scholarly journals Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses

2017 ◽  
Vol 114 (29) ◽  
pp. E5900-E5909 ◽  
Author(s):  
Valerie Chew ◽  
Liyun Lai ◽  
Lu Pan ◽  
Chun Jye Lim ◽  
Juntao Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Tumor Antigens ◽  
Cell Subset ◽  
High Dimensional ◽  
Mass Cytometry ◽  
Chemotactic Gradient ◽  
Activation Status

The recent development of immunotherapy as a cancer treatment has proved effective over recent years, but the precise dynamics between the tumor microenvironment (TME), nontumor microenvironment (NTME), and the systemic immune system remain elusive. Here, we interrogated these compartments in hepatocellular carcinoma (HCC) using high-dimensional proteomic and transcriptomic analyses. By time-of-flight mass cytometry, we found that the TME was enriched in regulatory T cells (Tregs), tissue resident memory CD8+ T cells (TRMs), resident natural killer cells (NKRs), and tumor-associated macrophages (TAMs). This finding was also validated with immunofluorescence staining on Foxp3+CD4+ and PD-1+CD8+ T cells. Interestingly, Tregs and TRMs isolated from the TME expressed multiple markers for T-cell exhaustion, including PD-1, Lag-3, and Tim-3 compared with Tregs and TRMs isolated from the NTME. We found PD-1+ TRMs were the predominant T-cell subset responsive to anti–PD-1 treatment and significantly reduced in number with increasing HCC tumor progression. Furthermore, T-bet was identified as a key transcription factor, negatively correlated with PD-1 expression on memory CD8+ T cells, and the PD-1:T-bet ratio increased upon exposure to tumor antigens. Finally, transcriptomic analysis of tumor and adjacent nontumor tissues identified a chemotactic gradient for recruitment of TAMs and NKRs via CXCR3/CXCL10 and CCR6/CCL20 pathways, respectively. Taken together, these data confirm the existence of an immunosuppressive gradient across the TME, NTME, and peripheral blood in primary HCC that manipulates the activation status of tumor-infiltrating leukocytes and renders them immunocompromised against tumor cells. By understanding the immunologic composition of this gradient, more effective immunotherapeutics for HCC may be designed.

Immune profiling of tumor-infiltrating T cells using mass cytometry.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2607-2607
Author(s):  
David Roumanes ◽  
Evan Newell ◽  
Michael Fehlings
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Antigens ◽  
Human Cancer ◽  
Human Tumor ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Subsets ◽  
High Dimensional ◽  
Tumor Bearing ◽  
Immune Profiling

2607 Background: Immunotherapy recent successes have opened new avenues for the treatment of cancer and the presence of tumor-specific CD8+ T cells in tumor-bearing individuals offer a promising therapeutic target. However, the detection and profiling of such T cells are challenging due to the need to detect rare antigen-specific T cell subpopulations in patient samples that are limited in size thus making it difficult to exploit these parameters for predictive signatures of clinical response. Moreover, the identification and analysis of neoantigen-specific CD8+ T-cells in tumor-bearing individuals is challenging due to the small pool of such cells. Methods: In order to identify therapy-relevant tumor antigens and to facilitate a concurrent in-depth characterization of cells directed towards these targets, immunoSCAPE leverages the high-dimensional immune profiling capabilities of cytometry by time of flight (CyTOF) combined with a unique technology allowing the identification rare antigen-specific T-cell subsets. Results: We applied this technology to patient tumor-infiltrating lymphocytes from human cancer samples and tumor-derived neoantigens recognized by T-cells were identified and characterized. Interestingly, the majority of patient-derived tumor infiltrates consisted of tumor-unrelated T-cells characterized by a diverse phenotype. Strikingly, the expression of CD39 was absent from these bystander cells, suggesting that CD39 could be a useful biomarker for the identification of putative tumor-reactive T cells. Conclusions: Simultaneous immune profiling revealed that tumor-unrelated, bystander CD8+ T-cells are phenotypically different in human tumor infiltrates and identified CD39 as a putative marker of neoantigen-specific T-cells. By providing insights into the nature, frequency and phenotype of antigen-specific T-cells, immunoSCAPE’s unique target discovery and high-dimensional immune profiling platform is a valuable tool for the development of novel diagnostic and therapeutic strategies in immunotherapy.

