scholarly journals IMMU-01. THE ONCOLYTIC VIRUS DELTA-24-RGD IN COMBINATION WITH AN AGONISTIC CD40 MAB INDUCES A DURABLE AND SYNERGISTIC ANTI-TUMOR IMMUNE EFFECT IN DIPG PRECLINICAL MODELS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i26-i27
Author(s):  
Sara Labiano ◽  
Virginia Laspidea ◽  
Marc Garcia-Moure ◽  
Montserrat Puigdelloses ◽  
Oren J Becher ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Costimulatory Molecule ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Complete Regression ◽  
Oncolytic Adenoviruses ◽  
Antigen Presenting ◽  
First World ◽  
Trial Phase

Abstract With a 2-year survival less than 20%, Diffuse Intrinsic Pontine Glioma (DIPG) is the principal cause of pediatric death. Despite recent advances in the current treatments, the outcome for children with DIPGs remains dismal. Since the approval of T-VEC for melanoma by the FDA, oncolytic adenoviruses have emerged as a promising therapeutic strategy for brain tumors. Thus, our group launched the first world clinical trial phase I with the oncolytic adenovirus Delta-24-RGD (DNX-2401 in the clinic) for newly diagnosed DIPG (NCT03178032), which has shown safety and feasibility. Despite DNX-2401 increases the recruitment of T cells into the tumor, they usually become inactive due to the suppressive tumor microenvironment evidencing the urgent need to improve this strategy focusing on the generation of effective long-term immune responses. Therefore, we decided to combine the Delta-24-RGD with the targeting of the costimulatory molecule CD40 in two unique orthotopic immunocompetent mouse models of DIPG. The activation of the CD40 receptor, which is expressed by antigen presenting cells (APC) such as microglia, macrophages and dendritic cells, is known to increase antigen presentation and enable T-cell priming and activation. Here, we have observed that in addition to Delta-24-RGD anti-tumor effects, the stimulation of CD40 on the tumor APCs results in a remodeling of the tumor immune compartment with a more efficient T-cell tumor infiltration. Of importance, there is an increase of the survival of mice treated with the combination as compared to single treatments or non-treated mice. In addition, the combination therapy induced a complete regression of tumors in 25% of treated mice indicating the development of long-term anti-tumor immunity. We believe that these results provide a translational breakthrough in the treatment of these lethal tumors and open the door for a future innovative clinical trial.

scholarly journals Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity.

1988 ◽  
Vol 168 (6) ◽  
pp. 2193-2206 ◽  
Author(s):  
M Awwad ◽  
R J North
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Regression ◽  
Cell Mediated Immunity ◽  
Complete Regression ◽  
Suppressor T Cells ◽  
Antibody Treatment ◽  
P815 Mastocytoma ◽  
Thymectomized Mice

This study shows that intravenous injection of 1 mg of anti-L3T4 mAb (GK1.5) into thymectomized mice bearing the syngeneic L5178Y lymphoma results, after a delay of 2-3 d, in complete regression of this tumor and in long-term host survival. A flow cytofluorometric examination of the spleen cells of mAb-treated mice revealed that antibody treatment resulted in the elimination of greater than 98% of L3T4+ T cells, but had no effect on the Lyt-2+ T cells subset. Tumor regression was immunologically mediated, because L5178Y lymphoma cells were shown to be L3T4-, and regression of the tumor failed to occur in mice that had been lethally irradiated before anti-L3T4 mAb was given. Tumor regression was mediated by tumor-sensitized Lyt2+ T cells, as evidenced by the finding that treatment of tumor-bearing mice with anti-Lyt-2 mAb alone, or in combination with anti-L3T4 mAb, resulted in enhancement of tumor growth and a significant decrease in host survival time. Moreover, the spleens of mice whose tumors were undergoing regression in response to anti-L3T4 mAb treatment contained Lyt-2+ T cells capable, on passive transfer, of causing regression of a tumor in recipient mice. These results can be interpreted as showing that removal of tumor-induced L3T4+ suppressor T cells results in the release of Lyt-2+ effector T cells from suppression, and consequently in the generation of enough Lyt-2+ T cell-mediated immunity to cause tumor regression. This can only be achieved, however, if immunity to the tumor is mediated exclusively by Lyt-2+ T cells, as is the case for the L5178Y lymphoma. In the case of the P815 mastocytoma, treatment with anti-L3T4 mAb was without a therapeutic effect, and this was in keeping with the finding that immunity to this tumor is mediated by L3T4+, as well by Lyt-2+ T cells.

