Peripheral blood T-cell receptor immune repertoire characterization of resectable stage IIIA non-small cell lung cancer patients receiving neo-adjuvant chemo-immunotherapy treatment from NADIM study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9041-9041
Author(s):  
Alberto Cruz Bermudez ◽  
Marta Casarrubios ◽  
Raquel Laza Briviesca ◽  
Belen Sierra-Rodero ◽  
Miguel Barquin ◽  
...  
Keyword(s):  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Pathological Response ◽  
Stage Iiia ◽  
Immune Repertoire ◽  
Tcr Repertoire ◽  
Response Groups ◽  
Viable Tumour

9041 Background: Characterization of the peripheral blood T-cell receptor (TCR) repertoire has become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, there is lack of knowledge about the clinical relevance of TCR repertoire in terms of pathological response and clinical outcomes (PFS and OS) in chemo-immunotherapy. To answer this question we have analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab. Methods: Using ION Torrent-based next-generation sequencing we have analysed TCR repertoire of peripheral blood from 30 patients receiving chemo-immunotherapy. Using 25ng of total RNA from PBMCs, clonal convergence, evenness and diversity were calculated at diagnosis (pre-treatment) and after 3 cycles of Nivolumab plus carboplatin (post-treatment). Regarding pathological responses, patients were classified in 3 groups: complete response (pCR) (0% viable tumour at the resection specimen), mayor response (pMR) ( < 10% viable tumour) and incomplete response (pIR) ( > 10% of viable tumour). At data analysis, PFS and OS median follow-up times were longer than 20 months. Results: No statistically significant differences in TCR repertoire in terms of evenness (p = 0,373), diversity (p = 0,691) or convergence (p = 0,054) between pre- and post-neoadjuvant treatment were observed. Similarly, no significant differences were observed in these metrics between pathological response groups. However, a detailed analysis of the clones showed that the percentage of frequent clones (greater than 0.1%) that increase after neoadjuvant therapy does show differences between the different pathological response groups (pIR vs pMR), being elevated in patients who presented responses greater than 90% (p = 0.0385). Regarding the clinical benefit, having this parameter higher than the median (43,90% in this cohort) is associated with a higher PFS (p = 0.0490) and OS (p = 0.078) using KM Log-rank test. Conclusions: Evenness, Diversity and Convergence derived from immune repertoire analysis do not appear to be clinically useful in the context of neoadjuvant chemo-immunotherapy in lung cancer. However, the detailed analysis of the clones seems promising. The increase of the most frequent clones after treatment seems to be associated to different clinical variables such as pathological response and PFS in these patients. Clinical trial information: NCT03081689.

Distinct contributions of CD4+ and CD8+naive and memory T-cell subsets to overall T-cell–receptor repertoire complexity following transplantation of T-cell–depleted CD34-selected hematopoietic progenitor cells from unrelated donors

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1915-1918 ◽  
Author(s):  
Matthias Eyrich ◽  
Tanja Croner ◽  
Christine Leiler ◽  
Peter Lang ◽  
Peter Bader ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Memory T Cell ◽  
Tcr Repertoire ◽  
Unrelated Donors

Normalization of restricted T-cell–receptor (TCR) repertoire is critical following T-cell–depleted (TCD) stem cell transplantation. We present a prospective study analyzing respective contributions of naive and memory T-cell subsets within the CD4+ and CD8+ compartments to the evolution of overall TCR-repertoire complexity following transplantation of CD34-selected peripheral blood progenitor cells from unrelated donors. During the first year after transplantation, sorted CD4/45RA, CD4/45R0, CD8/45RA, and CD8/45R0 subsets were analyzed at 3-month intervals for TCR-repertoire complexity by CDR3 size spectratyping. Skew in TCR-repertoire was observed only in early memory-type T cells. CD4+ and CD8+ subsets differed in clonal distribution of CDR3 sizes, with rapid Gaussian normalization of bands in CD4/45R0+ T cells. Naive T cells displayed normal repertoire complexity and contributed significantly to skew correction. Our data provide direct evidence for an important role of de novo maturation of naive T cells in normalization of an initially restricted TCR-repertoire following transplantation of CD34-selected, TCD-depleted peripheral blood progenitors from unrelated donors.