Multiparametric Analysis of Intra-Tumoral T-Cells in Hodgkin's Lymphoma Using Mass Cytometry (CyTOF)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1438-1438
Author(s):  
Jose Villasboas Bisneto ◽  
Stephen M Ansell
Keyword(s):  
T Cells ◽  
Data Analysis ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Single Cell ◽  
Hodgkin Lymphoma ◽  
Cell Subset ◽  
Mass Cytometry ◽  
Mean Frequency

Abstract Classic Hodgkin lymphoma (cHL) is characterized by a rich non-malignant immune infiltrate. T-cells are key components of the antitumoral immune response and studies characterizing subsets in cHL have yielded conflicting results. Initial studies suggested a predominance of TH2-polarized CD4+ T-cells, thought to allow tumor progression due to exhaustion and hypofunctionality. More recent data contest these findings, supporting the theory of tumor progression through evasion from a TH1-rich infiltrate that is potentially functional. The role of tumor evasion in cHL has been highlighted by compelling early clinical data with the use of PD-1 blockade in patients with advanced disease. A similar trial in patients with non-Hodgkin lymphoma (NHL) yielded far more modest results. Intrinsic differences in T-cell subpopulations in the tumor microenvironment may correlate to response to immune checkpoint inhibitor therapy. CyTOF or mass cytometry is a platform able to evaluate more than 45 simultaneous parameters on a single-cell level using nonradioactive nonbiological isotopes tagged to monoclonal antibodies. Measurements are made based on mass spectrometry, avoiding the hurdles of interference and spectral overlap experienced with fluorochromes. This constitutes an ideal tool for the study of the tumor microenvironment given its ability to assess a large number of parameters and resolve differences in a heterogeneous population. We hypothesize that the phenotype of intratumoral lymphocytes in cHL identifies T-cells that can effectively eradicate malignant cells. To test this hypothesis, we compared the phenotype of intratumoral T-cells in cHL to that of NHL and nodular lymphocyte-predominant Hodgkin Lymphoma (nlpHL). Tonsil and hyperplastic lymph node (LN) tissues were used as normal controls. Single-cell suspensions created from tumor specimens were stained with a metal-tagged antibody panel containing 31 surface markers and acquired on CyTOF. Multiparametric data analysis was performed on Cytobank using spanning-tree progression analysis of density-normalized events (SPADE) and t-Distributed Stochastic Neighbor Embedding (viSNE) algorithms. Inferential statistical analyses were performed with JMP®, Version 10.0.0 (SAS Institute Inc., Cary, NC, 1989-2007) using two-tailed tests and a 95% confidence interval. Cell subsets are expressed as percentages of parent population (CD45+CD3+CD19-). A total of 10 samples were studied (4 cHL, 1 nlpHL, 3 NHL, 1 tonsil, 1 LN). The total T-cell population ranged from 30.52 to 67.05% in cHL and 15.36 to 47% in NHL compared to 4.02% and 24.58% in tonsil and LN respectively. The CD4+ T-cell subset ranged from 58.05 to 35.3% in cHL, 50.03 to 82.61% in NHL and corresponded to 82.74% and 87.07% in tonsil and LN respectively. SPADE analysis identified two areas of asymmetric frequency of events amongst samples (figure 1 and 2). The CD4+ Tnaive subset (CD4+CD45RA+CCR7+) ranged from 7.8 to 31.2% of total T-cells in cHL compared to 10.7% in nlpHL, 0.17 to 3.02% in NHL and 6.2 to 6.7% in controls. The pooled mean frequency of CD4+ Tnaive subset was significantly higher in HL (cHL + nlpHL) compared to NHL (14.3% vs. 1.55%; p<0.05; figure 3A). The regulatory T-cell subset (Treg; CD25+CCR4+) ranged from 0.49 to 1.84% of total T-cells in HL compared to 9.3 to 21.04% in NHL, and 4.45 to 8.28% in controls. The pooled mean frequency of the Treg subset was significantly smaller in HL compared to NHL (1.28% vs. 16.23%; p<0.05; figure 3B). Our data supports the use of mass cytometry as a platform to study the tumor microenvironment in B-cell lymphomas. Multiparametric data analysis revealed significant differences in the intratumoral T-cell population between HL and NHL samples, namely in the CD4+ Tnaive and Treg subsets. Further validation in a larger sample is underway and will include panels to evaluate intracellular cytokine production and cell signaling pathways. Correlation between specific intratumoral T-cell phenotypic signatures and clinical outcomes may identify prognostic and predictive characteristics and provide insight to mechanisms of resistance to immunotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals STAT5 is a potent negative regulator of TFH cell differentiation

