Abstract A134: Single-cell roadmap of the evolution of T-cell response during anti-LAG3 and anti-PD1 combination treatment in metastatic melanoma patients

2019 ◽  
Author(s):  
Jani Huuhtanen ◽  
Henna H.E. Hakanen ◽  
Tapio Lönnberg ◽  
Olli Dufva ◽  
Katriina Peltola ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
Metastatic Melanoma ◽  
Combination Treatment ◽  
Cell Response ◽  
T Cell Response ◽  
Melanoma Patients

Analysis and Characterization of Antitumor T-cell Response After Administration of Dendritic Cells Loaded With Allogeneic Tumor Lysate to Metastatic Melanoma Patients

2008 ◽  
Vol 31 (1) ◽  
pp. 101-112 ◽  
Author(s):  
Nadege Bercovici ◽  
Nacilla Haicheur ◽  
Severine Massicard ◽  
Frederique Vernel-Pauillac ◽  
Olivier Adotevi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Cell Response ◽  
T Cell Response ◽  
Tumor Lysate ◽  
Allogeneic Tumor ◽  
Melanoma Patients

scholarly journals Allelic variation in Class I HLA determines pre-existing memory responses to SARS-CoV-2 that shape the CD8+ T cell repertoire upon viral exposure

2021 ◽  
Author(s):  
Joshua M. Francis ◽  
Del Leistritz-Edwards ◽  
Augustine Dunn ◽  
Christina Tarr ◽  
Jesse Lehman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cell Response ◽  
Hla Class I ◽  
T Cell Response ◽  
Class I ◽  
Epitope Specificity ◽  
Hla Genotype

AbstractEffective presentation of antigens by HLA class I molecules to CD8+ T cells is required for viral elimination and generation of long-term immunological memory. In this study, we applied a single-cell, multi-omic technology to generate the first unified ex vivo characterization of the CD8+ T cell response to SARS-CoV-2 across 4 major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCR α/β sequence diversity, and the utilization of pre-existing SARS-CoV-2 reactive memory T cell pools. Single-cell transcriptomics revealed functionally diverse T cell phenotypes of SARS-CoV-2-reactive T cells, associated with both disease stage and epitope specificity. Our results show that HLA variations influence pre-existing immunity to SARS-CoV-2 and shape the immune repertoire upon subsequent viral exposure.One-Sentence SummaryWe perform a unified, multi-omic characterization of the CD8+ T cell response to SARS-CoV-2, revealing pre-existing immunity conditioned by HLA genotype.

scholarly journals Targeted reconstruction of T cell receptor sequence from single cell RNA-sequencing links CDR3 length to T cell differentiation state

2016 ◽  
Author(s):  
Shaked Afik ◽  
Kathleen B. Yates ◽  
Kevin Bi ◽  
Samuel Darko ◽  
Jernej Godec ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Cell Response ◽  
T Cell Response ◽  
Effector Memory ◽  
Cell State ◽  
Tcr Repertoire ◽  
Single Cell Rna Sequencing

ABSTRACTThe T cell compartment must contain diversity in both TCR repertoire and cell state to provide effective immunity against pathogens1,2. However, it remains unclear how differences in the TCR contribute to heterogeneity in T cell state at the single cell level because most analysis of the TCR repertoire has, to date, aggregated information from populations of cells. Single cell RNA-sequencing (scRNA-seq) can allow simultaneous measurement of TCR sequence and global transcriptional profile from single cells. However, current protocols to directly sequence the TCR require the use of long sequencing reads, increasing the cost and decreasing the number of cells that can be feasibly analyzed. Here we present a tool that can efficiently extract TCR sequence information from standard, short-read scRNA-seq libraries of T cells: TCR Reconstruction Algorithm for Paired-End Single cell (TRAPeS). We apply it to investigate heterogeneity in the CD8+T cell response in humans and mice, and show that it is accurate and more sensitive than previous approaches3,4. We applied TRAPeS to single cell RNA-seq of CD8+T cells specific for a single epitope from Yellow Fever Virus5. We show that the recently-described "naive-like" memory population of YFV-specific CD8+T cells have significantly longer CDR3 regions and greater divergence from germline sequence than do effector-memory phenotype CD8+T cells specific for YFV. This suggests that TCR usage contributes to heterogeneity in the differentiation state of the CD8+T cell response to YFV. TRAPeS is publicly available, and can be readily used to investigate the relationship between the TCR repertoire and cellular phenotype.

Evaluation of cyclophosphamide as an immune enhancer for the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3093-3093
Author(s):  
Oliver Klein ◽  
Ian D. Davis ◽  
Grant A. McArthur ◽  
Andrew Mark Haydon ◽  
Phillip Parente ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Cell Response ◽  
Low Dose ◽  
Advanced Melanoma ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Vaccine Antigen

