Review for "MDSC subtypes and CD39 expression on CD8 + T cells predict the efficacy of anti PD‐1 immunotherapy in patients with advanced NSCLC"

2019 ◽  
Keyword(s):  
T Cells ◽  
Advanced Nsclc

scholarly journals Prognostic significance of peripheral CD8+CD28+ and CD8+CD28− T cells in advanced non-small cell lung cancer patients treated with chemo(radio)therapy

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Chao Liu ◽  
Wang Jing ◽  
Ning An ◽  
Aijie Li ◽  
Weiwei Yan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Natural Killer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Radio Therapy ◽  
Nsclc Patients

Abstract Background Noninvasive prognostic biomarkers are needed for advanced non-small cell lung cancer (NSCLC) patients with different histological types to identify cases with poor survival. Here, we investigated the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28− T cells in advanced NSCLC patients treated with chemo(radio)therapy and the impact of histological type on them. Methods Of 232 registered advanced NSCLC patients, 101 treatment-naïve individuals were eligible and included in our study. Flow cytometry was used to evaluate CD8+CD28+ T cells, CD8+CD28− T cells, CD4+ CD25hi T cells, B cells, natural killer cells, γδT cells, and natural killer T cells in patients’ peripheral blood. Results The median follow-up time was 13.6 months. Fifty-nine (58.4%) patients died by the end of our study. Fifty-three of the 101 advanced NSCLC cases selected for our study were adenocarcinomas (ADs), and 48 were squamous cell carcinomas (SCCs). Multivariate analyses showed that increased levels of CD8+CD28+ T cells independently predicted favorable overall survival (OS) [hazard ratio (HR): 0.51, 95% confidence interval (CI) 0.30–0.89, P = 0.021] and progression-free survival (PFS) (HR: 0.66, 95% CI 0.37–0.93, P = 0.038) in ADs, but the prediction in SCCs was not statistically significant. In contrast, high levels of CD8+CD28− T cells independently predicted unfavorable OS (HR: 1.41, 95% CI 1.17–3.06, P = 0.035) and PFS (HR: 2.01, 95% CI 1.06–3.85, P = 0.029) in SCCs, but the prediction in ADs was not statistically significant. ADs had higher levels of CD4+CD25hi T cells and CD8+CD28− T cells and lower NK cells (all P < 0.05) than SCCs. Conclusions Our findings uncovered the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28− T cells in advanced NSCLC patients treated with chemo(radio)therapy, which could help to identify patients with poor outcomes and refine treatment strategies.

Trial of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) in patients with EGFR-expressing recurrent/metastatic non-small cell lung cancer (NSCLC) and solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13124-e13124 ◽  
Author(s):  
Bharti Rathore ◽  
Pam Davol ◽  
Ritesh Rathore ◽  
Francis Cummings ◽  
Ariel E. Birnbaum ◽  
...  
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Stable Disease ◽  
Bispecific Antibody ◽  
Advanced Nsclc ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Activated T Cells ◽  
Gm Csf ◽  
Grade 3

e13124 Background: Patients (pts) with advanced NSCLC and solid tumors have a poor prognosis and novel approaches to improve targeting and cytotoxicity directed at these cancers are needed. Anti-CD3 activated T cells (ATC) can be expanded and armed with anti-CD3 x anti-EGFR bispecific antibody (EGFRBi). Methods: In a phase I trial using ATC armed with EGFRBi, 6 pts (NSCLC = 5 pts, pancreatic cancer =1 pt) were treated with 8 infusions (twice/week) for 4 weeks with 5, 10 billion armed ATC/dose to determine the maximum tolerated dose (3 pts each). T cells from leukopheresis were activated and expanded with anti-CD3/IL-2 for 14 days, harvested, armed with EGFRBi and cryopreserved. IL-2 (3 x 105 IU/m2/daily) and GM-CSF (250 µg/m2 twice/week) was given beginning 3 days prior to the 1st infusion and ending++ 3, performance status (PS 0= 2 pts, PS 1= 4 pts). Results: Restaging scans revealed stable disease in 2 pts and progression in 4 pts. One pt with NSCLC at each dose level had stable disease (23 mths, 11 mths). ATC infusions were well tolerated and noticeable toxicities included chills (grade 2= 1 pt, grade 3= 1 pt); headache (grade 1= 2 pts, grade 2= 2 pts), dizziness (grade 2= 1 pt), nausea (grade 1= 2 pts). Accrual continues for dose levels at 20, 40 billion armed ATC per dose. No major toxicities with IL-2 were observed; bone pain resulted in dose reductions for GM-CSF in 2 pts. Conclusions: Infusions of EGFRBi armed ATC can be safely accomplished in patients with advanced NSCLC and solid tumors; accrual continues.