2012 ◽  
Vol 209 (2) ◽  
pp. 243-250 ◽  
Author(s):  
Robert J. Johnston ◽  
Youn Soo Choi ◽  
Jeffrey A. Diamond ◽  
Jessica A. Yang ◽  
Shane Crotty
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Negative Regulator ◽  
Tfh Cells ◽  
Bcl6 Expression

Follicular helper T cells (TFH cells) constitute the CD4+ T cell subset that is specialized to provide help to germinal center (GC) B cells and, consequently, mediate the development of long-lived humoral immunity. TFH cell differentiation is driven by the transcription factor Bcl6, and recent studies have identified cytokine and cell–cell signals that drive Bcl6 expression. However, although TFH dysregulation is associated with several major autoimmune diseases, the mechanisms underlying the negative regulation of TFH cell differentiation are poorly understood. In this study, we show that STAT5 inhibits TFH cell differentiation and function. Constitutive STAT5 signaling in activated CD4+ T cells selectively blocked TFH cell differentiation and GCs, and IL-2 signaling was a primary inducer of this pathway. Conversely, STAT5-deficient CD4+ T cells (mature STAT5fl/fl CD4+ T cells transduced with a Cre-expressing vector) rapidly up-regulated Bcl6 expression and preferentially differentiated into TFH cells during T cell priming in vivo. STAT5 signaling failed to inhibit TFH cell differentiation in the absence of the transcription factor Blimp-1, a direct repressor of Bcl6 expression and TFH cell differentiation. These results demonstrate that IL-2, STAT5, and Blimp-1 collaborate to negatively regulate TFH cell differentiation.

targetSCAPE and ultraSCAPE: Simultaneous identification and deep profiling of human antigen-specific T cells and other immune cell subsets by mass cytometry.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15204-e15204
Author(s):  
Brian Abel ◽  
Faris Kairi ◽  
Alessandra Nardin ◽  
Evan Newell ◽  
Michael Fehlings
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
T Cell Subsets ◽  
Single Sample ◽  
High Dimensional ◽  
Cell Populations ◽  
Mass Cytometry ◽  
Immune Cell Subsets

e15204 Background: During clinical trial immune monitoring, especially in the field of immunotherapy, it is critical to collect in-depth phenotypic information from multiple immune cell populations in order to assess the biological activity of the immunotherapy, to identify biomarkers of response or disease progression, and/or to identify new drug targets. However, patient samples such as peripheral blood mononuclear cells or tissues, are often scarce and current methods face limitations in either achieving a sufficient depth of analysis and/or cell throughput. Methods: In order to identify therapy-relevant antigens and to facilitate a concurrent in-depth characterization of T cells directed towards these targets, immunoSCAPE leverages the high-dimensional immune profiling capabilities of mass cytometry and a unique methodology allowing the identification and characterization of rare antigen-specific T-cell subsets (targetSCAPE). By implementing a new cutting-edge technology that combines flow and mass cytometry in parallel with a combinatorial live cell barcoding strategy, we further increased the high-dimensional phenotyping capacities to over 100 different marker molecules on up to four different immune cell subsets simultaneously within the same sample. Results: We isolated 4 different immune cell populations from a single sample and combined 3 different phenotypic panels consisting of 35 makers each together with a combinatorial tetramer multiplex and phenotyping panel for deep profiling of myeloid cells, NK cells, B cells and T cells. We demonstrate the potential of this novel immuno-phenotyping method, by tracking virus-specific T cells while simultaneously characterizing 4 immune cell subsets with over 100 distinct phenotypic markers from a single sample, which is currently impossible employing modern flow cytometers or classical mass cytometry methods. Conclusions: With its ability to provide an unprecedented picture of the immune status within a single sample, including T cell specificity information and in-depth profiling of relevant immune cell subsets, ultraSCAPE in combination with targetSCAPE can provide detailed insights on the effects of immunotherapy on the immune cell population. Information learned from in-depth immune phenotyping of several immune cell subsets such as T, B, NK and myeloid cell subsets can be leveraged for the development of novel diagnostics, biomarker discovery and monitoring therapeutic strategies in immunotherapy clinical trials.