scholarly journals The T-Cell Receptor Repertoire Predicts Interim-PET in Patients with DLBCL Treated with R-CHOP: An Observational Study from a Prospective Clinical Trial

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 825-825
Author(s):  
Mohamed Shanavas ◽  
Mark Hertzberg ◽  
Rodney J Hicks ◽  
John F Seymour ◽  
Joshua W.D. Tobin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Cell Receptor ◽  
Variable Degree ◽  
Cell Responses ◽  
Interim Pet ◽  
Tcr Repertoire

Abstract T-cell infiltration of the tumor microenvironment (TME) in DLBCL is a key determinant of response to chemo-immunotherapy (Keane, Lancet Haem 2015). We have previously shown that greater diversity of the T-cell receptor (TCR) repertoire within the TME is correlated with improved survival following R-CHOP in DLBCL (Keane, CCR 2017). There are limited data on the impact of the intratumoral TCR repertoire on interim-PET (iPET), the relationship between intratumoral and circulating TCRs, and on dynamic changes of the TCR during therapy. In this study, we interrogated the TCR repertoire in a subset of DLBCL patients treated on the prospective Australasian Leukaemia Lymphoma Group NHL21 study (Hertzberg, Haematologica 2017), in which all patients had 4x RCHOP prior to iPET risk stratification. The CDR3 region of TCRβ chain underwent high-throughput unbiased TCRβ sequencing (Adaptive Biotechnologies). Metrics included: productive templates (total functional T-cells), productive rearrangements (functional T-cells with distinct specificity), productive clonality (repertoire unevenness due to clonal expansions), and maximal frequency clones (% most dominant single clone). Matched intratumoral diagnostic samples, blood at pre-therapy and post-cycle 4 (at the time of iPET) were tested. 42 patients (enriched for iPET+ cases) had sufficient material for testing. Median age was 55 (range 22-69) years and 72% were males. IPI was low/intermediate/high in 13/63/25% respectively. Cell of origin (COO) by Lymph 2CX method (nanoString) was ABC in 30%, and GCB in 44%. 40% were iPET+. In tissue, there was a median of 4652 productive templates, translating into 2998 productive rearrangements identified. Notably, the clonal repertoire of intratumoral TCRs in iPET+ patients was larger than iPET-ve patients (productive clonality 8.1 vs 5.1 x10-2, p=0.04), whereas the numbers of functional T-cells did not vary between groups. Comparing the tumor with the blood samples showed a high, but variable, degree of overlap between peripheral blood and the TME - TCR repertoire. Median number of top 100 tumor tissue clones shared in peripheral blood was 53.5 (range, 1-97) in pre-therapy and 39.5 (range, 0-93) in post-therapy blood, indicating that the both the circulation and the tumor likely contribute to immune-surveillance. In pre-therapy blood, the median productive templates and productive rearrangements were 44,950 (range, 6,003-273,765) and 29,090 (range, 5,190-152,706), and the median clonality was 8.5 (1.46-45.3) x 10-2. There were no differences between iPET+ and iPET-ve patients in these parameters. However, there was a marked change in T-cell composition between time points. Interestingly, in iPET-ve patients clonality measures were increased, with productive clonality 9.4 vs 14.4 x10-2, p=0.03; and % maximum productive frequency 3.39 vs 5.89, p=0.04. These findings demonstrate that the intratumoral TCR repertoire, and sequential blood sampling provide important information on outcome in DLBCL treated with RCHOP. A highly clonal T-cell repertoire in the TME was associated with iPET positivity after 4 cycles of R-CHOP. In line with findings in solid cancers treated with checkpoint blockade, development of clonal responses in peripheral blood was associated with iPET negativity. These findings indicate that clones expanded during therapy may be important in tumor clearance but that highly clonal T-cell responses in the tumor at diagnosis may hinder expansion of other T-cell responses to neoantigens. The circulating TCR composition is representative of the TME. These findings will assist the rationale design and therapeutic monitoring of novel immuno-therapeutic strategies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Peripheral selection of V delta 1+ cells with restricted T cell receptor delta gene junctional repertoire in the peripheral blood of healthy donors.

