316 EVICTION Study: Preliminary results in solid tumor patients with ICT01, a first-in-class, gamma9 delta2 T cell activating antibody targeting butyrophilin-3A

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A342-A342
Author(s):  
Aurelien Marabelle ◽  
Christiane Jungels ◽  
Johann De Bono ◽  
Norbert Vey ◽  
Martin Wermke ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activity ◽  
Ethics Committee ◽  
Preliminary Results ◽  
Link Type ◽  
Tumor Biopsies

BackgroundGamma9 Delta2 (γ9δ2) T cells are an important component of the innate anti-tumor immune response whose infiltration into solid tumors has been associated with a positive prognosis, making γ9δ2 T cells an attractive target for the next generation of cancer immunotherapy. Butyrophilins (BTNs) are a family of immune checkpoint molecules that regulate γ9δ2 T cell activity, including BTN3A that is a potent endogenous activator of γ9δ2 T cells following phosphoantigen (pAg) binding to the intracellular domain of BTN3A1. This observation led to the design and development of ICT01, a humanized, monoclonal antibody that binds all 3 isoforms of BTN3A1/A2/A3 and induces pAg-independent γ9δ2 T cell activation, for the treatment of patients with solid or hematologic tumors.MethodsEVICTION (www. clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31) is a first-in-human, two-part, open-label, clinical study to assess the safety, tolerability and activity of intravenous doses of ICT01 as monotherapy and in combination with pembrolizumab, in patients with advanced-stage, relapsed/refractory cancer. Following Competent Authority and Ethics Committee approvals, the study is being conducted at cancer centers in France, Belgium, Spain, Germany, and the UK. Patients provide signed informed consent prior to screening. Eligible patients receive ICT01 (Range: 20 µg to 200 mg) every 3 weeks with blood samples collected at multiple timepoints for immunophenotyping and cytokine analysis (IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13, TNFα). Tumor biopsies are collected at baseline and Day 28 and stained by immunohistochemistry for BTN3A, γ9δ2 T cells and other markers of anti-tumor immunity.ResultsCohort 1 comprising 6 patients with solid tumors (3 Colorectal, 1 Pancreatic, 1 Ovarian, 1 Melanoma) has been enrolled and treated with ICT01 doses ranging from 20 to 700 µg. No dose-limiting toxicities or related SAEs have been reported. Target occupancy on T cells at 4 hours post first dose was 10% at 70 µg (n=1), 31% at 200 µg (n=2) and 34% at 700 µg (n=2), which was reflected at 24 hours post dose by a 73%, 91% and 97% decrease from baseline in the number of circulating γ9δ2 T cells, respectively. On Day 7, γ9δ2 T cells remained decreased by 37%, 75% and 76%, respectively. There were no effects on CD4 or CD8 T cells, NK cells, or B cells. Transient increases in IFNγ, secreted by activated γ9δ2 T cells, were observed in 4/6 patients. No cytokine release syndrome was observed. Data from the paired tumor biopsies are still being generated and will be presented.ConclusionsThe preliminary results demonstrate that ICT01 has the potential to safely activate the innate anti-tumor potential of γ9δ2 T cells through BTN3A.Acknowledgements.Trial Registrationwww.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31Ethics ApprovalThis study was approved by the following Ethics Committees: COMITE DE PROTECTION DES PERSONNES, Sud-Méditerranée V (Gustave Roussy, IPC), Comité d’Ethique Institut Jules Bordet, COMITÉ DE ÉTICA DE INVESTIGACIÓN CLÍNICA CON MEDICAMENTOS del Hospital Universitari Vall d’Hebron, Ethikkommission an der TU Dresden, HRA London-Surrey Borders Research Ethics Committee.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

scholarly journals 368 Consistent pattern of immune activation induced by oncolytic adenovirus ONCOS-102 across diverse types of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A396-A396
Author(s):  
Lukasz Kuryk ◽  
Anne-Sophie Moller ◽  
Sandeep Kumar ◽  
Alexander Shoushtari ◽  
Luis Paz Ares ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Clinical Importance ◽  
Oncolytic Adenovirus ◽  
Link Type ◽  
Tumor Types

