scholarly journals T‐cells expressing a chimeric‐PD1‐Dap10‐CD3zeta receptor reduce tumour burden in multiple murine syngeneic models of solid cancer

Immunology ◽  
2020 ◽  
Vol 160 (3) ◽  
pp. 280-294 ◽  
Author(s):  
Geoffrey Parriott ◽  
Kelsey Deal ◽  
Shane Crean ◽  
Elle Richardson ◽  
Emily Nylen ◽  
...  
Keyword(s):  
T Cells ◽  
Solid Cancer ◽  
Tumour Burden

scholarly journals P02.02 Single-cell RNA sequencing of neuroblastoma tumors reveals immunoregulatory interactions as novel targets for immunotherapy

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A8.1-A8
Author(s):  
J Wienke ◽  
WM Kholosy ◽  
LL Visser ◽  
KM Keller ◽  
P Lijnzaad ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Single Cell ◽  
Cell Function ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Gene Set Enrichment Analysis ◽  
Mycn Amplification ◽  
Solid Cancer ◽  
Novel Targets

BackgroundImmunotherapy with CAR-T cells, as well as immune checkpoint blockade, show limited clinical efficacy in the pediatric solid cancer neuroblastoma, despite the success in various adult cancers. The lacking efficacy may be due to various immune evasion strategies employed by neuroblastoma tumors, leading to altered functionality of tumor-infiltrating immune cells. We aimed to provide a comprehensive overview of the composition and function of the neuroblastoma immune environment, as well as relevant immunoregulatory interactions (=), to identify novel targets for immunotherapy.Materials and Methods25 tumor samples from 20 patients (17 with high-risk disease, 6 with MYCN amplification), were collected during diagnostic biopsy pre-treatment (n=10) or during resection surgery after induction chemotherapy (n=15). Samples were enzymatically digested, single-cell FACS sorted and sequenced by Cel-Seq2 protocol.ResultsLymphoid cells in the TME consisted of αβ-, γδ-T cells, NK cells and B cells. Among αβ-T cells we identified CD8+ T cells, two functionally distinct clusters of CD4+ T cells, naive-like T cells and FOXP3+ regulatory T cells (Tregs). CD8+ T cells had reduced cytotoxic capacity compared to blood-derived T cells from a reference group. Tregs expressed high levels of PRDM1, LAYN and ICOS, suggesting an effector Treg profile, which is associated with increased inhibitory capacity. Although NK cells expressed the cytotoxic genes NKG7, KLRF1, GNLY, GZMB and PRF1, their expression was significantly lower than in blood-derived reference NK cells. Gene set enrichment analysis (GSEA) confirmed a reduced cytotoxic capacity of tumoral NK cells, which correlated with a decreased expression of activating receptors (r=0.41, p<0.001) and increased TGFβ signaling (r=-0.45, p<0.001). In addition, NK cells highly expressed the heterodimeric receptor KLRC1:KLRD1, which can inhibit NK cell function through HLA-E binding. High HLA-E expression by endothelial, immune and mesenchymal cells confirmed its inhibitory activity in the TME. Within the myeloid compartment we identified various immunosuppressive populations, comprising a cluster of IL10 and VEGFA expressing macrophages, three clusters of M2 differentiated macrophages expressing MMP9 and LGALS3, and dendritic cells with intact antigen presenting capacity, but high expression of numerous genes encoding immunosuppressive molecules such as IDO1, LGALS1, LGALS2, CCL22 and NECTIN2. In MYCN amplified tumors, specifically, we observed even lower cytotoxic capacity of CD8+ T and NK cells. We identified increased TGFB1 expression and defective antigen presentation by myeloid and tumor cells as potential causes for reduced cytotoxicity in MYCN amplified tumors. To identify relevant targets for immunotherapy we constructed an unbiased interaction network, which revealed NECTIN1=CD96 and MIF=CD74 as active immunoregulatory interactions between tumor and T/NK cells, and CD80/CD86=CTLA4, CLEC2D=KLRB1, HLA-E=KLRC1/KLRC2, CD99=PILRA, LGALS9=HAVCR2, and NECTIN2=TIGIT between myeloid and T/NK cells.ConclusionsCytotoxic lymphocytes in the neuroblastoma TME show reduced cytotoxic capacity, likely due to highly immunosuppressive myeloid cells, Tregs and numerous immunoregulatory interactions, which may serve as novel targets for immunotherapy in neuroblastoma.Disclosure InformationJ. Wienke: None. W.M. Kholosy: None. L.L. Visser: None. K.M. Keller: None. P. Lijnzaad: None. T. Margaritis: None. K.P.S. Langenberg: None. R.R. De Krijger: None. F.C.P. Holstege: None. J.J. Molenaar: None.

scholarly journals Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Hiroshi Katoh ◽  
Masahiko Watanabe
Keyword(s):  
T Cells ◽  
Cancer Progression ◽  
Immune Cell ◽  
Treatment Strategies ◽  
Suppressor Cells ◽  
Response To Treatment ◽  
Solid Cancer ◽  
Myeloid Derived Suppressor Cells ◽  
Immune Cell Population ◽  
Novel Treatment Strategies

Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs). Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.

