296 Immune correlates of clinical response to Avelumab in patients with advanced thymic epithelial tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A323-A323
Author(s):  
Yo-Ting Tsai ◽  
Arun Rajan ◽  
James Gulley ◽  
Jeffrey Schlom ◽  
Renee Donahue
Keyword(s):  
Clinical Response ◽  
Mononuclear Cells ◽  
Predictive Biomarkers ◽  
Lymphocytic Infiltration ◽  
Peripheral Blood Mononuclear ◽  
Thymic Epithelial Tumors ◽  
Link Type ◽  
Epithelial Tumors ◽  
Immune Correlates ◽  
Tcr Diversity

BackgroundThymic epithelial tumors (TET), consisting of thymomas and thymic carcinomas, are PD-L1-expressing tumors characterized by varying degrees of lymphocytic infiltration and a predisposition towards the development of paraneoplastic autoimmunity. As part of a phase I study (NCT01772004), the anti-tumor activity of patients with relapsed, advanced TET to avelumab (anti-PD-L1), was demonstrated and was accompanied by a high frequency of immune related adverse events (irAE). The current study aimed to identify immune related signatures that associate with clinical response and/or the development of irAE.MethodsEight patients with recurrent TET were treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Peripheral blood mononuclear cells (PBMC) were obtained before and during therapy, and interrogated by multicolor flow cytometry to evaluate 123 immune subsets, as well as by T-cell receptor (TCR) sequencing to evaluate TCR diversity.ResultsFour of 8 TET patients had partial responses and 3 had stable disease. All responders developed irAEs that resolved with immunosuppressive therapy, compared to only 1 of 4 non responders. Analyses of PBMC subsets prior to therapy showed that responders had higher absolute lymphocyte counts, and lower frequencies of B cells, Tregs, conventional dendritic cells (cDCs), and NK cells, compared to non-responders. There was also a trend towards a higher level of TCR diversity in those patients who subsequently had a radiological response and developed irAE.ConclusionsImmune profiling identified specific immune measures prior to therapy that differed between responders and non-responders, that may serve as predictive biomarkers to identify patients with relapsed TET most likely to benefit from avelumab and/or to develop irAE.Trial RegistrationNCT01772004Ethics ApprovalAll patients provided written informed consent for participation in a clinical trial that was approved by the Institutional Review Board at the National Cancer Institute (NCT01772004).

Early proliferation of PD-1+ CD8 T cells in peripheral blood as predictive of response to PD-1 inhibition for patients with advanced NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20648-e20648
Author(s):  
Rathi Narayana Pillai ◽  
Alice O. Kamphorst ◽  
Shu Yang ◽  
Taofeek Kunle Owonikoko ◽  
Gabriel Sica ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Response ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Nsclc Patient ◽  
Predictive Biomarkers ◽  
Fold Increase ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples

e20648 Background: Anti PD-1 and PDL-1 antibodies are now established immune targeted therapies for a subset of patients with advanced non-small cell lung cancer (NSCLC). There is a need for predictive biomarkers to better guide patient selection. We profiled peripheral blood samples from patients receiving PD-1 pathway targeted antibodies for lymphocyte subsets and correlated temporal changes with clinical response. Methods: NSCLC patients treated at our institution with PD-1 or PDL-1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) consented to an IRB-approved biomarker profiling protocol. We collected baseline peripheral blood samples before first treatment and subsequently prior to each new treatment cycle until progression of disease or for a maximum of six cycles. Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for kinetics of proliferation of PD1+CD8+ T cells. Clinical response to anti PD-1 therapy was classified according to Response Evaluation Criteria in Solid Tumors (RECIST1.1) criteria and correlated with T cell proliferation kinetics. Results: We enrolled 27 patients with baseline characteristics: median age 66, male 70%, smokers 85%, adenocarcinoma 70%; 10 (37%) patients achieved partial response (PR), 7 (26%) had stable disease (SD) and 10 (10%) had disease progression (PD) as best response. There was a > 1.5-fold increase in Ki67+CD8+ T cells expressing PD-1 within 4 weeks of treatment initiation in 80% of patients with PR compared with 30% in patients with SD and 30% in those with PD. Conclusions: Early proliferation of PD1+CD8+ T cells in peripheral blood is a potential pharmacodynamic biomarker of anti PD-1 immunotherapy that could serve as a tool to identify the NSCLC patient subset most likely to respond to PD-1 and PDL-1 inhibitors.