BackgroundSolid tumors exhibit highly variable compositions of immune infiltrates. Therapeutic compounds driving uniform remodeling of tumor microenvironment (TME) across tumor types may improve the efficacy of cancer immunotherapy. ONCOS-102, a granulocyte-macrophage colony stimulating factor (GM-CSF)-expressing oncolytic adenovirus (Ad5/3-D24-GMCSF), was tested for its safety, therapeutic efficacy and capacity to remodel TME in recently completed phase I/II clinical studies in anti-PD-1 refractory melanoma (NCT03003676) and malignant pleural mesothelioma (MPM) (NCT02879669).MethodsBiopsies were obtained from tumor lesions of patients treated with intra-tumoral injections of ONCOS-102 in combination with chemotherapy or pembrolizumab for MPM and melanoma, respectively. Tumor immune infiltrates were analyzed by immunohistology using several antibody panels. On-treatment biopsies were compared to paired baseline samples as wells as to samples from control patients treated with chemotherapy alone in the case of MPM. Gene expression data obtained by next generation RNA sequencing were used to complement the immunohistology analysis and all results were correlated to clinical outcomes.ResultsComparative TME analysis of anti-PD-1 refractory melanoma and MPM tumors revealed noticeably lower baseline T-cell infiltration in mesothelioma. Thus, fractions of CD8+ T-cells were significantly below 10% in 80% of MPM biopsies while approaching or exceeding this level in 60% of melanoma baseline samples. Comparison of tumor biopsies obtained at baseline or on-treatment, demonstrated increased infiltration by both CD4+ and CD8+ T-cells in large proportions of melanoma (CD4+: 13/20 (65%); CD8+: 16/19 (84%) and MPM (CD4+: 10/15 (67%); CD8+: 9/15 (60%) tumor lesions in response to ONCOS-102. Frequencies of cytotoxic T-cells with high granzyme-B expression also increased in response to the treatment in both tumor types, in particular when assessed as percentage of total CD8+ T-cells. Other observed changes induced by ONCOS-102 in samples taken from CR, PR and SD patients with MPM or melanoma included increased CD8/Treg ratio and modulation of PD-L1 expression. Biological and clinical importance of these findings was further supported by correlation between modulation of several subsets of genes related to the process of T-cell activation, such as cytotoxic granule components and co-stimulatory molecules, and clinical response to ONCOS-102 in melanoma and both tumor response and overall survival in MPM patients.ConclusionsONCOS-102 drives pro-inflammatory modulation of immune TME across tumor types of different origins, anatomical locations and immunological baseline characteristics. Our data support potential of ONCOS-102 to serve as a potent immune sensitizing agent in combination therapies with various classes of immunomodulatory compounds and chemotherapy.

scholarly journals 412 First-in-human phase I/IIa trial to evaluate the safety and initial clinical activity of DuoBody®-PD-L1×4–1BB (GEN1046) in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A437-A437
Author(s):  
Elena Garralda ◽  
Ravit Geva ◽  
Eytan Ben-Ami ◽  
Corinne Maurice-Dror ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
Informed Consent ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Dose Levels