Tetrahydrouridine-decitabine for non-cytotoxic epigenetic therapy of NSCLC to enhance immunotherapeutic effect of anti-PD1 in vivo.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11552-11552 ◽  
Author(s):  
Kai Kang ◽  
David S. Schrump ◽  
Anish Thomas ◽  
Kurt Alex Schalper ◽  
Yogen Saunthararajah ◽  
...  
Keyword(s):  
T Cells ◽  
Median Survival ◽  
Dna Methyltransferase ◽  
Cytidine Deaminase ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Memory ◽  
Epigenetic Therapy ◽  
Solid Cancer ◽  
Immune Recognition

11552 Background: NSCLC response to anti-PD1 therapy is ~20%, largely because most NSCLC avoids immune-recognition in the 1stplace, e.g., by epigenetics to suppress neo-antigen expression. DNA methyltransferase (DNMT1) mediates this repression and is depleted by decitabine (Dec). Unfortunately Dec has trivial distribution into solid cancer tissues because of rapid deamination by cytidine deaminase (CDA). Therefore, to improve tissue-distribution of Dec with the low Cmax/long Tmax profile needed for DNMT1-depletion without cytotoxicity, we combined Dec with a CDA inhibitor tetrahydrouridine (THU). Methods: C57/BL6 mice were inoculated with LL3-luc cells via tail vein. After documentation of lung invasion by live-imaging, mice (n = 5/group) were randomized to PBS, THU-Dec (10/0.1 mg/kg sc 3×/wk), anti-PD1 (5 mg/kg ip q5d, DX400 from Merck) or THU-Dec/anti-PD1 combination. Antigen presentation, PD, MDSCs, and T-cells were measured in blood and tumor. Results: THU-Dec or anti-PD1 alone decreased tumor by imaging and increased survival, however, THU-Dec/anti-PD1 combination extended median survival the most and completely regressed tumor in 2/5 mice (median survival days PBS 37, THU-Dec 56, anti-PD1 62, THU-Dec/anti-PD1 77). Rechallenge of cured mice with LL2-luc confirmed immune-memory effect, with no engraftment vs expected engraftment in controls. Consistent with the pharmacologic rationale, THU-Dec produced > 2-fold more DNMT1-depletion in tumor vs PBS. Consistent with non-cytotoxic effect, absolute lymphocyte counts were preserved with THU-Dec, while numbers of G-MDSC decreased (2.9 k/µL PBS vs 0.3 k/µL THU-Dec/anti-PD1, p < 0.01). Expression of neoantigens MAGE-A1 and MAGE-A3 increased > 4-fold with THU-Dec vs PBS (p < 0.01). THU-Dec/anti-PD1 increased tumor infiltrating lymphocytes 6-fold vs PBS (p < 0.01) and decreased regulatory T-cells 2.5-fold vs PBS (p < 0.01). IFNγ expression in tumor increased 2.4-fold with THU-Dec/anti-PD1 vs PBS (p < 0.01). Conclusions: THU-Dec/anti-PD1 produced marked survival improvements and cures in tumor-bearing mice, scientific validation of our clinical trial NCT02664181 combining THU-Dec/nivolumab in 2nd line for NSCLC.

scholarly journals 959 Safety and anti-tumor activity of TCR-engineered autologous, PRAME-directed T cells across multiple advanced solid cancers at low doses – clinical update on the ACTengine® IMA203 trial

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A1009-A1009
Author(s):  
Martin Wermke ◽  
Apostolia-Maria Tsimberidou ◽  
Ali Mohamed ◽  
Andrea Mayer-Mokler ◽  
Arun Satelli ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Patients ◽  
Adoptive Cell Therapy ◽  
Primary Objective ◽  
Immunological Methods ◽  
Solid Cancer ◽  
Median Dose ◽  
Human Dose ◽  
Dose Levels ◽  
Anti Tumor Activity