scholarly journals Mixed Effects Association of Single Cells Identifies an Expanded Th1-Skewed Cytotoxic Effector CD4+ T Cell Subset in Rheumatoid Arthritis

2017 ◽  
Author(s):  
Chamith Y. Fonseka ◽  
Deepak A. Rao ◽  
Nikola C. Teslovich ◽  
Susan K. Hannes ◽  
Kamil Slowikowsi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Single Cells ◽  
Cell Subset ◽  
Mixed Effects ◽  
Cd4 T Cell ◽  
High Dimensional ◽  
Hla Dr

AbstractHigh dimensional single-cell analyses have dramatically improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging due to technical and inter-individual variation. Here we present Mixed effects modeling of Associations of Single Cells (MASC), a novel reverse single cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounds and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27- HLA-DR+ effector memory cells, in RA patients (OR = 1.7; p = 1.1 × 10−3). The frequency of CD27- HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27- HLA-DR+ cell frequency decreased in RA patients who respond to immunosuppressive therapy. Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained ∼5-fold higher frequencies of CD27- HLA-DR+ cells, which comprised ∼10% of synovial CD4+ T cells. We find that CD27- HLA-DR+ cells are abundant producers of IFN-γ and also express perforin and granzyme A at elevated levels. Thus MASC identified the expansion of a unique Th1 skewed effector T cell population with cytotoxic capacity in RA. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single cell data.One Sentence SummaryMixed-effects regression of single cells identifies a cytotoxic Th1-like CD4+ T cell subset while accounting for inter-individual and technical variation.

CD4 T Cell Subset Profiling in Biliary Atresia Reveals ICOS- Regulatory T Cells as a Favourable Prognostic Factor

2018 ◽  
Author(s):  
Shuhao Zhang ◽  
Shyamal Goswami ◽  
Jiaqiang Ma ◽  
Lu Meng ◽  
Youping Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Prognostic Factor ◽  
Regulatory T Cells ◽  
Biliary Atresia ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
T Cell Subset

773 Adoptive Cell Therapy Response in Melanoma is Mediated by Stem-like CD8 T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A822-A822
Author(s):  
Sri Krishna ◽  
Frank Lowery ◽  
Amy Copeland ◽  
Stephanie Goff ◽  
Grégoire Altan-Bonnet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
High Dimensional ◽  
Tumor Control ◽  
Intrinsic Factors ◽  
Infiltrating Lymphocytes

