scholarly journals 469 A phase 1 first in human study of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, as a monotherapy and combined with pembrolizumab in patients with advanced solid malignancies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A498-A498
Author(s):  
Leah DiMascio ◽  
Dipti Thakkar ◽  
Siyu Guan ◽  
Eric Rowinsky ◽  
Jordi Rodon ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Phase 1 ◽  
Human Study ◽  
Cell Activity ◽  
Myeloid Cells

BackgroundV-domain Ig suppressor of T cell Activation (VISTA), an immune checkpoint regulator predominantly expressed on myeloid cells, represents a promising therapeutic target due to its role in suppressing pro-inflammatory, anti-tumor responses within the tumor microenvironment (TME). Based on VISTA’s broad expression across immune cell subtypes, HMBD-002 has been designed as a non-depleting, IgG4 monoclonal antibody with high affinity and specificity to VISTA across species (human, cynomolgus monkey, and rodent) that has the ability to block a predicted counter-structure binding site. In preclinical studies, HMBD-002 significantly inhibited tumor growth, both as a monotherapy and in combination with pembrolizumab, while decreasing infiltration of suppressive myeloid cells within the TME and increasing T cell activity. While rapid serum clearance and immune toxicities (e.g. cytokine release syndrome) have been reported for IgG1 antibodies, these were not observed preclinically with HMBD-002. In addition to VISTA expression on pro-inflammatory immune cells, examination of VISTA expression across cancer types has revealed that several malignancies, particularly human samples of triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC), express high levels of VISTA, thereby providing a rationale for exploring these indications in clinical studies.MethodsThis Phase 1, first in human study is being conducted in two parts and will evaluate multiple doses and schedules of intravenously (IV) administered HMBD-002, with or without pembrolizumab, in patients with advanced solid tumors. Part 1 (dose escalation) seeks to identify the maximum tolerated dose (MTD), or the maximum tested dose, of HMBD-002 as a monotherapy, and separately, in combination with pembrolizumab to define the recommend doses for subsequent disease directed studies (i.e., recommended phase 2 dose [RP2D]). Part 2 (dose expansion) will assess the anti-cancer activity of HMBD-002 as a monotherapy at the RP2D in previously treated patients with TNBC, and NSCLC, and in combination with pembrolizumab in patients with TNBC, NSCLC, and other VISTA-expressing malignancies. The size of the disease-directed cohorts will be determined based on an interim futility analysis conducted upon enrollment of 15 patients. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints will be monitored and reported. Correlative studies will assess pre- and post-treatment markers of immune activity in the periphery and the tumor microenvironment.AcknowledgementsThis work was funded in part by the Cancer Prevention and Research Institute of Texas (CPRIT).Ethics ApprovalThe study was approved by each participating Institution’s Institutional Review Board.

scholarly journals LncRNAs Target Ferroptosis-Related Genes and Impair Activation of CD4+ T Cell in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Fuwen Yao ◽  
Yongqiang Zhan ◽  
Zuhui Pu ◽  
Ying Lu ◽  
Jiao Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Cell Activity ◽  
Cell Receptor ◽  
Cell Infiltration ◽  
Poor Overall Survival

Gastric cancer (GC) is a malignant disease of the digestive tract and a life-threatening disease worldwide. Ferroptosis, an iron-dependent cell death caused by lipid peroxidation, is reported to be highly correlated with gastric tumorigenesis and immune cell activity. However, the underlying relationship between ferroptosis and the tumor microenvironment in GC and potential intervention strategies have not been unveiled. In this study, we profiled the transcriptome and prognosis data of ferroptosis-related genes (FRGs) in GC samples of the TCGA-STAD dataset. The infiltrating immune cells in GC were estimated using the CIBERSORT and XCELL algorithms. We found that the high expression of the hub FRGs (MYB, PSAT1, TP53, and LONP1) was positively correlated with poor overall survival in GC patients. The results were validated in an external GC cohort (GSE62254). Further immune cell infiltration analysis revealed that CD4+ T cells were the major infiltrated cells in the tumor microenvironment of GC. Moreover, the hub FRGs were significantly positively correlated with activated CD4+ T cell infiltration, especially Th cells. The gene features in the high-FRG score group were enriched in cell division, DNA repair, protein folding, T cell receptor, Wnt and NIK/NF-kappaB signaling pathways, indicating that the hub FRGs may mediate CD4+ T cell activation by these pathways. In addition, an upstream transcriptional regulation network of the hub FRGs by lncRNAs was also developed. Three lncRNAs (A2M-AS1, C2orf27A, and ZNF667-AS1) were identified to be related to the expression of the hub FRGs. Collectively, these results showed that lncRNA A2M-AS1, C2orf27A, and ZNF667-AS1 may target the hub FRGs and impair CD4+ T cell activation, which finally leads to poor prognosis of GC. Effective interventions for the above lncRNAs and the hub FRGs can help promote CD4+ T cell activation in GC patients and improve the efficacy of immunotherapy. These findings provide a novel idea of GC immunotherapy and hold promise for future clinical application.