BackgroundAdoptive cell therapy demonstrated significant clinical benefit in patients with hematological malignancies but results in most solid tumors have been less encouraging so far.In the IMA203 trial we are treating advanced solid cancer patients utilizing TCR-engineered T cells (TCR-T) directed against an HLA-A*02-restricted peptide derived from the highly prevalent cancer testis antigen PRAME. This target was selected due to homogenous expression and exceptionally high target peptide density per tumor cell (assessed by quantitative mass spectrometry), two features we hypothesize to be critical determinants of anti-tumor activity in TCR-T trials.MethodsThis ongoing first-in-human, dose escalation, multi-indication trial enrolls HLA-A*02:01- and PRAME-positive recurrent and/or refractory solid cancer patients, who failed all available standard treatments. Eligible patients undergo leukapheresis and an autologous TCR-T product is manufactured. After lymphodepletion with fludarabine and cyclophosphamide, T cells are infused, followed by low-dose IL-2. The primary objective of the trial is to assess the safety and tolerability of IMA203. Secondary objectives are to evaluate the anti-tumor activity and pharmacodynamics using molecular and immunological methods.ResultsAs of August 15, 2021, 16 heavily pre-treated patients received IMA203 T cells across multiple escalating dose levels (DL). Absolute IMA203 doses infused ranged from 0.08 to 0.81x109 transduced CD8 T cells per patient, which to our knowledge did not lead to anti-tumor responses in other TCR-T trials. Treatment-emergent adverse events after IMA203 infusion were transient and manageable. Most common events were expected cytopenias (G1-4), CRS and ICANS (both G1-2) and 1 DLT in DL2 (reported earlier). All evaluable patients (N=12) achieved disease control (i.e. best overall response: stable disease [SD] or partial response [PR]) and 6 patients demonstrated PRs according to RECIST1.1 with 2 of these PRs being confirmed. While all 3 patients treated at DL1 (median dose: 0.11x109) experienced SD, a PR was observed in 6/9 patients treated beyond DL1 (median dose: 0.30x109). Responses were seen in patients with synovial sarcoma (N=3), malignant melanoma (N=2) and head and neck cancer (N=1). Robust engraftment of T cells was observed in all patients and tumor infiltration by TCR-modified T cells was demonstrated in patients with evaluable on-treatment biopsies.ConclusionsTo our knowledge IMA203 is the first TCR-T product candidate that induced frequent tumor responses across multiple solid cancers using transduced T cells at doses below 1 billion and has a manageable safety profile. The next step is to assess response rates at higher dose levels and durability of responses.Trial RegistrationNCT03686124Ethics ApprovalThe study was approved by the institutional review board/ethics committee as required for each participating site.

scholarly journals Parthanatos-inducing zinc agent C010DS-Zn elicits anti-tumor immune responses involving T cells and macrophages in vivo

2021 ◽  
Author(s):  
Jinhyuk F Chung ◽  
Zhisheng Her ◽  
Wai Mun Kong ◽  
Qingfeng Chen
Keyword(s):  
T Cells ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Solid Cancer ◽  
Dna Damages ◽  
Complex Agent ◽  
Cancer Models ◽  
Low Passage

Immune checkpoint inhibitors opened a new horizon in cancer therapy by enabling durable and complete responses in patients, but their wider application against general solid cancers has been hampered by the lack of a broadly acting anti-cancer immune response initiating agents. Parthanatos is a previously unexplored immunogenic programmed necrosis mechanism that is triggered by the hyperactivation of PARP DNA repair and executed by an efficient DNA-fragmentation mechanism. We developed a proprietary macromolecular zinc complex agent C010DS-Zn that efficiently induced parthanatos against 4T1 murine cancer cells in vitro, which was characterized as PARP-mediated necrotic death with massive DNA damages. Ex vivo screening of its cytotoxicity against a panel of 53 low-passage human solid cancer PDX tumor fragments demonstrated its consistent delivery of characteristically DNA-damaging cell death that was unseen in the corresponding apoptosis positive controls. Further characterization of its in vivo treatment effects versus the immunosuppressive 4T1-Balb/c and immunogenic CT26-Balb/c syngeneic cancer models showed that sufficiently high intravenous C010DS-Zn treatments led to robust initiation of the tumor-suppressed antitumor immune compartments such as T cells and macrophages. At lower non-anticancer doses, C010DS-Zn treatment still led to significantly reduced macrophage content and inflammation in the 4T1 tumor, suggesting its potential utility against macrophage-mediated inflammations such as those seen in MAS or COVID19. Given the observation of its low serum bioavailability in a rat pharmacokinetic study, these results suggest potential development opportunities for C010DS-Zn to become a widely applicable immune initiation agent with chemo-like broad applicability upon its pharmacokinetic improvements.