scholarly journals Longitudinal high-dimensional analysis identifies biomarkers of response to anti-PD-1 immunotherapy

2021 ◽  
Author(s):  
Run-Ze Li ◽  
Xing-Xing Fan ◽  
Ze-Bo Jiang ◽  
Jumin Huang ◽  
Hu-Dan Pan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Response To Therapy ◽  
High Dimensional ◽  
Meso Scale Discovery ◽  
Peripheral Blood Mononuclear ◽  
Poor Outcomes ◽  
Nsclc Patients

Abstract The response to immunotherapy could be better predicted by using a wide set of biomarkers, including serum tumor markers; however, robust immune markers associated with efficacy have yet to be validated. In this study, changes in immune cell subsets from NSCLC patients treated with anti-PD1 therapy were longitudinally monitored by high-dimensional cytometry by time of flight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines kits. The frequencies of circulating CD8+ and CD8+CD101hiTIM3+ (CCT T) subsets were significantly correlated with clinical response and survival. Enrichment of these populations in peripheral blood mononuclear cells (PBMCs) indicated a poor clinical response to ICB therapy. Cell function assays revealed that these subsets were remarkably impaired, which supported the poor outcomes observed. Additionally, longitudinal analysis showed that KLRG1 expression and cytokines were associated with the response to therapy. Overall, our results provide novel potential biomarkers for guiding the management of NSCLC patients eligible to anti-PD-1 therapy, and contribute insights for new therapeutic strategies.

scholarly journals Serum Interferon (IFN)-Neutralizing Antibodies and Bioactivities of IFNs in Patients with Severe Type II Essential Mixed Cryoglobulinemia

2003 ◽  
Vol 10 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Carolina Scagnolari ◽  
Milvia Casato ◽  
Francesca Bellomi ◽  
Francesca De Pisa ◽  
Ombretta Turriziani ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Clinical Response ◽  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Mixed Cryoglobulinemia ◽  
Mrna Levels ◽  
Type Ii ◽  
Essential Mixed Cryoglobulinemia ◽  
Peripheral Blood Mononuclear ◽  
Severe Type

ABSTRACT The efficacy of alpha interferon (IFN-α) in the treatment of severe type II essential mixed cryoglobulinemia (EMC) has been reported previously. In some patients, the development of neutralizing antibodies to recombinant IFN-α (rIFN-α) can affect the clinical response achieved with rIFN-α; a second treatment with natural IFN-α preparations may reinduce the clinical response. In the present study the ability of leukocyte IFN (LeIFN) to restore the response was investigated from a pharmacodynamic viewpoint. Specifically, the pharmacodynamic profiles of different IFN-α preparations were studied by measuring the serum neopterin levels and the levels of expression of protein MxA mRNA in in vivo peripheral blood mononuclear cells in two patients with EMC whose resistance to rIFN-α2a treatment increased concomitantly with the development of neutralizing antibodies. These markers were measured before injection and at 24 and 48 h after a single injection of rIFN-α2a, consensus IFN [(C)IFN], or LeIFN. No increase or only a slight increase in MxA mRNA levels was detectable after administration of rIFN-α2a or (C)IFN, whereas a significant increase (≥10-fold) in MxA mRNA expression was recorded following administration of LeIFN. The neutralizing antibodies to rIFN-α2a cross-react with (C)IFN. Sera from these patients neutralized most but not all of the subtypes present in the natural IFN-α (LeIFN) mixture, and no significant increase in neopterin levels was observed after these patients were switched to LeIFN treatment. In summary, the data demonstrate that the problem of neutralizing antibodies still exists and that LeIFN may induce an increase in the level of MxA mRNA expression but not an increase in neopterin levels in patients who are resistant to treatment with rIFN-α2a or (C)IFN.

Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3016-3016 ◽  
Author(s):  
Joseph Grosso ◽  
Christine E. Horak ◽  
David Inzunza ◽  
Diana M. Cardona ◽  
Jason S. Simon ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Clinical Activity ◽  
Post Dose ◽  
Peripheral Blood Mononuclear ◽  
Immune Biomarkers

3016 Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. In a phase I study, nivolumab, a PD-1 receptor blocking antibody, demonstrated durable clinical activity. Evaluation of the expression of the PD-1 ligand, PD-L1, by IHC with the 5H1 Ab suggested a correlation between pretreatment tumor PD-L1 expression and clinical response (Topalian et al, NEJM 2012). Methods: 304 pts with non-small cell lung cancer (NSCLC, n=127), melanoma (MEL, n=107), renal cell (RCC, n=34), colorectal (n=19) or prostate cancer (n=17) received nivolumab between 2008-2012 (0.1−10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Formalin-fixed paraffin-embedded tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed to explore potential pharmacodynamic/ predictive biomarkers associated with nivolumab therapy. Tumor surface PD-L1 expression was evaluated by IHC using an automated assay based on a sensitive and specific PD-L1 mAb (28-8) distinct from 5H1. PD-L1 positivity (PD-L1+) was defined as ≥5% cell membrane staining of any intensity. Lymphocyte subsets in PBMC were measured using flow cytometry. Results: Tumor membrane PD-L1 was measured in 101 MEL and NSCLC pts. 17/38 (45%) of MEL and 31/63 (49%) of NSCLC biopsies were PD-L1+. A numerically higher objective response rate (ORR), longer progression-free survival (PFS), and overall survival (OS) was seen with PD-L1+ in MEL pts (Table).Analysis of the association of PD-L1 expression with ORR, PFS and OS in NSCLC is ongoing. A correlative analysis of pt response with pre-/post-dose levels of lymphocytes will be presented. Conclusions: These data, using a novel, automated PD-L1 IHC assay and mAb, support the hypothesis of tumor PDL1+ predicting activity of nivolumab in advanced cancer, which is being prospectively assessed in phase III trials. Clinical trial information: NCT00730639. [Table: see text]

scholarly journals Association of NF-κB polymorphisms with clinical outcome of non-medullary thyroid carcinoma

2017 ◽  
pp. 307-318 ◽  
Author(s):  
Theo S Plantinga ◽  
Mirela S Petrulea ◽  
Marije Oosting ◽  
Leo A B Joosten ◽  
Doina Piciu ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Clinical Response ◽  
Genetic Variants ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Clinical Parameters ◽  
Peripheral Blood Mononuclear ◽  
Medullary Thyroid ◽  
Functional Studies ◽  
Clinical Associations