scholarly journals New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

Biomedicines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 55 ◽  
Author(s):  
Volker Schirrmacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Tumor Immunity ◽  
Cancer Vaccines ◽  
Cell Mediated Immunity ◽  
Anti Cancer ◽  
Antigen Presenting ◽  
Molecular Patterns

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection.

scholarly journals CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

2005 ◽  
Vol 25 (17) ◽  
pp. 7743-7757 ◽  
Author(s):  
Kei Ohnuma ◽  
Tadanori Yamochi ◽  
Masahiko Uchiyama ◽  
Kunika Nishibashi ◽  
Satoshi Iwata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Costimulatory Molecule ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Caveolin 1 ◽  
Extracellular Region ◽  
Antigen Presenting

ABSTRACT CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptor-associated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-κB. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigen-specific T-cell proliferation.

scholarly journals CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.

1995 ◽  
Vol 182 (2) ◽  
pp. 459-465 ◽  
Author(s):  
M F Krummel ◽  
J P Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Costimulatory Molecule ◽  
Surface Glycoprotein ◽  
T Cell Proliferation ◽  
Cell Surface Glycoprotein ◽  
Costimulatory Signals ◽  
Low Levels ◽  
Opposing Effects ◽  
Antigen Presenting

The importance of the B7/CD28/CTLA-4 molecules has been established in studies of antigen-presenting cell-derived B7 and its interaction with the T cell costimulatory molecule CD28. CTLA-4, a T cell surface glycoprotein that is related to CD28, can also interact with B7-1 and B7-2. However, less is known about the function of CTLA-4, which is expressed at highest levels after activation. We have generated an antibody to CTLA-4 to investigate the consequences of engagement of this molecule in a carefully defined system using highly purified T cells. We show here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4. Cross-linking of CTLA-4 together with the TCR and CD28 strongly inhibits proliferation and IL-2 secretion by T cells. Finally, results show that CD28 and CTLA-4 deliver opposing signals that appear to be integrated by the T cell in determining the response to activation. These data strongly suggest that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTLA-4.

A phase Ia/Ib, open-label first-in-human study of the safety, tolerability, and feasibility of gene-edited autologous NeoTCR-T cells (NeoTCR-P1) administered to patients with locally advanced or metastatic solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3151-TPS3151
Author(s):  
Bartosz Chmielowski ◽  
Samuel Ejadi ◽  
Roel Funke ◽  
Todd Stallings-Schmitt ◽  
Mitch Denker ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Adoptive T Cell Therapy ◽  
Autologous Tumor ◽  
T Cell Therapy ◽  
Trial Phase

TPS3151 Background: Neoepitopes (neoE) derived from private tumor-exclusive mutations represent compelling targets for personalized TCR-T cell therapy. An ultra-sensitive and high-throughput process was developed to capture tumor mutation-targeted CD8 T cells from patient blood. NeoTCRs cloned from the captured CD8 T cells, when engineered into fresh CD8 and CD4 T cells, effected killing of patients’ autologous tumor cells in vitro. These observations have been leveraged for the development of a fully personalized adoptive T cell therapy (NeoTCR-P1). A Phase 1 clinical trial testing NeoTCR-P1 in subjects with solid tumors is ongoing (NCT03970382). Methods: During the initial trial phase, escalating doses of NeoTCR-P1 T cells administered without and with IL-2 in the regimen, and following conditioning chemotherapy, will be evaluated in subjects with advanced or metastatic solid tumors (melanoma, urothelial cancer, colorectal cancer, ovarian cancer, HR+ breast cancer, and prostate cancer). The objective of the Phase 1a study is to establish a recommended Phase 2 dose. Primary endpoints include the incidence and nature of DLTs and overall process feasibility. The proliferation, persistence, and trafficking of NeoTCR-T cells will be characterized. In the expansion trial phase, preliminary anti-tumor activity of NeoTCR-P1 will be assessed in selected tumors. The combination of NeoTCR-P1 dosing plus nivolumab will be tested in a Phase 1b study. Conclusion: This is the first clinical study of an autologous, fully personalized adoptive T cell therapy directed against private tumor-exclusive mutations, generated without using recombinant viral vectors. Clinical trial information: NCT03970382 .

scholarly journals Long-lasting CD8 T cell memory in the absence of CD4 T cells or B cells.