BackgroundAgonistic 4-1BB monoclonal antibodies were preclinically validated as promising cancer immunotherapies, both as monotherapy and as potentiators of the activity of PD-(L)1–blocking agents. However, toxicity and a narrow therapeutic window have hampered their clinical development. DuoBody-PD­-L1×4-1BB, a first-in-class, bispecific, next-generation checkpoint immunotherapy, was designed to overcome these limitations by activating T cells through conditional 4-1BB costimulation, while simultaneously blocking the PD-L1 axis. We present preliminary data from the ongoing, first-in-human, open-label, phase I/IIa trial of DuoBody-PD-L1×4-1BB in advanced solid tumors (NCT03917381).MethodsDuring dose escalation, patients with metastatic or unresectable solid tumors not eligible for standard therapy received flat-dose DuoBody-PD-L1×4-1BB (25–1200 mg) intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Secondary endpoints included pharmacokinetic parameters and antitumor activity (RECIST 1.1). Pharmacodynamic biomarkers and antitumor activity (iRECIST) were assessed as exploratory endpoints.ResultsAs of June 22, 2020, 61 patients were enrolled (median age: 59 years). The most common cancer types were colorectal (19.7%), ovarian (14.8%), pancreatic (9.8%), and NSCLC (9.8%). Patients had previously received a median (range) of 3 (1–11) treatments; 44.2% had prior anti-PD-(L)1 immunotherapy. Patients received a median (range) of 4 (1–15) treatment cycles; Cmax was observed shortly after the end of infusion (mean T½: 2.3–10.3 days). Maximum tolerated dose was not reached; 6 patients experienced DLTs. The most common (=10%) treatment-related AEs (all grades; grades 3–4) were transaminase elevation (24.6%; 9.8%), hypothyroidism (16.4%; 1.6%), and fatigue (13.1%; 1.6%). Treatment-related grade-3 transaminase elevations decreased upon corticosteroid administration; no treatment-related bilirubin increases or grade-4 transaminase elevations occurred. Disease control, including stable disease at first assessment and partial responses in triple-negative breast cancer, ovarian cancer, and immune checkpoint inhibitor (ICI)–pretreated NSCLC, occurred in 40/61 patients (65.6%). Pharmacologic activity, as measured by modulation of adaptive immunity mediators, was observed across a broad range of dose levels. Peripheral proliferating (Ki67+) CD8+ effector memory T cells and serum interferon-gamma levels showed maximum induction relative to baseline (p=0.01) 8 days following treatment.ConclusionsDuoBody-PD-L1×4-1BB demonstrated biologic activity and a manageable safety profile. Encouraging early clinical activity across different dose levels was observed in a heavily pretreated population with advanced solid tumors, including those resistant to prior immunotherapy or typically less sensitive to ICIs. Expansion cohorts of patients for whom DuoBody-PD-L1×4-1BB treatment could be relevant and biologically sound have started enrollment. Updated data will be presented.AcknowledgementsThe authors thank Manish Gupta, Lei Pang, and Thomas Breuer at Genmab A/S; Alice Bexon, Alexander Muik, and Friederike Gieseke at BioNTech SE; and Zuzana Jirakova (formerly at BioNTech SE) for their valuable contributions. This trial was funded by Genmab A/S and BioNTech SE.Trial RegistrationClinicalTrials. gov; trial number: NCT03917381Ethics ApprovalThis trial is undertaken following full approval of the final protocol, amendments, informed consent form, applicable recruiting materials, and subject compensation programs by the Independent Ethics Committee/Institutional Review Board.ConsentWritten informed consent, in accordance with principles that originated in the Declaration of Helsinki 2013, current ICH guidelines including ICH-GCP E6(R2), applicable regulatory requirements, and sponsor policy, was provided by the patients.

scholarly journals P07.02 Regulation of CD19 CAR T- cell activation based on engineered Nuclear factor of activated T cells artificial transcription factors

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A23-A23
Author(s):  
D Lainšček ◽  
V Mikolič ◽  
Š Malenšek ◽  
A Verbič ◽  
R Jerala
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Activity ◽  
External Control ◽  
Car T Cells ◽  
Car T Cell ◽  
Artificial Transcription Factors ◽  
Car T

BackgroundCD19 CAR T- cells (Chimeric antigen receptor T cells that recognize CD19) present a therapeutic option for various malignant diseases based on their ability to specifically recognize the selected tumour surface markers, triggering immune cell activation and cytokine production that results in killing cancerous cell expressing specific surface markers recognized by the CAR. The main therapeutic effect of CAR is a specific T cell activation of adequate cell number with sequential destruction of tumorous cells in a safe therapeutic manner. In order to increase T cell activation, different activation domains were introduced into CAR. CAR T-cells are highly efficient in tumour cell destruction, but may cause serious side effects that can also result in patient death so their activity needs to be carefully controlled.1 Several attempts were made to influence the CAR T cell proliferation and their activation by adding T cell growth factors, such as IL-2, into patients, however this approach of increasing the number of activating T cells with no external control over their number can again lead to non-optimal therapeutic effects. Different improvements were made by designing synthetic receptors or small molecule-inducible systems etc., which influence regulated expansion and survival of CAR T cells.2Material and MethodsIn order to regulate CD19 CAR-T cell activity, different NFAT2 based artificial transcription factors were prepared. The full length NFAT2, one of the main players in T cell IL2 production, a key cytokine for T cell activation and proliferation was truncated by deletion of its own activation domain. Next, we joined via Gibson assembly tNFAT21-593 coding sequence with domains of different heterodimerization systems that interact upon adding the inductor of heterodimerization. The interaction counterparts were fused to a strong tripartite transcriptional activator domain VPR and/or strong repressor domain KRAB resulting in formation of an engineered NFAT artificial transcription (NFAT-TF) factors with external control. To determine the activity of NFAT-TF HEK293, Jurkat or human T cells were used.ResultsBased on luciferase assay, carried out on NFAT-TF transfected HEK293 cells we first established that upon adding the external inductor of heterodimerization, efficient gene regulation occurs, according to VPR or KRAB domain appropriate functions. Findings were then transferred to Jurkat cells that were electroporated with appropriate DNA constructs, coding for NFAT-TF and CD19 CAR. After Raji:Jurkat co-culture ELISA measurements revealed that IL2 production and therefore CD19 CAR-T cell activity can be controlled by the action of NFAT-TF. The same regulation over the activity and subsequent proliferation status was also observed in retrovirally transduced human T-cells.ConclusionWe developed a regulatory system for therapeutic effect of CD19 CAR-T cells, a unique mechanism to control T cell activation and proliferation based on the engineered NFAT2 artificial transcription factor.ReferencesBonifant CL, et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 2016;3:16011.Wu C-Y, et al. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 2015;80:350.Disclosure InformationD. Lainšček: None. V. Mikolič: None. Š. Malenšek: None. A. Verbič: None. R. Jerala: None.