BackgroundAdoptive T cell therapy (ACT) utilizing ex vivo-expanded autologous tumor infiltrating lymphocytes (TILs) can result in complete regression of human cancers.1 Successful immunotherapy is influenced by several tumor-intrinsic factors.2 3 Recently, T cell-intrinsic factors have been associated with immunotherapy response in murine and human studies.4 5 Analyses of tumor-reactive TILs have concluded that anti-tumor neoantigen-specific TILs are enriched in subsets defined by the expression of PD-1 or CD39.6 7 Thus, there is a lack of consensus regarding the tumor-reactive TIL subset that is directly responsible for successful immunotherapies such as ICB and ACT. In this study, we attempted to define the fitness landscape of TIL-enriched infusion products to specifically understand its phenotypic impact on human immunotherapy responses.MethodsWe compared the phenotypic differences that could distinguish bulk ACT infusion products (I.P.) administered to patients who had complete response to therapy (complete responders, CRs, N = 24) from those whose disease progressed following ACT (non-responders, NRs, N = 30) by high dimensional single cell protein and RNA analysis of the I.P. We further analyzed the phenotypic states of anti-tumor neoantigen specific TILs from patient I.P (N = 26) by flow cytometry and single cell transcriptomics.ResultsWe identified two CD8+ TIL populations associated with clinical outcomes: a memory-progenitor CD39-negative stem-like TIL (CD39-CD69-) in the I.P. associated with complete cancer regression (overall survival, P < 0.0001, HR = 0.217, 95% CI 0.101 to 0.463) and TIL persistence, and a terminally differentiated CD39-positive TIL (CD39+CD69+) population associated with poor TIL persistence post-treatment. Although the majority (>65%) of neoantigen-reactive TILs in both responders and non-responders to ACT were found in the differentiated CD39+ state, CR infusion products also contained a pool of CD39- stem-like neoantigen-specific TILs (median = 8.8%) that was lacking in NR infusion products (median = 23.6%, P = 1.86 x 10-5). Tumor-reactive stem-like T cells were capable of self-renewal, expansion, and persistence, and mediated superior anti-tumor response in vivo.ConclusionsOur results support the hypothesis that responders to ACT received infusion products containing a pool of stem-like neoantigen-specific TILs that are able to undergo prolific expansion, give rise to differentiated subsets, and mediate long-term tumor control and T cell persistence, in line with recent murine ICB studies mediated by TCF+ progenitor T cells.4 5 Our data also suggest that TIL subsets mediating ACT-response (stem-like CD39-) might be distinct from TIL subsets enriched for anti-tumor-reactivity (terminally differentiated CD39+) in human TIL.6 7AcknowledgementsWe thank Don White for curating the melanoma patient cohort, and J. Panopoulos (Flowjo) for helpful discussions on high-dimensional analysis, and NCI Surgery Branch members for helpful insights and suggestions. S. Krishna acknowledges funding support from NCI Director’s Innovation Award from the National Cancer Institute.Trial RegistrationNAEthics ApprovalThe study was approved by NCI’s IRB ethics board.ReferencesGoff SL, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 2016;34:2389–2397.Snyder A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189–2199.McGranahan N, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463–1469.Sade-Feldman M, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 2019;176:404.Miller BC, et al. Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol 2019;20:326–336.Simoni Y, et al. Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018;557:575–579.Gros A, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014;124:2246–2259.

scholarly journals A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Mohamed-Reda Benmebarek ◽  
Bruno L. Cadilha ◽  
Monika Herrmann ◽  
Stefanie Lesch ◽  
Saskia Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Myeloid Leukemia ◽  
Tumor Antigens ◽  
Adoptive T Cell Therapy ◽  
Single Chain ◽  
T Cell Therapy ◽  
Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

272 Use of LioCyx-M, autologous hepatitis B virus (HBV)-Specific T cell receptor (TCR) T-cells, in advanced HBV-related hepatocellular carcinoma (HCC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A297-A297
Author(s):  
Fu-Sheng Wang ◽  
Fanping Meng ◽  
Jiehua Jin ◽  
Yuanyuan Li ◽  
Regina Wanju Wong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
T Cell Receptor ◽  
Dose Level ◽  
Cell Receptor ◽  
Hbv Dna ◽  
B Virus