597 In situ vaccination with oncolytic vesicular stomatitis virus improves anti-tumor immune response and outcome in bladder cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A632-A632
Author(s):  
Coby Rangsitratkul ◽  
Christine Lawson ◽  
Lee-Hwa Tai
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Cell Lines ◽  
Vesicular Stomatitis Virus ◽  
Cd8 T Cells ◽  
Solid Cancer ◽  
Bcg Therapy ◽  
Vesicular Stomatitis ◽  
Human Immune ◽  
Bladder Sparing

BackgroundThe majority of nonmuscle invasive bladder cancer (NMIBC) cases progress towards muscle invasive disease. Transurethral resection followed by chemotherapy and/or BCG immunotherapy can stall progression in the minority of NMIBC cases. Cystectomy prior to muscle invasion provides the best option for survival. However, bladder removal significantly affects morbidity and quality of life. There are no effective treatment options for patients with chemo/BCG-resistant and late stage disease. Compared to other solid cancer types, the urinary bladder is an ideal organ to evaluate oncolytic virotherapies due to the urgent medical need for alternative bladder-sparing therapies and its established immunosensitivity to BCG therapy. The current study will determine whether a novel oncolytic Vesicular Stomatitis Virus (VSVd51) containing human immune transgenes can treat NMIBC.MethodsA novel recombinant OV containing a human immune transgene was rescued on the VSVd51 backbone. Features of immunogenic cell death (ICD) on mouse and human bladder cancer cell lines were measured by microscopy, flow cytometry, immunoblot, luminometry, qRT-PCR and ELISA following infection by recombinant VSVd51. The mediating role of immune effector cells was evaluated through pharmacologic in vivo depletion, while combination injection of recombinant VSVd51 following BCG failure was performed in the C57Bl/6-MB49 model. Measurements of ICD was additionally carried out in human BC spheroids and bladder cancer patient tissue following recombinant VSVd51 infection ex vivo.ResultsRecombinant VSVd51 liberated danger signals (calreticulin, HMGB1, ATP) and immunogenic cytokines/chemokines were detected from infected mouse and human BC cell lines. Intravesical instillation of recombinant VSVd51 promoted enhanced activation of systemic and bladder infiltrating natural killer (NK) and cytotoxic CD8+ T cells. The increased functionality of NK and CD8+ T cells was associated with improved survival as determined through depletion studies. Moreover, improved survival and reduced bladder tumor volume was observed in recombinant VSVd51 treated mice who failed BCG therapy. In parallel, VSVd51-induced inflammation of the tumor microenvironment was recapitulated in human BC cell lines, spheroids and patient tissue exposed to recombinant VSVd51 infection.ConclusionsThese translational results suggest that a recombinant VSVd51 is a promising immunotherapy that could provide a bladder-sparing therapeutic benefit in individuals diagnosed with NMIBC each year.Ethics ApprovalThe study was approved by the CIUSSS de l’Estrie CHUS Ethics Board, approval number 2018-2465.

Mutation burden as a biomarker of response to immune checkpoint therapy in nine solid cancers.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 35-35 ◽  
Author(s):  
Shridar Ganesan ◽  
Gyan Bhanot ◽  
Janice M. Mehnert ◽  
Ann W. Silk ◽  
Jeffrey S. Ross ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Immune Checkpoint ◽  
Solid Cancer ◽  
Cancer Type ◽  
Her2 Breast Cancer ◽  
Mutation Burden ◽  
Gene Expression Signatures ◽  
Cancer Types

35 Background: A high mutation burden a biomarker of response to immune checkpoint therapy in melanoma, non-small cell lung cancer, and colorectal cancer. It is unknown whether mutation burden is predictive of response in other cancer types, and whether it is identifiable using available clinical assays. Methods: Using data for 10,745 tumors from 33 solid cancer types in TCGA, we looked for a mutation burden threshold (iCAM) in each cancer type associated with gene expression signatures of a blocked immune response of robust CD8+T cell response and up-regulation of immune checkpoint genes. Results: A unique iCAM threshold was identified in nine cancers: melanoma and lung, colon, endometrial, and gastric adenocarcinoma; serous ovarian, bladder urothelial, cervical, and ER+ HER2− breast cancer. iCAM thresholds applied to published clinical data for patients treated with immune checkpoint therapy showed that iCAM+ patients had significantly better response. iCAM+ tumors can be identified from clinical-grade NGS assays with high accuracy . In a prospective melanoma cohort of patients treated with anti- PD-1 patients with iCAM+ tumors had significantly better objective response rates, progression free survival, and overall survival compared patients to iCAM− tumors. Pattern of somatic mutations were different in iCAM+ and iCAM− tumors, suggesting different mechanism of carcinogenesis in iCAM+ versus iCAM− tumors. Higher fractions of leukocytes were NK (Natural Killer) cells and macrophages were M1 polarized, and a lower fraction of T cells were regulatory T cells in iCAM+ tumors compared to iCAM− tumors. Over 75% of the genes significantly up-regulated in iCAM+ tumors in every cancer types were in the immune response pathway, confirming immune response to be the main differentiator in iCAM+ veruss iCAM− tumors. Conclusions: In nine cancer types, a clinically useful mutation burden threshold (iCAM) associated with gene expression signatures of blocked immune response can identify likely responders to immune checkpoint therapy, and iCAM status is identifiable using currently available clinical NGS assays.

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