1993 ◽  
Vol 178 (1) ◽  
pp. 121-127 ◽  
Author(s):  
K Beldjord ◽  
C Beldjord ◽  
E Macintyre ◽  
P Even ◽  
F Sigaux
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
General Assumption ◽  
Gamma Delta ◽  
Stable Pattern ◽  
Healthy Donors ◽  
Tcr Repertoire ◽  
Gamma Delta T Cell

To characterize the T cell receptor (TCR) repertoire expressed by the V delta 1+ gamma/delta T cell population, we have studied the V delta 1-J delta 1 junctional sequences from peripheral blood samples of healthy donors. We show that, surprisingly, this repertoire is restricted in most healthy adults, with a donor-specific and relatively stable pattern, whereas this repertoire remains unrestricted in infants, and is similar to that of thymocytes. These data contrast with the general assumption that the junctional repertoire of V delta 1+ gamma/delta T cells is extensive, and strongly suggest that peripheral recruitment of V delta 1+ cells bearing particular TCR occurs in humans during the postnatal stage.

T cell receptor β-chain repertoire analysis to reveal potential predictive biomarker for the use of immune checkpoint blockade in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14152-e14152 ◽  
Author(s):  
Ye Li ◽  
Shun Chang Jiao ◽  
Liang Liang Wu ◽  
Sheng Jie Sun ◽  
Hua Feng Wei ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Predictive Biomarker ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Tcr Repertoire ◽  
Before And After

e14152 Background: Immune checkpoint blockade (ICB) targeted to CTLA-4, PD-1, and PD-L1 can promote antitumor T cell immunity and clinical responses. Tracking the dynamic changes of the T Cell Receptor (TCR) Immune Repertoire can reflect the evolution of the immune system in tumor immunotherapy patients, predict the immune response to ICB, and provide high-value information for clinical monitoring of immune function status of cancer patients to make effective clinical decisions. The purpose of this study was to explore the correlation between the peripheral blood TCR repertoire dynamic changes and the immune response of patients with anti-PD-1/PD-L1, and to accurately guide the individualized treatment of immunotherapy. Methods: We sequenced the TCRβ genes from T cells contained in peripheral blood mononuclear cells (PBMCs) from 24 advanced solid tumors patients (PD/7, PR/4, SD/13) treated with immune checkpoint blockade. Peripheral blood samples were collected from baseline, 8-week, and 16-week after treatment for each patient. bioinformatic analysis was used to detect the diversity and clonality changes of TCRβ-CDR3 sequence before and after treatment with ICB in patients, and provide auxiliary technology for further guiding clinical tumor immunotherapy. Results: The analysis result of Chao index showed that the TCR-CDR3 diversity in the PR group was significantly increased after treatment than SD or PD group. (pvalue = 0.001), and the number of CDR3 aa clonotypes also increased significantly (pvalue = 0.012). A total of 61 Vβ gene fragments and 15 Jβ gene fragments were uniquely identified during immunotherapy . There was a significant difference in the number of Vβ gene fragments between baseline samples and after treatment in PR group (pvalue = 0.042). Conclusions: In this project, PBMC samples was used to evaluate the changes of TCR repertoire between before and after treatment with immune checkpoint blockade in advanced solid tumor patients. The immune function status was significantly changed before and after treatment. Patients with PR had significantly increased diversity in TCR repertoire than patients with SD or PD. The results provide T cell receptor β-chain repertoire sequencing and analysis has potential to assess whether immune checkpoint blockade promotes global T cell expansion and/or loss of T cell clonotype diversity, and to identify predictive biomarker for the use of immune checkpoint blockade.

Morphologic and functional characterization of human peripheral blood T cells expressing the T cell receptor γ/δ*

1989 ◽  
Vol 19 (7) ◽  
pp. 1183-1188 ◽  
Author(s):  
Silvano Ferrini ◽  
Daniela Zarcone ◽  
Maurizio Viale ◽  
Giannamaria Cerruti ◽  
Romano Millo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Functional Characterization ◽  
Cell Receptor

Analysis of the peripheral blood t-cell receptor (tcr) repertoire in monozygotic twins discordant for crohn's disease

Autoimmunity ◽  
1994 ◽  
Vol 17 (3) ◽  
pp. 241-248 ◽  
Author(s):  
Beena Gulwani-Akolkar ◽  
Linda Shalon ◽  
Pradip N. Akolkar ◽  
Stanley E. Fisher ◽  
Jack Silver
Keyword(s):  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Monozygotic Twins ◽  
Cell Receptor ◽  
Tcr Repertoire
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