BackgroundWe have demonstrated the ability of Hepatitis-B-virus (HBV)-specific T cell receptor (TCR) bioengineered T cells to recognize and lyse Hepatocellular carcinoma (HCC) cells expressing HBV antigens derived from HBV-DNA integration in patients with liver transplant.1 LioCyx-M is an immunotherapeutic product composing of autologous T cells transiently modified with in-vitro transcribed mRNA encoding HBV-specific TCR. The transient TCR expression makes LioCyx -M amenable to a dose escalating posology.MethodsThe primary endpoint of this phase 1 trial is to assess the safety and tolerability of LioCyx-M in patients with advanced HBV-HCC without curative treatment options. Eligible patients were diagnosed with Barcelona clinic liver cancer stage B or C HCC (Child-Pugh < 7 points), receiving >1 year antiviral treatment prior to enrollment. These patients had matching HLA class I genotypes which present HBV encoded antigen. Peripheral blood was collected from each patient prior to each dose for LioCyx-M manufacturing. Patients received 4 escalating doses of 1×104 cells/kg, 1×105 cells/kg, 1×106 cells/kg, 5×106 cells/kg bodyweight (BW) in the first treatment cycle, each intravenously administered weekly. Patients underwent 1-month safety assessment post the 4th infusion, according to Common Terminology NCI CTCAE Version 4.0.3. If there were no dose associated toxicities, patients were eligible to continue administration of LioCyx-M at dose of 5 × 106 cells/kg BW weekly. Tumor response per RECIST 1.1 criteria and survival time were assessed.ResultsAt data cutoff (30 April 2020), eight patients were enrolled, with a median age of 53 (range: 49 - 67). These patients received a median number of 6 (range: 4 - 12) infusions of LioCyx-M. 1 patient developed Grade 3 elevations in alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and bilirubin after receiving LioCyx-M at dose level of 1×105 cells/kg BW. Another patient had Grade 1 transient fever after receiving LioCyx-M at dose level 5×106 cells/kg BW in the 4th, 5th and 6th infusions. No treatment-related adverse events (trAEs) such as cytokine release syndrome or neurotoxicity were observed. No fatal trAEs were observed. The median time to progression was 1.9 months (range: 0.2 - 9.5 months). The median overall survival was 34 months (range: 3 - 38.2 months).ConclusionsThe encouraging clinical outcome and tolerable safety highlight the good benefit-risk profile of LioCyx-M. Therefore, further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 proof-of-concept clinical study.AcknowledgementsFunding: Lion TCR.Trial RegistrationNCT03899415Ethics ApprovalThe study was approved by Fifth Medical Center of Chinese PLA General Hospital’s Ethics Board, approval number R2016185DI010.ReferenceTan AT, Yang N, Lee Krishnamoorthy T, et al. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy. Gastroenterology 2019;156(6):1862–1876.e9.

scholarly journals Long-Term Depletion of Naive T Cells in Patients Treated for Hodgkin's Disease

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3662-3672 ◽  
Author(s):  
Nobukazu Watanabe ◽  
Stephen C. De Rosa ◽  
Anthony Cmelak ◽  
Richard Hoppe ◽  
Leonore A. Herzenberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Counts

Abstract We investigated the representation of T cells in patients who had been treated for Hodgkin's disease (HD). We found a marked depletion in both CD4 and CD8 naive T-cell counts that persists up to 30 years after completion of treatment. In contrast, CD4 and CD8 memory T-cell subsets recovered to normal or above normal levels by 5 years posttreatment. Thus, the previously-reported long-term deficit in total CD4 T-cell counts after treatment for HD is due to specific depletion of naive T cells. Similarly, total CD8 T-cell counts return to normal by 5 years only because CD8 memory T cells expand to higher than normal levels. These findings suggest that the treatment (mediastinal irradiation) results in a longterm dysregulation of T-cell subset homeostasis. The profound depletion of naive T cells may explain the altered T-cell function in treated patients, including the poor response to immunization after treatment for HD. Further, in some individuals, we identified expansions of unusual subsets expressing low levels of CD8. Eight-color fluorescence-activated cell sorting analyses showed that these cells largely express CD8αα homodimers and CD57, consistent with the phenotype of potentially extrathymically derived T cells. In addition, these cells, both CD4+ and CD4−, are probably cytotoxic lymphocytes, as they express high levels of intracellular perforin. In adults treated for HD, an increased activity of extrathymic T-cell differentiation may partially compensate for the loss of thymic-derived T cells.

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