1996 ◽  
Vol 183 (5) ◽  
pp. 2153-2163 ◽  
Author(s):  
F Di Rosa ◽  
P Matzinger
Keyword(s):  
T Cell ◽  
B Cells ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Cellular Interactions ◽  
Cell Memory ◽  
Long Term Retention ◽  
Cd8 T Cell Memory ◽  
Antigen Presenting

The cellular basis of immunological memory has been a debated issue. It is not clear whether CD8 T cell memory is maintained by long-lived cells or by specific or nonspecific restimulation. Here, we have approached the question from a different angle, asking whether the cellular interactions that are required to maintain memory are the same as those necessary to activate cytotoxic T lymphocytes. We studied the CD8 memory response to the male antigen H-Y in mice deficient in CD4 cells, or B cells and found that memory in these mice was virtually unimpaired. These results suggest that CD8 memory is CD4 independent and that there is no requirement for long term retention of immune complexes on follicular dendritic cells, nor for B cells as antigen-presenting cells.

scholarly journals Expression and functional significance of an additional ligand for CTLA-4

1993 ◽  
Vol 90 (23) ◽  
pp. 11054-11058 ◽  
Author(s):  
D J Lenschow ◽  
G H Su ◽  
L A Zuckerman ◽  
N Nabavi ◽  
C L Jellis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Costimulatory Molecule ◽  
T Cell Proliferation ◽  
Antigen Presenting

Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.

Construction and Pre-Clinical Evaluation of An Anti-CD19 Chimeric Antigen Receptor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4623-4623 ◽  
Author(s):  
James Kochenderfer ◽  
Steven Feldman ◽  
Yangbing Zhao ◽  
Hui Xu ◽  
Mary Black ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Costimulatory Molecule ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Target Cells ◽  
Single Chain ◽  
Cell Counts

Abstract Adoptive T cell immunotherapy can cause regression of established malignancy. One promising approach is to transfer genes encoding chimeric antigen receptors (CARs) that specifically recognize tumor-associated antigens to T cells before the T cells are adoptively transferred to patients. We have constructed a CAR that consists of an anti-CD19 single chain variable region (scFv) that is coupled to a portion of the CD28 costimulatory molecule and the signaling component of the CD3-zeta chain. CD19 is a promising target for immunotherapy because most malignant B cell express CD19, but the only normal cells that express CD19 are B cells, B cell precursors, and perhaps follicular dendritic cells. We have demonstrated that gamma-retroviruses encoding the anti-CD19 CAR can be used to transduce human T cells and that these transduced T cells specifically recognize CD19+ targets. To transduce T cells, we stimulated T cells with the anti-CD3 monoclonal antibody OKT3 on day 0 then conducted sequential retroviral transductions on day 2 and on day 3. Transductions were performed by spin-loading retroviruses onto RetroNectin (Takara) coated culture plates followed by overnight incubation of the OKT3- stimulated T cells on the plates. Forty-five to sixty-seven percent of T cells expressed the anti-CD19 CAR as measured by flow cytometry 7–8 days after transduction (n=8). Anti-CD19-CAR-transduced CD8+ and CD4+ T cells produced IFNg and IL-2 specifically in response to stimulation with CD19+ target cells. The transduced T cells specifically killed primary chronic lymphocytic leukemia (CLL) cells. T cells from CLL patients that were either untreated or previously treated with fludarabine plus rituximab could be transduced and induced to proliferate sufficiently to provide enough cells for clinical adoptive T cell transfer. In addition, we adapted this protocol for use in CLL patients with very high peripheral blood leukemia cell counts by depleting CD19+ cells using magnetic bead sorting prior to OKT3 stimulation. In preparation for a clinical trial that will enroll patients with advanced B cell malignancies, we have generated a producer cell clone that produces GALV (Gibbon ape leukemia virus)-enveloped gamma-retroviruses encoding the anti-CD19 CAR, and we have produced sufficient retroviral supernatant for the proposed clinical trial under good manufacturing practice (GMP) conditions.

scholarly journals Polyclonal stimulation of resting B lymphocytes by antigen-specific T lymphocytes.

