreover, this decrease in immune infiltration also resulted in loss of anti-PD-L1 + anti-CTLA-4 therapy efficacy. We next performed studies assessing the kinetics with which β-catenin levels diminish upon doxycycline removal. Switching animals to regular drinking water resulted in rapid reduction of nuclear β-catenin levels, including 50 percent reduction after two days of doxycycline removal and almost complete reduction of nuclear β-catenin after four days.ConclusionsWe describe a novel mouse model in which we induce autochthonous melanoma tumors in mice along with inducible expression of a non-degradable, nuclear β-catenin modulated by doxycycline in the drinking water. Activation of β-catenin signaling in melanoma tumors resulted in reduction of immune cells in the TME as well as loss of checkpoint blockade immunotherapy efficacy. This activation can be rapidly reversed by removing doxycycline, allowing for future studies evaluating the consequences of turning off β-catenin once it has already driven a non-T cell-inflamed TME.AcknowledgementsThis work was supported by the Wissler Fellowship from the University of Chicago (SS) K99/R00 (NCI; SS), and R35CA210098 (TG).

IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor

2018 ◽  
Vol 36 (4) ◽  
pp. 346-351 ◽  
Author(s):  
Keishi Adachi ◽  
Yosuke Kano ◽  
Tomohiko Nagai ◽  
Namiko Okuyama ◽  
Yukimi Sakoda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
T Cell Survival

scholarly journals SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma

2021 ◽  
Author(s):  
Lu Yuan ◽  
Xixi Wu ◽  
Longshan Zhang ◽  
Mi Yang ◽  
Xiaoqing Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Lung Adenocarcinoma ◽  
Expression Profile ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Regulatory Pathways ◽  
Chronic Lung Diseases ◽  
Potential Biomarker

AbstractPulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

scholarly journals PIMATM point-of-care testing for CD4 counts in predicting antiretroviral initiation in HIV-infected individuals in KwaZulu-Natal, Durban, South Africa

2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Mandisa Skhosana ◽  
Shabashini Reddy ◽  
Tarylee Reddy ◽  
Siphelele Ntoyanto ◽  
Elizabeth Spooner ◽  
...  
Keyword(s):  
South Africa ◽  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Count ◽  
Point Of Care ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Kwazulu Natal ◽  
Cd4 T Cell Count

Introduction: Limited information is available on the usefulness of the PIMATM analyser in predicting antiretroviral treatment eligibility and outcome in a primary healthcare clinic setting in disadvantaged communities in KwaZulu-Natal, South Africa.Materials and methods: The study was conducted under the eThekwini Health Unit, Durban, KwaZulu-Natal. Comparison of the enumeration of CD4+ T-cells in 268 patients using the PIMATM analyser and the predicate National Health Laboratory Services (NHLS) was undertaken during January to July 2013. Bland-Altman analysis to calculate bias and limits of agreement, precision and levels of clinical misclassification at various CD4+ T-cell count thresholds was performed.Results: There was high precision of the PIMATM control bead cartridges with low and normal CD4+ T-cell counts using three different PIMATM analysers (%CV < 5). Under World Health Organization (WHO) guidelines (≤ 500 cells/mm3), the sensitivity of the PIMATM analyser was 94%, specificity 78% and positive predictive value (PPV) 95%. There were 24 (9%) misclassifications, of which 13 were false-negative in whom the mean bias was 149 CD4+ T-cells/mm3. Most (87%) patients returned for their CD4 test result but only 67% (110/164) of those eligible (≤ 350 cells/mm3) were initiated on antiretroviral therapy (ART) with a time to treatment of 49 days (interquartile range [IQR], 42–64 days).Conclusion: There was adequate agreement between PIMATM analyser and predicate NHLS CD4+ T-cell count enumeration (≤ 500 cells/mm3) in adult HIV-positive individuals. The high PPV, sensitivity and acceptable specificity of the PIMATM analyser technology lend it as a reliable tool in predicting eligibility and rapid linkage to care in ART programmes.Keywords: HIV; Point of Care; PIMATM CD4+ T cell counts; antiretroviral therapy; prediction/eligibility; South Africa

scholarly journals Development of an Immune-Related Gene Signature for Prognosis in Melanoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Jia-An Zhang ◽  
Xu-Yue Zhou ◽  
Dan Huang ◽  
Chao Luan ◽  
Heng Gu ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Treatment Method ◽  
Gene Signature ◽  
Cell Infiltration ◽  
Venn Diagram ◽  
Immune Cell Infiltration ◽  
Tumor Purity ◽  
New Treatment ◽  
Immune Related Genes