The NF-κB inflammatory pathway plays a major role in cancer development and clinical progression. Activation of NF-κB signaling is promoted by NFKB1 and inhibited by NFKBIA. The present study aimed to determine the relevance ofNFKB1rs4648068 andNFKBIArs2233406 genetic variants for non-medullary thyroid cancer (NMTC) susceptibility, progression and clinical outcome. This case–control and cohort study consists of a Romanian discovery cohort (157 patients and 258 controls) and a Dutch validation cohort (138 patients and 188 controls). In addition, patient cohorts were analyzed further for the association of genetic variants with clinical parameters. Functional studies were performed on human peripheral blood mononuclear cells. No associations were observed between the studied genetic variants and TC susceptibility. Although no statistically significant associations with clinical parameters were observed forNFKB1rs4648068, the heterozygous genotype ofNFKBIArs2233406 was correlated with decreased radioactive iodide sensitivity requiring higher cumulative dosages to achieve clinical response. These findings were discovered in the Romanian cohort (P < 0.001) and confirmed in the Dutch cohort (P = 0.01). Functional studies revealed that thisNFKBIArs2233406 genotype was associated with elevated TLR4-mediated IL-1β production. In conclusion, genetic variation inNFKBIA, an inhibitor of NF-κB signaling, is associated with clinical response to RAI therapy and with increased production of the pro-inflammatory cytokine IL-1β, providing a potential mechanism for the observed clinical associations. These data suggest that NF-κB signaling is involved in NMTC pathogenesis and that the inflammatory tumor microenvironment could contribute to RAI resistance.

scholarly journals Correlation of response of aplastic anemia patients to antilymphocyte globulin with in vitro lymphocyte stimulatory effect: predictive value of in vitro test for clinical response

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2225-2230 ◽  
Author(s):  
T Abe ◽  
H Matsuoka ◽  
S Kojima ◽  
Y Kamachi ◽  
I Tsuge ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Clinical Response ◽  
Proliferative Response ◽  
Mononuclear Cells ◽  
In Vitro Test ◽  
Antilymphocyte Globulin ◽  
Peripheral Blood Mononuclear ◽  
Color Flow ◽  
Significant Difference

Abstract Therapy with antilymphocyte globulin (ALG) has been shown to be effective in restoring hematopoiesis to some patients with aplastic anemia. It would be useful to have a method for predicting those likely to be responders versus nonresponders. The mode of immunostimulatory action of ALG is of interest in addition to its immunosuppressive action. We examined in vitro the distribution of the proliferative responses of ALG-stimulated peripheral blood mononuclear cells (PBMCs) obtained from 18 patients with aplastic anemia, eight of whom responded to ALG and 10 who did not. We found a significant difference in the proliferative response of PBMCs obtained from the eight responders versus the 10 nonresponders (P less than .01). Two-color flow cytometry analysis of the patients' PBMCs stimulated by ALG in vitro showed that the CD4-positive subsets were activated to a greater extent by ALG than the CD8-positive subsets. Moreover, a positive correlation with the clinical response of patients to ALG with granulocyte-macrophage colony- stimulating factor produced by their PBMCs stimulated by ALG suggests that the immunostimulatory property of ALG has an important role in the treatment of aplastic anemia. Our results suggest that the clinical response to ALG therapy is correlated with its lymphocyte proliferative effect in vitro, and indicates that the assessment of the proliferative response of PBMCs in vitro would be useful in predicting the clinical response to ALG therapy.

scholarly journals 6 Immune correlates of clinical benefit in patients with HPV-associated malignancies treated with bintrafusp alfa

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A6-A6
Author(s):  
Yo-Ting Tsai ◽  
Renee Donahue ◽  
Nicole Toney ◽  
Julius Strauss ◽  
James Gulley ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Predictive Biomarkers ◽  
Cooperative Research ◽  
Open Label ◽  
Hpv 16 ◽  
Link Type ◽  
Immune Correlates