Prognostic impact of circulating endothelial cell counts in patients with advanced non-small cell lung cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21045-e21045
Author(s):  
Nutan Jyothi DeJoubner ◽  
Hyunseok Kang ◽  
Qunna Li ◽  
Wayne A C Harris ◽  
Rena Stewart ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Progenitor Cells ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cd4 Counts ◽  
Risk Of Death ◽  
Cell Counts

e21045 Background: Blood progenitor cells expressing the stem cell marker CD34 have been associated with prognosis in cancer. We hypothesized that non-small cell lung cancer (NSCLC) patients with higher numbers of circulating CD34+ endothelial progenitor cells (CD34+/CD146+/CD45-, CEC) would have worse post-treatment outcomes and patients with more hematopoietic progenitor cells (CD34+/CD45+/CD45dim/CD133+, HPC) would have better outcomes. Methods: Blood samples from patients with advanced NSCLC were analyzed at 3 time points: prior to chemotherapy, after cycle one, and at completion of treatment or progression of disease, in an IRB-approved protocol. CEC, HPC, and immune subsets were measured by flow cytometry optimized for rare event detection. Primary outcomes were progression and death from the time of study entry. Patients were categorized and compared for progression free survival (PFS) and overall survival (OS) based on median cell counts. Differences between groups were tested using log-rank test and Cox regression. Results: A total of 62 patients were enrolled with mean age of 64 (37-87 years). There were 29 deaths after a median follow-up of 8.1 months. 40 patients progressed at a median of 5.4 months. Median numbers of CEC, HPC, and CD4+ T-cells were (0.05/uL, 0.41/uL, and 637/uL, respectively). Lower CEC at baseline was associated with a favorable PFS compared to those with higher counts (median PFS of 7.3 months versus 4.3 months, p=0.049). In a multivariate analysis after adjusting for age, gender, smoking, race, TNM stage, pathology, performance status and CD4 counts at baseline, patients with high CEC had almost 3-fold risk of death (HR=2.70, p=0.04) and disease progression (HR=3.03, p < 0.01) compared with patients with low numbers of CEC. In the same model, patients with fewer CD4+ T cells had > 3 fold risk of death compared with patients with higher numbers (HR=3.79, p=0.01). HPC content was not associated with OS or PFS. Conclusions: In patients with advanced NSCLC, higher CEC and lower CD4 counts at diagnosis are associated with worse outcomes. Higher CEC may serve as a cellular biomarker for extent of disease or tumor biology. Patients with poor T-cell immunity prior to treatment have worse survival.

Analysis of regulatory T cells in patients of NSCLC with malignant pleural effusion.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17511-e17511
Author(s):  
Prabhat Singh Malik ◽  
Vinod Raina ◽  
Amar Singh ◽  
Dipendrea Kumar Mitra
Keyword(s):  
T Cells ◽  
Pleural Effusion ◽  
Peripheral Blood ◽  
Chemokine Receptors ◽  
Malignant Pleural Effusion ◽  
Advanced Nsclc ◽  
Treg Cells ◽  
Healthy Controls ◽  
Anatomic Site ◽  
Treg Frequency

e17511 Background: Enrichment of regulatory T (Treg) cells at the affected anatomic site in cancer may suppress the anti-tumor immune response influencing the cancer progression. Understanding of the clinical relevance of Treg mediated suppression of anti-tumor immune response and mechanisms underlying their preferential trafficking to the affected anatomic site is still limited. The aim of this study was to enumerate the frequencies of Treg cells in malignant pleural effusion and peripheral blood of patients with advanced NSCLC and it’s trend after treatment. Methods: Treg frequencies were evaluated in pleural effusion and peripheral blood of the patients with advanced NSCLC (n=27) using flowcytometry and compared with peripheral blood of age and sex matched healthy controls (n=15) and tubercular pleural effusions (n=10). The Treg cells were characterized as CD4+CD25+Foxp3+ T cells gated on CD4+CD25+ T cells. We assessed the effect of treatment response on Treg frequency. We have also looked for the expression of chemokine receptors CCR4 and CCR6 on the Tregs in pleural effusion and peripheral blood of the patients. Results: Compared to healthy controls, frequency of CD4+CD25+Foxp3+ Tregs was significantly increased in peripheral blood of patients with NSCLC (p=0.0036). In pleural effusion of patients, Treg frequency was higher than their corresponding peripheral blood (p=0.025). As compared to tubercular pleural effusion Treg frequency was higher in malignant effusion (p<0.0001). We had 12 patients who completed treatment and in whom response evaluation was available. Treg frequency reduced at the time of response (PR or SD) and increased again at disease progression. Surface expression of CCR4 and CCR6 was higher on Treg cells as compared to non Treg CD4 cells among the patients (p=0.0001; p=0.001 respectively). However, there was no difference in expression of these chemokine receptors on Tregs in pleural fluid and peripheral blood. Conclusions: Tregs are increased in patients of NSCLC, both at disease site and in systemic circulation. This increase may be chemokine receptors mediated. Treg frequency changes with treatment and response. Modulation of Tregs may have therapeutic implication in the management of advanced NSCLC.

Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9091-9091
Author(s):  
Deborah Jean Lee Wong ◽  
Jeffrey Gary Schneider ◽  
Raid Aljumaily ◽  
Wolfgang Michael Korn ◽  
Jeffrey R. Infante ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Advanced Nsclc ◽  
De Novo ◽  
Cd8 T Cell ◽  
Outcome Data ◽  
Low Grade

9091 Background: Although IL-10 has anti-inflammatory properties, it stimulates cytotoxicity and proliferation of intratumoral antigen activated CD8+ T cell at higher concentrations. AM0010 is anticipated to activate antigen stimulated, intratumoral CD8 T cells while PD-1 inhibits them, providing the rationale for combining AM0010 and anti-PD-1 antibody. Methods: We treated a cohort of 34 NSCLC pts with AM0010 (10-20mg/kg QD, SC) and a PD-1 inhibitor [pembrolizumab (2mg/kg, q3wk IV; n=5) or nivolumab (3mg/kg, q2wk IV; n=29)]. Tumor responses were assessed by irRC every 8 weeks. Immune responses were measured by analysis of serum cytokines (Luminex), activation of blood derived T cells (FACS) and peripheral T cell clonality (TCR sequencing). Tumor PD-L1 expression was confirmed by IHC (22C3). Results: Pts had a median of 2 prior therapies. Median follow-up is 9.6 mo (range 0.5-77.3) in this fully enrolled cohort. AM0010 plus anti-PD-1 was well-tolerated. TrAEs were reversible and transient, with most being low grade, most commonly fatigue and pyrexia. G3/4 TrAEs were thrombocytopenia (7), anemia (6), fatigue (4), rash (3), pyrexia (2), hypertriglyceridemia (1) and pneumonitis (1). As of Jan. 31 2017, 22 pts had at least 1 tumor assessment. Partial responses (PRs) were observed in 8 pts (36.4%). 17 of these 22 pts had tissue for analysis of percent of tumor cells with PD-L1 expression (22C3): 58.8% had <1%, 17.7% had 1-49% and 23.5% had >50%. Best response data stratified for PD-L1 are shown in the table. Median PFS and OS for the entire cohort have not been reached. Updated outcome data that includes all enrolled pts will be available at the meeting. AM0010 plus anti-PD1 increased serum Th1 cytokines (IL-18, IFNγ), the number and proliferation of PD1+ Lag3+ activated CD8+ T cells and a de-novo oligoclonal expansion of T cell clones in the blood while decreasing TGFβ. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated in advanced NSCLC pts. The efficacy and the observed CD8+ T cell activation is promising. Clinical trial information: NCT02009449. [Table: see text]

Expression of soluble DC-HIL/gpnmb receptor in the blood of metastatic non-small cell lung carcinoma treated with anti-PD1/PDL1 monoclonal antibodies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14038-e14038
Author(s):  
Jin-Sung Chung ◽  
Vijay Ramani ◽  
Masato Kobayashi ◽  
Vinita Popat ◽  
Ponciano D Cruz ◽  
...  
Keyword(s):  
T Cells ◽  
Advanced Nsclc ◽  
Soluble Form ◽  
Clinical Samples ◽  
Blood Levels ◽  
Cell Lung Carcinoma ◽  
Excellent Outcome ◽  
Ifn Γ ◽  
Low Levels ◽  
Nsclc Patients