3093^ Background: We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with resected melanoma; however the same vaccine induced only a few vaccine antigen specific immune responses in patients with advanced disease. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with the immune-modulator cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine. Methods: LUD2002-013 was an open-label phase II study intended to evaluate the safety and immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. The first cohort of patients received vaccine alone; a second cohort with 19 patients was added after evaluation of responses in Cohort 1 and received vaccine in combination with low-dose cyclophosphamide. Patients received 3 injections of NY-ESO-1 ISCOMATRIX preceded, in Cohort 2, by cyclophosphamide at a dose of 300 mg/m2 every four weeks. Assessment of clinical and immunological responses was undertaken at week 11. Results: Fifteen patients of Cohort 2 completed at least one cycle of vaccination. No objective responses were observed with three patients having stable disease for more than three months. The inclusion of cyclophosphamide into the vaccination protocol did not lead to any significant toxicity. Seven of fourteen patients in Cohort 2 developed a vaccine induced NY-ESO-1 specific CD4 T cell response, a significant increase compared to cohort 1 (p=0.019). No differences were observed in the frequency of vaccine induced antibody or CD8 T cell responses. No change in the frequency of peripheral blood regulatory T cells or myeloid derived suppressor cells was detected. Conclusions: The administration of low dose cyclophosphamide has significantly increased the NY-ESO-1 specific CD4 T cell response of the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma. Given the emerging importance of CD4 T cells in tumour regression, the present findings warrant further clinical exploration of combining cyclophosphamide with vaccines and other immune-modulatory agents. Clinical trial information: NCT00518206.

Vaccination of Metastatic Melanoma Patients With Autologous Tumor-Derived Heat Shock Protein gp96-Peptide Complexes: Clinical and Immunologic Findings

2002 ◽  
Vol 20 (20) ◽  
pp. 4169-4180 ◽  
Author(s):  
Filiberto Belli ◽  
Alessandro Testori ◽  
Licia Rivoltini ◽  
Michele Maio ◽  
Giovanna Andreola ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Metastatic Melanoma ◽  
Elispot Assay ◽  
T Cell Response ◽  
Autologous Tumor ◽  
Heat Shock Protein Gp96 ◽  
Peptide Complexes ◽  
Melanoma Patients

PURPOSE: To determine the immunogenicity and antitumor activity of a vaccine consisting of autologous, tumor-derived heat shock protein gp96-peptide complexes (HSPPC-96, Oncophage; Antigenics, Inc, Woburn, MA) in metastatic (American Joint Committee on Cancer stage IV) melanoma patients. PATIENTS AND METHODS: Sixty-four patients had surgical resection of metastatic tissue required for vaccine production, 42 patients were able to receive the vaccine, and 39 were assessable after one cycle of vaccination (four weekly injections). In 21 patients, a second cycle (four biweekly injections) was given because no progression occurred. Antigen-specific antimelanoma T-cell response was assessed by enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Immunohistochemical analyses of tumor tissues were also performed. RESULTS: No treatment-related toxicity was observed. Of 28 patients with measurable disease, two had a complete response (CR) and three had stable disease (SD) at the end of follow-up. Duration of CR was 559+ and 703+ days, whereas SD lasted for 153, 191, and 272 days, respectively. ELISPOT assay with PBMCs of 23 subjects showed a significantly increased number of postvaccination melanoma-specific T-cell spots in 11 patients, with clinical responders displaying a high frequency of increased T-cell activity. Immunohistochemical staining of melanoma tissues from which vaccine was produced revealed high expression of both HLA class I and melanoma antigens in seven of eight clinical responders (two with CR, three with SD, and the three with long-term disease-free survival) and in four of 12 nonresponders. CONCLUSION: Vaccination of metastatic melanoma patients with autologous HSPPC-96 is feasible and devoid of significant toxicity. This vaccine induced clinical and tumor-specific T-cell responses in a significant minority of patients.

Limited Antitumor T Cell Response in Melanoma Patients Vaccinated with Interleukin-2 Gene-Transduced Allogeneic Melanoma Cells

1996 ◽  
Vol 7 (16) ◽  
pp. 1955-1963 ◽  
Author(s):  
Flavio Arienti ◽  
Josep Sulé-Suso ◽  
Filiberto Belli ◽  
Luigi Mascheroni ◽  
Licia Rivoltini ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Interleukin 2 ◽  
Melanoma Cells ◽  
T Cell Response ◽  
Melanoma Patients

scholarly journals Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response

2020 ◽  
Author(s):  
Anastasia Gangaev ◽  
Elisa A Rozeman ◽  
Maartje W Rohaan ◽  
Daisy Philips ◽  
Sanne Patiwael ◽  
...  
Keyword(s):  
T Cell ◽  
Mechanism Of Action ◽  
Peripheral Blood ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Tumor Site ◽  
Cell Responses ◽  
Melanoma Patients

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If activation of circulating tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses towards 71 melanoma associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the melanoma-reactive CD8 T cell response in peripheral blood was unaltered upon PD-1 blockade. In contrast, a broadening of the melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. On the basis of these results, we conclude that PD-1 and CTLA-4 blockade impact the tumor-reactive CD8 T cell response in a distinct manner. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.

scholarly journals Clonal replacement of tumor-specific T cells following PD-1 blockade

2019 ◽  
Author(s):  
Kathryn E. Yost ◽  
Ansuman T. Satpathy ◽  
Daniel K. Wells ◽  
Yanyan Qi ◽  
Chunlin Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Carcinoma ◽  
Single Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Checkpoint Blockade ◽  
T Cell Clones ◽  
Cell Clones ◽  
Clonal Replacement

AbstractImmunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) pre- and post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8+CD39+T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.

Sign in / Sign up

Export Citation Format

Share Document