Melanoma remains a potentially deadly malignant tumor. The incidence of melanoma continues to rise. Immunotherapy has become a new treatment method and is widely used in a variety of tumors. Original melanoma data were downloaded from TCGA. ssGSEA was performed to classify them. GSVA software and the "hclust" package were used to analyze the data. The ESTIMATE algorithm screened DEGs. The edgeR package and Venn diagram identified valid immune-related genes. Univariate, LASSO and multivariate analyses were used to explore the hub genes. The "rms" package established the nomogram and calibrated the curve. Immune infiltration data were obtained from the TIMER database. Compared with that of samples in the high immune cell infiltration cluster, we found that the tumor purity of samples in the low immune cell infiltration cluster was higher. The immune score, ESTIMATE score and stromal score in the low immune cell infiltration cluster were lower. In the high immune cell infiltration cluster, the immune components were more abundant, while the tumor purity was lower. The expression levels of TIGIT, PDCD1, LAG3, HAVCR2, CTLA4 and the HLA family were also higher in the high immune cell infiltration cluster. Survival analysis showed that patients in the high immune cell infiltration cluster had shorter OS than patients in the low immune cell infiltration cluster. IGHV1-18, CXCL11, LTF, and HLA-DQB1 were identified as immune cell infiltration-related DEGs. The prognosis of melanoma was significantly negatively correlated with the infiltration of CD4+ T cells, CD8+ T cells, dendritic cells, neutrophils and macrophages. In this study, we identified immune-related melanoma core genes and relevant immune cell subtypes, which may be used in targeted therapy and immunotherapy of melanoma.

scholarly journals Primary vulvar squamous cell carcinomas with high T cell infiltration and active immune signaling are potential candidates for neoadjuvant PD-1/PD-L1 immunotherapy

2021 ◽  
Vol 9 (10) ◽  
pp. e003671
Author(s):  
Kim E Kortekaas ◽  
Saskia J Santegoets ◽  
Liselotte Tas ◽  
Ilina Ehsan ◽  
Pornpimol Charoentong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Squamous Cell ◽  
Molecular Subtype ◽  
Cell Infiltration ◽  
Immune Signaling ◽  
T Cell Infiltration ◽  
Expression Of Genes

BackgroundA profound insight into the immune landscape of vulvar squamous cell carcinoma (VSCC) is lacking. Here, an in-depth interrogation of T cell infiltration, local immune contexture, signaling pathways and checkpoint molecule expression was performed in early-stage and late-stage VSCC.MethodsThe type, location, and infiltration pattern of T cells were studied in 109 patients with primary VSCC FIGO stage I–III. RNA expression of genes involved in immune oncology and oncogenic signaling pathways was analyzed in 40 VSCC, matched for prognostic clinicopathological variables, analyzed for HPV and p53 status, and selected based on T cell infiltration.ResultsHigh intraepithelial infiltration with CD4 or CD8 T cells was associated with longer overall and recurrence-free survival and formed an independent prognostic factor, outperforming molecular subtype and stage of the disease. Strong T cell infiltrated VSCC displayed a coordinated immune response reflected by a positive association between T cells and different lymphocyte and myeloid cell subsets. The expression of genes involved in the migration of T cells and myeloid cells, T cell activation and costimulation, interferon (IFN)-γ signaling, cytotoxicity and apoptosis was higher than in low infiltrated tumors. An active immune signaling profile was observed in all inflamed, part of the altered-excluded and not in altered-immunosuppressed or deserted VSCC. While several checkpoint molecules were overexpressed, only PD-L1 expression displayed discriminatory ability and clinical usefulness. High PD-L1 expression was detected in all inflamed and ~60% of the altered-excluded VSCC.ConclusionAn active immune signaling profile is present in 35% of primary FIGO I–III VSCCs, suggesting potential responsiveness to neoadjuvant PD-1/PD-L1 immunotherapy.

T Cell Responses during Long-Term Continuous Infusion of MT103 (MEDI-538; Anti-CD19 BiTE) in Patients with Relapsed B-NHL: Data from Dose-Escalation Study MT103-104.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2725-2725 ◽  
Author(s):  
Matthias Klinger ◽  
Peter Kufer ◽  
Petra Kirchinger ◽  
Ralf Lutterbüse ◽  
Eugen Leo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Expansion ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Counts ◽  
T Cell Expansion