BackgroundThe safety and efficacy of bintrafusp alfa, a first-in-class bifunctional fusion protein targeting TGFβ and PD-L1 pathways, have been demonstrated in patients with HPV-related cancers in an open-label, multicenter phase 1 trial (NCT02517398), and an open-label, single-center phase 2 trial (NCT03427411). The current study aimed to identify immune related biomarkers prior to and following 1 cycle of bintrafusp alfa that associate with clinical benefit.MethodsImmune parameters were compared in patients (n=65) deriving clinical benefit from bintrafusp alfa (defined as BOR of stable disease (SD) or better, which included SD, mixed, partial, and complete responses) versus patients with a BOR of progressive disease (PD). Peripheral blood was obtained from patients before and after 1 cycle of therapy, and evaluated for complete blood counts, plasma cytokines/soluble factors, 158 immune subsets, and T cells specific for HPV-16 E6 and E7.ResultsPrior to therapy, patients who developed a BOR of SD or better had lower counts of neutrophils, monocytes, and platelets, lower levels of TGF-β1 and sCD73, and higher levels of sCD27:sCD40L than patients with a BOR of PD. Lower baseline frequencies of MDSCs, monocytes, naïve CD4+ and CD8+ T cells, and CD8+ T cells that express CD73, an immune checkpoint associated with adenosine metabolism, were detected in patients with a BOR of SD or better than those with PD. Following 1 cycle of treatment, lymphocyte counts were reduced, while neutrophil counts and the NLR were increased, in patients with PD compared to those with a BOR of SD or better. IL-8, a cytokine involved in tumor progression and associated with reduced clinical benefit to immune checkpoint inhibitors, was increased in patients with PD compared to those with a BOR of SD or better, while conventional dendritic cells and CD8+ T cells expressing the proliferative marker ki67 were increased in patients with a BOR of SD or better compared to those with PD. Greater increases in the frequency and magnitude of HPV-16 specific CD8+ T-cells were also detected in individuals with a BOR of SD or better compared to PD.ConclusionsImmune profiling identified specific measures prior to therapy, as well as changes induced early after therapy (preceding restaging), that may serve as predictive biomarkers to identify patients with HPV-related cancers most likely to benefit from bintrafusp alfa. These findings also provide the rationale to combine bintrafusp alfa with other therapies including HPV-targeted therapeutic vaccines and agents that block IL-8 signaling.AcknowledgementsThis research was supported by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, and through a Cooperative Research and Development Agreement with EMD Serono Research & Development Institute and GSK.Ethics ApprovalThe study protocol was approved by ethics committees at all participating institutions, and each patient provided written informed consent before study enrollment.

scholarly journals Correlation of response of aplastic anemia patients to antilymphocyte globulin with in vitro lymphocyte stimulatory effect: predictive value of in vitro test for clinical response

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2225-2230 ◽  
Author(s):  
T Abe ◽  
H Matsuoka ◽  
S Kojima ◽  
Y Kamachi ◽  
I Tsuge ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Clinical Response ◽  
Proliferative Response ◽  
Mononuclear Cells ◽  
In Vitro Test ◽  
Antilymphocyte Globulin ◽  
Peripheral Blood Mononuclear ◽  
Color Flow ◽  
Significant Difference

Therapy with antilymphocyte globulin (ALG) has been shown to be effective in restoring hematopoiesis to some patients with aplastic anemia. It would be useful to have a method for predicting those likely to be responders versus nonresponders. The mode of immunostimulatory action of ALG is of interest in addition to its immunosuppressive action. We examined in vitro the distribution of the proliferative responses of ALG-stimulated peripheral blood mononuclear cells (PBMCs) obtained from 18 patients with aplastic anemia, eight of whom responded to ALG and 10 who did not. We found a significant difference in the proliferative response of PBMCs obtained from the eight responders versus the 10 nonresponders (P less than .01). Two-color flow cytometry analysis of the patients' PBMCs stimulated by ALG in vitro showed that the CD4-positive subsets were activated to a greater extent by ALG than the CD8-positive subsets. Moreover, a positive correlation with the clinical response of patients to ALG with granulocyte-macrophage colony- stimulating factor produced by their PBMCs stimulated by ALG suggests that the immunostimulatory property of ALG has an important role in the treatment of aplastic anemia. Our results suggest that the clinical response to ALG therapy is correlated with its lymphocyte proliferative effect in vitro, and indicates that the assessment of the proliferative response of PBMCs in vitro would be useful in predicting the clinical response to ALG therapy.

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