1984 ◽  
Vol 159 (3) ◽  
pp. 861-880 ◽  
Author(s):  
A L DeFranco ◽  
J D Ashwell ◽  
R H Schwartz ◽  
W E Paul
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Lymphocytes ◽  
Cell Interaction ◽  
T Cell Stimulation ◽  
Cross Linkage ◽  
Immune Defect ◽  
Antigen Presenting

Resting B lymphocytes are activated, proliferate, and differentiate into antibody-secreting cells when cultured with long-term lines of major histocompatibility complex (MHC)-restricted, antigen-specific T cell in the presence of the antigen for which the T cells are specific. Under optimal conditions, essentially all B cells are activated and approximately 35% enter S phase in the absence of antigens for which the B cells are specific. Activation and proliferation are observed in cells from both normal mice and mice with the xid-determined immune defect. Highly purified B cells bearing Ia molecules for which the T cells are "cospecific" can present antigen to T cells with the resulting T cell stimulation leading to the activation and proliferation of the antigen-presenting B cells. However, B cells that do not bear Ia molecules for which the T cells are cospecific are also activated and proliferate if antigen and a source of antigen-presenting B cells or macrophage-rich cells of proper histocompatibility type are present. Thus, resting B cells, both normal and "xid", can be activated by non-MHC restricted factors without receptor cross-linkage. Experiments are presented that support the concept that local production and action of such unrestricted activating factors may be responsible for the MHC-restriction of T cell-B cell interaction seen in many circumstances.

scholarly journals Phase 1 Results of CNCT19: CD19 CAR Constructed of a New Anti-CD19 Chimeric Antigen Receptor in Relapsed or Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2622-2622
Author(s):  
Runxia Gu ◽  
Fang Liu ◽  
Dehui Zou ◽  
Bingcheng Liu ◽  
Wei Liu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Memory T Cells ◽  
Lymphoblastic Leukemia ◽  
Antigen Receptor ◽  
Cytokine Release ◽  
Cytokine Release Syndrome

Data from systemic clinical trials about chimeric antigen receptor-modified T cell therapy against CD19 (CD19 CAR) differ in CAR design, T-cell activation and transduction methods at different institutions. However, according to these clinical trials, the single-chain fragment variable (scFv) sequence specific for tumor antigen were mostly derived from the FMC63 or SJ25C1 clones. Our previous study showed that the CD19 CAR constructed in our laboratory derived from clone HI19α (HI19α-4-1BB-ζ CAR) was highly effective in preclinical models. Herein, we conducted a single-arm, phase I clinical trial to evaluate the safety and efficacy of HI19α-4-1BB-ζ CAR (CNCT19) in patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). From November 2016 through December 2018, 20 R/R B-ALL patients were enrolled into this clinical trial. Complete remission (CR) or complete remission with incomplete count recovery (CRi) was achieved in 100% (18/18) of patients that could be evaluated on day 28 after infusion, which accounted for 90% of all 20 enrolled patients. After a median follow-up of 17.0 months (range, 0.2 - 19.8), the median overall survival (OS) for the entire cohort of patients was 9.6 months (95% CI 4.2 - 15.0), and was not reached for 14 patients bridge to allogeneic transplantation. The median relapse free survival (RFS) of all patients was 9.0 months (95% CI, 6.7 - 11.2). Two patients died within 28 days due to cytokine release syndrome (CRS), while other patients experienced controllable cytokine-release syndrome and neurotoxicity. In order to better understand the correlation between T cell subsets and long-term response, we consistently evaluated the T cell phenotype and expansion kinetics in peripheral blood after CART infusion. The results revealed that the percentage of CD8+ naïve T cells (TN) collected from peripheral blood 20min after CAR infusion, were significantly lower in patients who relapsed from CART therapy than patients with continues CR (p=0.003), while central memory T cells (TCM), effective memory T cells (TEM) and effector T cells (TE) had similar proliferation kinetics between these two groups. In addition, multivariate analysis indicated that low percentage of CD8+TN cells was an independent factor associated with shorter RFS (p=0.033, 95% CI 0.031-0.861). This report is the first trial to provide evidence that CNCT19, a CD19 CAR constructed of a new anti-CD19 chimeric antigen receptor HI19α, has potent antileukemia activities in patients with R/R B-ALL. Furthermore, our results indicate the phenotype and kinetics of T cells are possible biomarkers to predict the long-term prognosis of CART treatment. Disclosures Lv: Juventas Cell Therapy Ltd.: Employment.

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