scholarly journals 665 Transcriptional landscape of tumor-reactive TIL in lung cancer and melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A693-A693
Author(s):  
Jiajia Zhang ◽  
Justina Caushi ◽  
Boyang Zhang ◽  
Zhicheng Ji ◽  
Taibo Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
Informed Consent ◽  
T Cell ◽  
Cancer Center ◽  
Lung Cancers ◽  
Functional Assays ◽  
Link Type ◽  
Institutional Review

BackgroundMelanoma and lung cancers have two of the highest response rates to immune checkpoint inhibitors (ICIs).1 However, patients may respond unpredictably, partly due to heterogeneity in the quantity and quality of tumor-specific T cells. In this study, we performed an integrated transcriptomic analysis of anti-tumor CD8+ TIL from non-small cell lung cancer (NSCLC) and melanoma. Our goal was to study the global transcriptomic landscape of tumor-specific T cells and to compare their functional programming in lung cancer vs. melanoma.MethodsTIL from 19 patients (15 NSCLC and 3 melanoma) were sequenced using combined single-cell (sc) RNA-seq/TCR-seq. All NSCLC patients received neoadjuvant anti-PD-1 (nivolumab, NCT02259621) whereas melanoma patients received a personal neoantigen vaccine (NCT01970358). Neoantigen-, tumor-associated antigen-, and viral-specific CD8+ T cell clonotypes were identified using functional assays and were validated by TCR cloning as previously described.2 3 Transcriptional profiles of antigen-specific T cells were identified using the TCRβ CDR3 as a barcode to link with the antigen specificity output from the functional assays. The prevalence, phenotype, and differentiation trajectory of tumor-specific T cells were compared between the two cancer types.ResultsA total of 175,826 CD8+ TIL were analyzed, of which 30,174 single cells were from the melanoma cohort and 145,652 were from the NSCLC cohort. Tumor-specific T cells were detected at variable frequencies among CD8+ TIL (median=1.2%, range 0.01%–35.8%) across nine patients, with melanoma having more clonal tumor-specific T cells as compared to NSCLC. CD8+ TIL from melanoma were more enriched in an activated tissue resident T cell (TRM) cluster characterized by upregulated expression of CXCL13, CRTAM, 4-1BB, XCL1/2, and FABP5, whereas those from NSCLC have a greater representation of a cytotoxic TRM cluster with an exhaustion signature (coexpression of GZMB, GZMH, PDCD1, and CTLA4). Distinct from EBV-specific T cells and flu-specific T cells, tumor-specific T cells primarily resided in TRM clusters in both cancers. More MANA-specific TIL from melanoma presented with an effector phenotype and were more proliferative as compared to those from NSCLC. To reveal the differentiation trajectory and regulatory programs of tumor-specific T cells upon tumor recognition and association with response to ICIs, pseudotime/velocity analysis of tumor-specific TIL is underway.ConclusionsThis is the first analysis to inform on the global transcriptomic landscape of tumor-specific CD8+ TIL in lung cancer and melanoma at single cell resolution. This provides a useful framework to study the underlying mechanisms of T cell exhaustion and dysfunction in human cancer.Trial RegistrationNCT02259621,NCT01970358ReferencesYarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. The New England Journal of Medicine 2017;377(25):2500.Caushi JX, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 2021;1–7.Oliveira G, et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature 2021;1–7.Ethics ApprovalThe melanoma clinical trial was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board (IRB) (NCT01970358). The NSCLC clinical trial was approved by the Institutional Review Boards (IRB) at Johns Hopkins University (JHU) and Memorial Sloan Kettering Cancer Center (NCT02259621). All participants gave informed consent before taking part.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

scholarly journals Double Strike Approach for Tumor Attack: Engineering T Cells Using a CD40L:CD28 Chimeric Co-Stimulatory Switch Protein for Enhanced Tumor Targeting in Adoptive Cell Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Luis Felipe Olguín-Contreras ◽  
Anna N. Mendler ◽  
Grzegorz Popowicz ◽  
Bin Hu ◽  
Elfriede Noessner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Adoptive Cell Therapy ◽  
Tumor Rejection ◽  
Target Cells ◽  
Type I