e14038 Background: Anti-PD1/PDL1 therapy benefits only a minority (10-20%) of treated NSCLC. Identifying markers distinguishing responders vs. non-responders will improve management of NSCLC. DC-HIL receptor is a new checkpoint whose inhibitory mechanisms are divergent from the PD1 pathway. Tumor cells express DC-HIL receptor and its soluble form (sDC-HIL). We tested whether sDC-HIL expression regulates NSCLC response to anti-PD1/PDL1 Ab using animal models and human clinical samples. Methods: Tet-Off controlled sDC-HIL-transfected LL2 lung cancer cells were i.v. injected into mice (lung mets) and treated with doxycycline (Dox). Day 6, mice were sorted into 2 groups with/without Dox and treated with i.p. 200 μg Ab, every 2 d /6 shots. Day 18, # of lung-LL2 cells were counted by FACS and IFN-γ+ T cells in tumors analyzed. Advanced NSCLC patients (n = 51) treated with immune checkpoint inhibitors were every 6 weeks evaluated for partial response (PR), stable (SD) and progressive disease (PD) by RECIST. Serum were collected on weeks 0, 2, and 6 and assayed for sDC-HIL amounts by ELISA. Results: In mice treated with Dox (halt sDC-HIL expression), anti-PDL1 Ab treatment markedly reduced lung mets and increased IFN-γ+ T cells (p < 0.001), whereas this excellent outcome was not noted in Dox-untreated mice (induce sDC-HIL). For NSCLC, PD1/PDL1 therapy produced PR (n = 3), SD (n = 25) and PD (n = 23) at week 6. sDC-HIL blood levels at week 0 did not correlate with tumor size, but the levels at week 6 of PD patients were significantly higher than PR/SD patients (8.4 ± 5.6 vs. 4.0 ± 1.6 ng/ml, p = 0.001, Mann-Whitney test) and healthy donors (2.6 ± 0.9 ng/ml). Most patients (26 out of 30 cases) showed fluctuation in sDC-HIL levels during treatment. PD-patients (14/15 cases) showed increasing or persistently elevated levels ( > 4 ng/ml), with one case at low levels ( < 4 ng/ml). SD/PR-patients (13/15) had decreasing or persistently low levels, with 2 exceptions with high levels in all time points. Conclusions: sDC-HIL blood level may serve as a biomarker to indicate tumor-resistance of advanced NSCLC patients to PD1/PDL1 therapy. The degree and direction of sDC-HIL fluctuation may be useful to predict prognosis for NSCLC.

Measurement of PD-1, TIM-3 and LAG-3 protein in non-small cell lung carcinomas (NSCLCs) with acquired resistance to PD-1 axis blockers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14611-e14611 ◽  
Author(s):  
Ila Datar ◽  
Nikita Mani ◽  
Brian S. Henick ◽  
Anna Wurtz ◽  
Edward Kaftan ◽  
...  
Keyword(s):  
T Cells ◽  
Advanced Nsclc ◽  
Staining Pattern ◽  
Acquired Resistance ◽  
Inhibitory Receptors ◽  
Tissue Sections ◽  
Clinical Responses ◽  
Pre Treatment ◽  
Membranous Staining ◽  
Tumor Area

e14611 Background: PD-1 axis blockade induces lasting clinical responses in ~20% of patients with advanced NSCLC. However, most patients eventually develop resistance. Acquired resistance is poorly understood, but may be mediated by alternative immune suppressive pathways. Methods: Using multiplex immunofluorescence we simultaneously measured levels of DAPI, CD3 (D7AE6), PD-1 (EH33), TIM-3 (D5D5R) and LAG-3 (17B4) in 11 whole tissue sections obtained from patients with NSCLC before PD-1 axis blockade and after acquired resistance (8 cases with progression on-treatment and 3 with progression off-therapy). Markers were measured in the whole tumor area or in CD3+ T-cells using fluorescence co-localization. The association between markers and changes upon acquired resistance were studied. Results: Expression of PD-1, TIM-3 and LAG-3 was seen in all cases with membranous staining pattern and signal predominantly located in CD3+ T-cells. Levels of TIM-3 and LAG-3 in T-cells were significantly correlated (Spearman’s R = 0.65, P = 0.001), but were not associated with PD-1 (R = -0.03, P = 0.86 for TIM-3 and PD-1; and R = 0.24, P = 0.28 for LAG-3 and PD-1). Compared to pre-treatment samples, 6 cases (55%) showed significantly higher levels of PD-1 or LAG-3 on acquired resistance and 5 cases (45%) had higher TIM-3. Of these, 4 cases had higher levels of the 3 markers and were on-therapy at progression. Lower levels of PD-1, TIM-3, and LAG-3 were found on acquired resistance in 5 (45%), 6 (55%), and 4 (36%) cases, respectively. Four of these cases showed lower levels of all inhibitory receptors, 3 of which were off-therapy at progression. Only one case had no change in LAG-3 levels. Conclusions: PD-1, TIM-3 and LAG-3 were expressed in the majority of NSCLCs with signal predominantly located in T-lymphocytes. Among acquired resistance cases, higher levels of PD-1, TIM-3 and LAG-3 were associated with progression on-treatment. Lower levels of the markers were associated with progression off-therapy. Although multiple mechanisms may exist, up-regulation of alternative immune inhibitory receptors such as TIM-3 and LAG-3 could mediate acquired resistance to PD-1 axis blockers in a proportion of NSCLCs.

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