Molecular and immune predictors of response and toxicity to combined CTLA-4 and PD-1 blockade in metastatic melanoma (MM) patients (pts).

9579 Background: Combined treatment with ipilimumab and nivolumab (Ipi/Nivo) achieves clinical responses in > 50% of mm pts. However, responses are not universal and toxicity may be limiting, thus biomarkers of response and toxicity are needed to optimize and personalize this therapy. Methods: Tumor biopsies were collected before (n = 29) and on treatment (n = 7) from mm pts (n = 40) treated with Ipi/Nivo. Whole exome sequencing (WES), gene expression profiling, TCR sequencing, and immunohistochemistry (IHC) were performed to define molecular and immune features of the tumors. Radiographic responses in patients were assessed via RECIST 1.1criteria, and patients were classified as responders (R) deriving clinical benefit (with SD, PR, CR) and non-responders (NR) not deriving clinical benefit (PD). Toxicity was also scored, with patients dichotomized into low toxicity ( < grade 2) versus high toxicity ( > grade 3) re: immune-related (IR) toxicities. Results: In this cohort, the response rate was 80%, with 53% of patients experiencing > grade 3 toxicity. There was no significant difference in baseline mutational load in responders (R) vs non-responders (NR) to Ipi/Nivo, but NR had a higher burden of copy number alterations (CNA; p = 0.013), with frequent alterations detected in PTEN, JAK2, and B2M. There were no significant differences in baseline CD8+ T cell density, expression of immune-related genes, or T cell clonality for R vs NR pts. Ipi/Nivo treatment increased intratumoral T cell clonality, but this did not correlate with response. A more diverse peripheral T cell repertoire at baseline was detected in pts who developed IR toxicity (p < 0.05). Conclusions: This data suggests that responses to Ipi/Nivo in mm may occur in the absence of high mutational load or brisk immune infiltrate at baseline. Putative mechanisms of resistance to Ipi/Nivo include high burden of CNA and alterations in PTEN, JAK2, and B2M. Together these studies identify candidate biomarkers of resistance and toxicity for Ipi/Nivo, though they need to be tested in larger cohorts and across cancer types.

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Clinical significance of T cell clonality and expression levels of immune-related genes in endometrial cancer

Oncology Reports ◽

10.3892/or.2017.5536 ◽

2017 ◽

Vol 37 (5) ◽

pp. 2603-2610 ◽

Cited By ~ 19

Author(s):

Yuji Ikeda ◽

Kazuma Kiyotani ◽

Poh Yin Yew ◽

Sho Sato ◽

Yuichi Imai ◽

...

Keyword(s):

Endometrial Cancer ◽

T Cell ◽

Clinical Significance ◽

Expression Levels ◽

Immune Related Genes ◽

T Cell Clonality ◽

Cell Clonality

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Clonality of T-cell repertoire in the tumor microenvironment (TME) and peripheral blood of metastatic melanoma patients treated with CTLA4 blockade and interferon-α (IFN).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.9 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 9-9

Author(s):

Ahmad A. Tarhini ◽

Aya Agha ◽

Zahra Rahman ◽

Sharon Benzeno ◽

Erik Yusko ◽

...

Keyword(s):

T Cell ◽

Metastatic Melanoma ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Interferon Α ◽