Activation of co-stimulatory pathways in cytotoxic T lymphocytes expressing chimeric antigen receptors (CARs) have proven to boost effector activity, tumor rejection and long-term T cell persistence. When using antigen-specific T cell receptors (TCR) instead of CARs, the lack of co-stimulatory signals hampers robust antitumoral response, hence limiting clinical efficacy. In solid tumors, tumor stroma poses an additional hurdle through hindrance of infiltration and active inhibition. Our project aimed at generating chimeric co-stimulatory switch proteins (CSP) consisting of intracellular co-stimulatory domains (ICD) fused to extracellular protein domains (ECD) for which ligands are expressed in solid tumors. The ECD of CD40L was selected for combination with the ICD from the CD28 protein. With this approach, it was expected to not only provide co-stimulation and strengthen the TCR signaling, but also, through the CD40L ECD, facilitate the activation of tumor-resident antigen-presenting cells (APCs), modulate activation of tumor endothelium and induce TCR-MHC independent apoptotic effect on tumor cells. Since CD28 and CD40L belong to different classes of transmembrane proteins (type I and type II, respectively), creating a chimeric protein presented a structural and functional challenge. We present solutions to this challenge describing different CSP formats that were successfully expressed in human T cells along with an antigen-specific TCR. The level of surface expression of the CSPs depended on their distinct design and the state of T cell activation. In particular, CSPs were upregulated by TCR stimulation and downregulated following interaction with CD40 on target cells. Ligation of the CSP in the context of TCR-stimulation modulated intracellular signaling cascades and led to improved TCR-induced cytokine secretion and cytotoxicity. Moreover, the CD40L ECD exhibited activity as evidenced by effective maturation and activation of B cells and DCs. CD40L:CD28 CSPs are a new type of switch proteins designed to exert dual beneficial antitumor effect by acting directly on the gene-modified T cells and simultaneously on tumor cells and tumor-supporting cells of the TME. The observed effects suggest that they constitute a promising tool to be included in the engineering process of T cells to endow them with complementary features for improved performance in the tumor milieu.

scholarly journals Physiological strength electric fields modulate human T cell activation and polarisation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Christina E. Arnold ◽  
Ann M. Rajnicek ◽  
Joseph I. Hoare ◽  
Swechha Mainali Pokharel ◽  
Colin D. Mccaig ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Electric Fields ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Activity ◽  
Research Area ◽  
Functional Changes ◽  
Cell Functions ◽  
Human T Cell

AbstractThe factors and signals driving T cell activation and polarisation during immune responses have been studied mainly at the level of cells and chemical mediators. Here we describe a physical driver of these processes in the form of physiological-strength electric fields (EFs). EFs are generated at sites where epithelium is disrupted (e.g. wounded skin/bronchial epithelia) and where T cells frequently are present. Using live-cell imaging, we show human primary T cells migrate directionally to the cathode in low strength (50/150 mV/mm) EFs. Strikingly, we show for the first time that EFs significantly downregulate T cell activation following stimulation with antigen-activated APCs or anti-CD3/CD28 antibodies, as demonstrated by decreased IL-2 secretion and proliferation. These EF-induced functional changes were accompanied by a significant dampening of CD4+ T cell polarisation. Expression of critical markers of the Th17 lineage, RORγt and IL-17, and the Th17 polarisation mediator phospho-STAT3 were reduced significantly, while STAT1, ERK and c-Jun phosphorylation were comparatively unaffected suggesting STAT3 modulation by EFs as one mechanism driving effects. Overall, we identify electrical signals as important contributors to the co-ordination and regulation of human T cell functions, paving the way for a new research area into effects of naturally occurring and clinically-applied EFs in conditions where control of T cell activity is paramount.

scholarly journals Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions

2020 ◽  
Vol 21 (17) ◽  
pp. 6118 ◽  
Author(s):  
Marianna Szczypka
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Splice Variants ◽  
Cell Activity ◽  
Cell Functions ◽  
Simultaneous Inhibition ◽  
And Function

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP—a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