550 An Axl-targeting monoclonal antibody that inhibits Axl activity and potently stimulates the innate immune response

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A587-A587
Author(s):  
Diego Alvarado ◽  
Laura Vitale ◽  
Mike Murphy ◽  
Thomas O’Neill ◽  
Edward Natoli ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Cancer ◽  
Cell Activity ◽  
Negative Regulator

BackgroundAxl is a member of the TAM (Tyro3/Axl/MerTK) family of receptor tyrosine kinases and a negative regulator of innate immunity. Activation of Axl through its ligand Gas6 leads to suppression of myeloid cell activity, while its activation in tumor cells drives tumor growth, metastasis, and is associated with acquired resistance to targeted therapies, radiotherapy and chemotherapy.MethodsPurified monoclonal antibodies and variants thereof were tested in human cancer lines and primary human myeloid cells for effects on Axl signaling and immune activation, respectively.ResultsWe describe a humanized IgG1 Axl-targeting monoclonal antibody (mAb), CDX-0168, that binds to the ligand-binding domain of Axl with sub-nanomolar affinity and potently inhibits Gas6 binding. In tumor cells, CDX-0168 inhibits Gas6-dependent Axl phosphorylation and signaling and elicits tumor cell killing via ADCC in vitro and in vivo. In primary human immune cells, CDX-0168 treatment induces potent release of pro-inflammatory cytokines and chemokines from dendritic cells, monocytes and macrophages through an Fc receptor-dependent mechanism and enhanced T cell activation in mixed lymphocyte reactions. Axl inhibition may further enhance antitumor activity associated with PD-(L)1 blockade. To this end, we generated a tetravalent bispecific Axl x PD-L1 antibody combining CDX-0168 with a potent anti-PD-L1 mAb (9H9) using an IgG-scFv format. The bispecific antibody elicits greater cytokine release and T cell activation in vitro than the combination of the parental antibodies, while maintaining robust Axl and PD-L1 blockade.ConclusionsAdditional studies investigating simultaneous blockade of the Axl and PD-L1 pathways with other agents may further exploit the potential for this novel anti-cancer therapeutic approach.

A multiplex immunofluorescence assay to assess immune checkpoint inhibitor-targeted CD8 activation and tumor colocalization in FFPE tissues.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2629-2629 ◽  
Author(s):  
Tony Navas ◽  
Kristin Fino ◽  
King Leung Fung ◽  
Facundo Cutuli ◽  
Robert J. Kinders ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cell Activity ◽  
Immunofluorescence Assay ◽  
Cd8 Cells ◽  
Tumor Tissues