High Dose ◽

T Cell Repertoire ◽

Cell Repertoire ◽

T Cell Clonality ◽

Cell Clonality

9 Background: Patients with metastatic melanoma were treated with tremelimumab and IFN in a previously reported study (Tarhini. J Clin Oncol. 2012). Clonality of T-cell repertoire was analyzed in terms of clinical response both in TME and in peripheral blood. Methods: Patients received tremelimumab 15 mg/kg I.V. every 12 weeks. High dose IFN (HDI) was administered concurrently. Responses were assessed by RECIST as complete (CR) or partial (PR), stable disease (SD) or progression (PD). T-cell receptor beta chain (TCRB) repertoire was immunosequenced in peripheral blood mononuclear cells (PBMC) (N=33 patients) and tumor (N=18) utilizing Adaptive Biotechnologies immunoSEQ platform to determine repertoire clonality and T-cell fractions at pre-treatment (tumor, PBMC), one month (PBMC), and 3 months (PBMC). The clonality metric quantitates, the extent of mono- or oligo-clonal expansion by measuring the shape of the clone frequency distribution. Values range from 0 to 1; values approaching 1 indicate a nearly monoclonal population. Results: In pretreatment TME, T-cell clonality was significantly (p = 0.0008) different and greater in patients who achieved disease control (CR, PR, SD) versus those with PD. Further, there was a significant (p = 0.044) difference between the increased TCR fraction in TME in responders (CR, PR) and non-responders (SD, PD). There was a trend towards association between pretreatment TME T-cell clonality and overall survival (OS) (p = 0.24) and progression free survival (PFS) (p = 0.18) not reaching significance. Within the circulation (PBMC), no significant associations were found by examining the pretreatment samples. However, early on-treatment (day 29) there was significant association and decrease in T-cell clonality and OS (p = 0.005) and PFS (p = 0.003). Conclusions: T-cell clonality in the TME pretreatment is a promising biomarker of immunotherapeutic benefit in our study. While baseline PBMC clonality was not associated with clinical benefit, early on-treatment (day 29) was significantly associated. These findings require validation in an independent cohort and exploration in relation to other immunotherapeutics. Clinical trial information: NCT00610857.

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T cell repertoire analysis of non-small cell lung cancer patients treated with neoadjuvant nivolumab alone or in combination with ipilimumab (NEOSTAR trial).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8532 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8532-8532 ◽

Cited By ~ 3

Author(s):

Alexandre Reuben ◽

Jianjun Zhang ◽

Heather Y. Lin ◽

Latasha Little ◽

Curtis Gumbs ◽

...

Keyword(s):

T Cell ◽

Small Cell ◽

T Cell Repertoire ◽

Small Cell Lung ◽

Cell Repertoire ◽

Pre Treatment ◽

Nsclc Patients ◽

T Cell Clonality ◽

Post Therapy ◽

Cell Clonality

8532 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) are being explored in resectable non-small cell lung cancer (NSCLC). Here, we studied the composition and changes in the T cell repertoire in a cohort of NSCLC patients (n = 44) treated with neoadjuvant nivolumab (N) alone or in combination with ipilimumab (NI) followed by surgery (NEOSTAR trial). Methods: Sequencing of the variable CDR3β chain of the T cell receptor (TCR) involved in antigen binding was performed in pre-treatment and surgical tumors, matched adjacent uninvolved lung specimens, as well as paired longitudinal blood at baseline, prior to each dose of therapy, prior to surgery, and within 8 weeks post-surgery. T cell repertoire density, diversity, and clonality (reactivity) were evaluated in addition to tumor PD-L1 expression pre- and post-neoadjuvant treatment. Results: Median T cell diversity in the blood post-therapy was 3.3-fold higher in NI- compared to N-treated patients (40,993 [NI, n = 3] vs 12,177 [N, n = 4] unique TCR rearrangements, n.s.). However, median T cell clonality in the blood was 3.5-fold higher in N- than NI-treated patients post-therapy (0.093 [N, n = 4] vs 0.026 [NI, n = 3], n.s.). Median clonality was 3.8-fold higher in the tumor post-therapy in patients receiving NI than in those receiving N (0.076 [NI, n = 7] vs 0.020 [N, n = 5], n.s.). Interestingly, diversity in the blood at baseline and in the tumor post-therapy were positively correlated ([n = 7], r = 0.82; p = 0.023), which may reflect an influx of cells from the periphery following ICIs. Importantly, higher baseline T cell clonality in the blood was associated with a lower % of viable tumor at time of surgery in both treatment arms ([n = 7], r = -0.77; p = 0.04). Conclusions: Our study is the first to assess the TCR repertoire in NSCLC patients treated with combination neoadjuvant NI and highlights potential mechanistic differences compared to N alone. Neoadjuvant NI is associated with higher clonality in tumors and lower clonality in blood post-therapy, suggesting increased T cell trafficking into the tumor. Finally, lower pre-treatment clonality in the periphery was correlated with higher % viable tumor post-neoadjuvant ICIs. Clinical trial information: NCT03158129.