Novel HPV-E7 immune modulators to activate HPV-specific T cells to eliminate cervical cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18027-e18027
Author(s):  
Lihua Shi ◽  
Di Zhang ◽  
Susan Tam ◽  
Man-Cheong Fung
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cell Activity ◽  
Epitope Peptide ◽  
Hpv E7

e18027 Background: Human papilloma virus (HPV) infection can lead to several types of cancers in both men and women. HPV+ tumor cells constitutively express the HPV-E7 antigen which can act as an oncogene to promote tumor growth and malignant transformation. Here, we report the application of novel Tavo Immune Modulator (TIM) biologics molecules which are consisted of a pMHC complex with an epitope peptide derived from HPV-E7 and co-stimulatory modulators of T cell activity. The HPV-E7 TIM molecules can specifically recognize and activate HPV-E7-specific T cells for the elimination of HPV affected cells. Methods: HPV-E7 TIM molecules were engineered as fusion molecules with HLA-A*02:01 MHC complexed with an HPV-E7 (11-20) epitope peptide at the N-termini, and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with HPV-E7 specific T cells was confirmed by immunostaining and flow cytometry. The activation and expansion of antigen specific CD8+ T cells were elucidated in T cell activation and recall assays. Results: HPV-E7 TIM molecules with various T cell co-stimulator molecules were engineered to specifically recognize HPV-specific T cells. Activation of T cells was antigen-specific and depended on the presence of an engineered T cell modulatory component on the TIM framework. The effects of various costimulatory molecules in different combinations on T cell activation were explored and an optimal combination was identified which facilitated high potency antigen-specific T cell activation. Such molecular combinations could facilitate T cell expansion and activation in T cell recall assays. Efficacy of HPV-E7 TIM molecules by inhibiting tumor growth in a syngeneic tumor model is ongoing. Conclusions: This study demonstrates that HPV-E7 TIM molecules selectively recognize and activate HPV-specific CD8+ T cells in the presence of a combination of two T cell costimulatory factors. Such novel biologics provide distinctive approaches in the treatment of HPV-related cancers and warrant further investigation. Additional in vitro and in vivo studies are ongoing to demonstrate the utility in eliminating HPV-infected tumor cells. Full data will be presented at the meeting.

A phase I study to evaluate the T-cell engager AMV564 alone and in combination with pembrolizumab in subjects with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Alexander Starodub ◽  
Sarina Anne Piha-Paul ◽  
Raghad Karim ◽  
Curtis Ruegg ◽  
Victoria Smith ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gastroesophageal Junction ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Advanced Solid Tumors

3101 Background: Overcoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. AMV564 is a bivalent, bispecific T-cell engager that binds CD3 and CD33. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data (Cheng 2017; Blood;130:51) and an ongoing clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to deplete MDSC while sparing monocytes and neutrophils. Methods: In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection for 2 out of 3 wks per cycle, alone or in combination with pembrolizumab (200 mg every 3 wks). Key objectives are to evaluate AMV564 safety, identify a maximum tolerated or recommended phase 2 dose, and evaluate PK, immunophenotype of myeloid and T cell compartments, and preliminary efficacy. Results: Eleven patients have been enrolled: 8 monotherapy (3 at 15 mcg/d, 5 at 50 mcg/d) and 3 combination (5 mcg/d). Tumor types include ovarian (n = 2), small bowel, gastroesophageal junction, endometrial, rectal, penile, urothelial, squamous cell carcinoma (skin), appendiceal, and non-small cell lung. AMV564 was associated with grade (G) 1-2 injection site reactions and G1-2 fevers, which were manageable with acetaminophen and diphenhydramine, as well as G2 weight gain and G3 anemia. No dose-liming toxicity has been observed in any cohort. Three monotherapy patients (15 mcg/d) were evaluable for efficacy with ≥1 on-treatment scan; 2 had SD and 1 PD per RECIST 1.1 criteria. T cell activation, as shown by redistribution from the periphery (margination), was apparent in the first week of dosing for most patients. Compensatory myelopoiesis led to initial expansion of MDSC which were then depleted by AMV564. Increased cytotoxic T cell activation and T-helper (Th) 1 response was evidenced by increased T-bet positive CD4 and CD8 cells and controlled or decreased regulatory T cells. In some patients, effector memory CD8 cell populations (Tem and Temra) were expanded. Conclusions: AMV564 is safe and tolerable when administered SC at doses of 15 mcg/d alone and 5 mcg/d in combination with pembrolizumab. AMV564 depleted MDSC populations and altered T cell profiles consistent with activation of cytotoxic T cells and a Th1 response. Clinical trial information: NCT04128423 .

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