2629 Background: Immune checkpoint inhibitors promote antitumor immune responses by enhancing T-cell activity. Measuring the pharmacodynamic effects of these drugs is challenging, as it requires assessing both immune cell and cancer cell populations. To evaluate T cell activation in tumor tissue from patient biopsies, we developed a robust multiplexed immunofluorescence assay. Methods: Our assay uses novel oligo-conjugated antibodies (Ultivue) for simultaneous quantitation of TCR activation (phospho-CD3zeta), immune checkpoint signaling via PD-1 (p-SHP1/p-SHP2), and the net stimulation/inhibition resulting from the integration of these two pathways in CD8 cells (p-ZAP70), while also providing the proximity of CD8 cells to tumor tissues, identified by β-catenin. The method was clinically validated using custom tissue microarrays (TMA) containing tumor biopsies of 3 different histologies (CRC, NSCLC, and breast). Results: From a total of 192 tumor core biopsies, 20/64 NSCLC, 9/64 CRC, and 3/65 breast TMA cores were found to have a significant number of CD8+ tumor infiltrating lymphocytes (TILs) at baseline ( > 50 cells in the examined section). In 18 of the 20 NSCLC cores, ≥50% of CD8 cells both inside and outside of the tumor were activated (CD3z-pY142+). In 6/9 CRC cores, ≥50% of CD8+ cells inside tumor tissues were activated, and in 4/9 CRC cores, ≥50% of CD8+ cells in stroma were activated. In 2/3 breast tumor cores, 90% of CD8+ cells inside tumor tissues were activated; in the remaining core, 90% of CD8+ cells in stroma were activated. Interestingly, all 192 cores had minimal to no expression of activated Zap70 (pY493) in CD8+ cells. Conclusions: Depending on tumor histology, baseline biopsy samples may contain variable numbers of activated CD8+ TILs (CD3z-pY142+), which may reside inside or outside of tumor regions and express very low levels of Zap70-pY493. Anti-PD-1 therapy is predicted to enhance T-cell cytotoxic activity, as demonstrated by an increased number of TILs and elevated Zap70-pY493 expression. This assay is being used for pharmacodynamic evaluations in ongoing immunotherapy clinical trials. Funded by NCI Contract No HHSN261200800001E.

scholarly journals SIRT5 Contributes to Colorectal Cancer Growth by Regulating T Cell Activity

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Ke Wang ◽  
Zuojian Hu ◽  
Cuiping Zhang ◽  
Lujie Yang ◽  
Li Feng ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Metabolic Regulation ◽  
Cell Activation ◽  
Cell Activity ◽  
Cell Receptor ◽  
Treg Cells ◽  
T Helper 1 ◽  
Colorectal Tumorigenesis

Over the past several years, SIRT5 has attracted considerable attention in metabolic regulation. However, the function of SIRT5 in tumorigenesis by regulating tumor microenvironment is poorly understood. In this work, we found that Sirt5 knockout mice were resistant to AOM and DSS-induced colitis-associated colorectal tumorigenesis and the level of IFN-γ in their tumor microenvironment was higher. Additionally, proteome and network analysis revealed that SIRT5 was important in the T cell receptor signaling pathway. Furthermore, we determined that a deficiency of Sirt5 induced stronger T cell activation and demonstrated that SIRT5 played a pivotal role in regulating the differentiation of CD4+ regulatory T (Treg) cells and T helper 1 (Th1) cells. An imbalance in the lineages of immunosuppressive Treg cells and the inflammatory Th1 subsets of helper T cells leads to the development of colon cancer. Our results revealed a regulatory role of SIRT5 in T cell activation and colorectal tumorigenesis.

NVG-111, a novel ROR1xCD3 bispecific antibody for non-Hodgkin lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7549-7549
Author(s):  
David Granger ◽  
Satyen Gohil ◽  
Alessandro Barbarulo ◽  
Annalisa Baccaro ◽  
Vincent Muczynski ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Human Study ◽  
Phase 2 ◽  
Cytokine Release ◽  
Non Hodgkin Lymphoma

7549 Background: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a type I transmembrane protein is highly expressed on an array of haematological and solid tumours. NVG-111 is a humanised, tandem scFv ROR1xCD3 bispecific antibody previously shown to elicit potent killing of tumour cells in vitro and in vivo by engaging a membrane-proximal epitope in the Wnt5a-binding Frizzled domain of ROR1 and redirecting T cell activity. The in vitro potency and pharmacodynamic responses to NVG-111 were assessed to support progression to a first-in-human study. Methods: The potency of NVG-111 in vitro was determined by evaluating the concentration response for cytotoxicity, T cell activation, and cytokine release in co-cultured Jeko-1 and unstimulated human T cells. Comparative data were generated for the marketed CD19xCD3 bispecific antibody, blinatumomab. Potency data for NVG-111 were used together with allometric scaling from murine PK studies to inform planned clinical doses. Results: NVG-111 demonstrated T cell-dependent cytotoxicity, T cell activation and levels of cytokine release similar in potency to blinatumomab. Cytotoxic responses of both NVG-111 and blinatumomab were more potent than T cell activation and cytokine release. Dose response curves for NVG-111 showed a decrease in activity beyond the concentration of maximal response (ie “hook effect”). We hypothesise this is due to receptor saturation, inhibiting synapse formation. NVG-111 has progressed to a Phase 1/2 first-in-human study in patients with debulked, relapsed/refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), the drug given as add-on to ≥2nd line therapy with a Bruton’s tyrosine kinase inhibitor, or venetoclax. Phase 1 includes escalating doses of 0.3 to 360 µg/day via continuous infusion over 3 cycles (each 21 days on, 7 days off) to establish safety, PK, pharmacodynamics (PD) and recommended phase 2 dose (RP2D). Predicted exposure at 0.3 µg/day is ̃EC20 for cytotoxicity in vitro and below the lowest EC10 for cytokine release. PD biomarkers in the study include systemic cytokines. Phase 2 will study efficacy and safety of the RP2D in CLL and MCL, with primary endpoint complete response rate; other efficacy endpoints include minimal residual disease and progression free survival. Conclusions: NVG-111 shows potent T-cell mediated lymphoma cell cytotoxicity in vitro at concentrations well below those associated with extensive cytokine release. NVG-111 is in an ongoing Phase 1/2 study and may present a novel option for adoptive immunotherapy in patients with non-Hodgkin lymphoma and potentially other cancers. Clinical trial information: 2020-000820-20. [Table: see text]