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Analysis of T-Cell Clonality Pattern in Tumor Samples of Breast Cancer Patients

The International Journal of Biological Markers ◽

10.1177/172460080502000305 ◽

2005 ◽

Vol 20 (3) ◽

pp. 177-183 ◽

Cited By ~ 4

Author(s):

B.M. Cikota ◽

M.V. Branković-Magić ◽

V.S. Jović ◽

S.S. Radulović ◽

Z.M. Magić

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Cancer Patients ◽

Cell Populations ◽

Breast Cancer Patients ◽

Significant Difference ◽

T Cell Clonality ◽

Cell Clonality

Purpose and methods A large body of experimental evidence has confirmed that different tumors, including breast carcinomas, can stimulate specific T-cell-mediated immune responses. In this study we have analyzed patterns of T-cell clonality in tumor samples of 54 breast cancer patients classified as lymph node negative, N0 (n=16), or lymph node positive, N+ (n=38). The clonality of T-cells was analyzed by the PCR-PAGE method. Results Monoclonal/oligoclonal (M/O) T-cell populations were found in 15 breast cancer patients, nine N+ and six N0. In all analyzed groups (N+ + N0, N+, N0) the incidence of relapse was not significantly different between patients with M/O and patients with polyclonal T-cells. Comparison of disease-free interval (DFI) between patients divided according to the presence of TCR? monoclonality/oligoclonality showed a marginally significant difference only in the group of N+ patients within the first 24 months of follow-up. Patients with a M/O T-cell population had a shorter DFI than patients with a polyclonal T-cell population. This difference was not observed when the complete follow-up period was considered in the same group of patients. Furthermore, there was no significant difference in overall survival (OS) between patients with M/O and patients with polyclonal T-cells. Conclusion Our results imply that tumor infiltrating T-cells are usually polyclonal. The pattern of T-cell clonality does not correlate with the incidence of relapse and the duration of DFI and OS in the analyzed groups of breast cancer patients, excluding N+ patients with M/O T-cells who had a shorter DFI in the first 24 months of follow-up. This observation suggests that polyclonal T-cell populations may provide a broader spectrum of T-cell-mediated antitumor response.

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Lactate dehydrogenase, Beta-2 Microglobulin Levels and CD4/CD8 Lymphocyte Ratio in Patients with Mycosis Fungoides in Stage 1A

Acta Medica ◽

10.32552/2020.actamedica.503 ◽

2020 ◽

Vol 51 (4) ◽

pp. 16-21

Author(s):

Duygu Gülseren ◽

Ecem Bostan ◽

Sibel Doğan ◽

Başak Yalıcı-Armağan ◽

Neslihan Akdoğan ◽

...

Keyword(s):

Lactate Dehydrogenase ◽

T Cell ◽

Mycosis Fungoides ◽

Peripheral Blood ◽

Lymphocyte Ratio ◽

Significant Difference ◽

Beta 2 ◽

Beta 2 Microglobulin ◽

T Cell Clonality ◽

Cell Clonality

Objective: Mycosis fungoides is the most common type of primary cutaneous T-cell lymphomas. In this study, we aimed to investigate the biochemical parameters of beta-2 microglobulin, lactate dehydrogenase, CD4/CD8 lymphocyte ratio determined by flow cytometry, and T cell clonality in patients with MF and to correlate these parameters in stage 1A and other stages. Materials and Methods: A hundred sixty-one (87 Male, 74 Female) patients followed-up between January 1995 and January 2019 were retrospectively evaluated. Patients’ demographics, stage of the disease, peripheral lymph node and organ involvement, peripheral blood beta-2-microglobulin, lactate dehydrogenase levels, CD4/CD8 + lymphocyte ratio and presence of T cell clonality in biopsy samples were evaluated. Results: Median beta-2 microglobulin levels were 1608.5 ng/ml for stage 1A and 1970.5 ng/ml for other stages. Peripheral blood median CD4/CD8 lymphocte ratio was 1.60 for stage 1A and 1.85 for other stages. We found statistically significant difference between two groups in terms of beta-2 microglobulin levels and peripheral blood median CD4/CD8 lymphocte ratio (p=0.001, p=0.04). No statistically significant difference was found between two groups in terms of lactate dehydrogenase levels and T-cell clonality (p=0.234, p=0.525). Conclusion: Our study supports that high peripheral blood beta-2 microglobulin level and CD4/CD8 lymphocyte ratio at the time of diagnosis may imply advanced stage and poor prognosis in Mycosis Fungoides.

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