Abstract MT103 (MEDI-538) is a bispecific single-chain antibody construct directed at CD3 on human T cells and CD19 on human B lymphoma and normal B cells. Transient linkage of B and T cells by MT103 provides T cells with a T cell receptor (TCR)-like signal leading to redirected lysis of B cell targets without apparent need of costimulation and inducing T cells to proliferate, secrete cytokines and upregulate surface activation markers. TCR-like signalling by MT103 is strictly dependent on the presence of target cells. Redirected lysis of CD19-positive cells by MT103 is seen at low picomolar concentrations and at low effector-to-target ratios. The in-vivo half-life of MT103 is approximately two hours. In the ongoing dose escalation study MT103-104, patients with relapsed B-NHL have so far received continuous infusion of MT103 at maintenance flow-rates of 0.5, 1.5, 5 and 15 μg/m2/24h for 4 or 8 weeks following a 3+3 dose escalation design. Serum concentrations of MT103 remained constant over the entire treatment period at a level depending on the respective maintenance flow-rate. Depletion of circulating B (lymphoma) cells could be observed more frequently with increasing dose levels (DL) from DL1 to DL3, and in all evaluable patients at DL4. Three of six evaluable patients at DL4 showed clinical responses (2 PR, 1 CR) according to standardized Cheson criteria, but no patient of DL1-3. The time courses of absolute CD4 and CD8 T cell counts in peripheral blood were determined by flow cytometry. CD8 T lymphocytes were further subdivided for analysis into naïve T cells, TCM (central memory T cells), TEM (effector memory T cells) and TEMRA (non-proliferating terminally differentiated CTL), and CD4 T lymphocytes into naïve T cells, TCM and TEM. Activation of CD4 and CD8 T cell subsets was determined by measuring upregulation of CD69, CD25 and HLA-DR. Serum levels of cytokines were determined as additional biomarkers for T cell activation. In 50% of patients at DL1 to DL3, CD4 and CD8 T cell counts increased during the course of treatment - over pre-treatment levels. The TEM subset from both CD4 and CD8 T cells accounted for most of the observed increases, while the naïve T cell subsets showed no increase but also no signs of apoptosis. The non-proliferative TEMRA subset of CD8 T cells also remained unchanged in most patients. This indicated that the selective increase of proliferation-competent TEM subsets was attributed to MT103-induced T cell proliferation. At DL4, all evaluable patients showed signs of T cell expansion after 2 weeks of MT103 infusion, which was most pronounced in those who developed a partial or complete remission. The increase of CD8 T cell counts was more pronounced than that of CD4 T cells. T cell expansion was accompanied by upregulation of T cell activation markers as well as by increases in serum concentrations of cytokines like IFN-γ. T cell expansion and activation reverted in all cases when the infusion of MT103 was stopped. In summary, MT103 induced a reversible secondary T cell response involving T cell activation and proliferation as well as T cell cytotoxicity against circulating B cells and lymphoma tissue. The dose-dependent T cell expansion observed during long-term infusion of MT103, particularly within the cytotoxic TEM subset of CD8 T cells, appears to play a key role for clinical activity.

Immunopharmacodynamic response to blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7020-7020 ◽  
Author(s):  
Andrea Schub ◽  
Virginie Nägele ◽  
Gerhard Zugmaier ◽  
Christian Brandl ◽  
Youssef Hijazi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphoblastic Leukemia ◽  
Granzyme B ◽  
Significant Proportion ◽  
Target Cells ◽  
Cell Counts

7020 Background: Blinatumomab is an anti-CD19/anti-CD3 bispecific T cell engager (BiTE) that induces target cell-dependent, polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19+ target cells. Methods: In a phase 2 study, adult patients (N=36) with relapsed/refractory B-precursor ALL received continuous blinatumomab IV infusion for 28 days in ≤5 treatment/consolidation cycles. Whole blood and serum samples were collected throughout treatment and analyzed for lymphocyte subpopulations, cytokines, granzyme B, and blinatumomab serum concentrations. Results: Lymphocytes in all patients responded in a similar fashion. After infusion start, peripheral B cell counts dropped to ≤1 B cell/μL in <1 week and remained undetectable throughout treatment. Peripheral T cells showed a redistribution characterized by swift disappearance within the first 2-6 hrs and subsequent recovery to baseline within several days. Otherwise, T cell counts remained at least stable in most patients. In some patients even an expansion of the T cell compartments was observed, most likely due to specific proliferation of activated T cells but could not be defined as prerequisite for treatment efficacy. During the first infusion days, a significant proportion of T cells newly expressed the activation marker CD69, and the T cell effector molecule granzyme B was detectable in serum. Additionally, a transient cytokine release dominated by IL-10, IL-6 and IFN-γ was observed in most patients shortly after first infusion start, which was alleviated or absent in subsequent cycles. Blinatumomab serum steady state concentrations (mean±SD) were 198±61 pg/mL and 694±236 pg/mL at doses of 5 and 15 μg/m²/d, respectively, which is comparable to those from previous studies. Conclusions: Immunopharmacodynamic response to blinatumomab was characterized by B cell depletion, T cell activation and redistribution, and release of granzyme B and cytokines, suggesting T cell engagement according to the expected BiTE mode of action. The tested pharmacodynamic markers did not allow for predictive differentiation between patients achieving a hematologic response and those who did not. Clinical trial information: NCT01209286.

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