406 CDX527–01, a phase 1 dose-escalation and expansion study of the PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A431-A431
Author(s):  
Michael Yellin ◽  
Tracey Rawls ◽  
Diane Young ◽  
Philip Golden ◽  
Laura Vitale ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Phase 1 ◽  
Clinical Activity ◽  
Tumor Types ◽  
Anti Tumor Activity

BackgroundCD27 ligation and PD-1 blockade elicit complementary signals mediating T cell activation and effector function. CD27 is constitutively expressed on most mature T cells and the interaction with its ligand, CD70, plays key roles in T cell costimulation leading to activation, proliferation, enhanced survival, maturation of effector capacity, and memory. The PD-1/PD-L1 pathway plays key roles in inhibiting T cell responses. Pre-clinical studies demonstrate synergy in T cell activation and anti-tumor activity when combining a CD27 agonist antibody with PD-(L)1 blockade, and clinical studies have confirmed the feasibility of this combination by demonstrating safety and biological and clinical activity. CDX-527 is a novel human bispecific antibody containing a neutralizing, high affinity IgG1k PD-L1 mAb (9H9) and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb (2B3) genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies have demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations, and together with the IND-enabling studies support the advancement of CDX-527 into the clinic.MethodsA Phase 1 first-in-human, open-label, non-randomized, multi-center, dose-escalation and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 is ongoing. Eligible patients have advanced solid tumor malignancies and have progressed on standard-of-care therapy. Patients must have no more than one prior anti-PD-1/L1 for tumor types which have anti-PD-1/L1 approved for that indication and no prior anti-PD-1/L1 for tumor types that do not have anti-PD-1/L1 approved for that indication. CDX-527 is administered intravenously once every two weeks with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The dose-escalation phase initiates with a single patient enrolled in cohort 1. In the absence of a dose limiting toxicity or any ≥ grade 2 treatment related AE, cohort 2 will enroll in a similar manner as cohort 1. Subsequent dose-escalation cohorts will be conducted in 3+3 manner. In the tumor-specific expansion phase, up to 4 individual expansion cohort(s) of patients with specific solid tumors of interest may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX 527. Tumor assessments will be performed every 8-weeks by the investigator in accordance with iRECIST. Biomarker assessments will include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment.ResultsN/AConclusionsN/ATrial RegistrationNCT04440943Ethics ApprovalThe study was approved by WIRB for Northside Hospital, approval number 20201542

HUMAN T-CELL ACTIVATION IS AUGMENTED BY MONOCLONAL ANTIBODY TO IgD

1982 ◽  
Vol 399 (1 Immunoglobuli) ◽  
pp. 227-237
Author(s):  
Denis R. Burger ◽  
David Regan ◽  
Karen Williams ◽  
Gerrie Leslie
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human T Cell

Altered immune cell profiles and impaired CD4 T cell activation in single and multi‐food allergic adolescents

2021 ◽  
Author(s):  
Melanie R. Neeland ◽  
Sandra Andorf ◽  
Thanh D. Dang ◽  
Vicki L. McWilliam ◽  
Kirsten P. Perrett ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Cd4 T Cell

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.

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