Metronomic cyclophosphamide regimen electively depletes CD4+ CD25+ regulatory T cells in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
F. Ghiringhelli Esq. ◽  
S. Ladoire ◽  
L. Zitvogel ◽  
B. Chauffert
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Tumor Angiogenesis ◽  
Selective Reduction ◽  
Absolute Number ◽  
Tumor Rejection ◽  
Low Doses ◽  
Proliferation Capacity

2561 Background: CD4+CD25+ regulatory T cells (Treg) are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that low doses of cyclophosphamide (CPM) could significantly decrease both number and suppressive functions of Treg, facilitating vaccine-induced tumor rejection. Repeated low doses of cyclophosphamide, referred to as metronomic treatment aiming at reducing tumor angiogenesis, are used in patients with advanced, chemoresistant tumors. Methods: Six patients with metastatic solid tumors were treated after informed consent with metronomic CPM - 50 mg orally twice a day, with one week on, and one week off, until progression or limiting toxicity. Peripheral blood mononucleated cells (PBMC) were sampled before and after 4 weeks of treatment. Occurrence of blood leucocyte subpopulation and capacity of Treg to inhibit NK and T cells patients functions were measured. Results: metronomic CPM induced a profound and selective reduction of circulating Treg, both in percentage (7.7 ± 0.8 % before versus 3.3 ± 0.8 % after, p < 0.005) and absolute number (25.2 ± 7.5 cells/mm3 before versus 6.1 ± 3.3 cells/mm3 after, p < 0.0006). Inhibitory functions of Treg on conventional T cells and NK cells lead to a restoration of peripheral T cell proliferation - i.e. PBMC from cancer patients exhibited 17 ± 3% T cells proliferation capacity after CD3 CD28 stimulation versus 44 ± 5% (p < 0.01) 1 month after the beginning of the treatment, and versus 45 ± 6% in healthy volunteers- and innate NK killing activities - i.e. PBMC from cancer patients exhibited 9 ± 1% NK killing capacity against K562 target versus 26 ± 5% (p < 0.005) after 4 week treatment. Conclusions: Metronomic CPM has not only effect on tumor angiogenesis, but also strongly curtail immunosuppressive Treg, which could favor a better control of tumor progression. No significant financial relationships to disclose.

scholarly journals Tumor specific regulatory T cells in the bone marrow of breast cancer patients selectively upregulate the emigration receptor S1P1

2017 ◽  
Vol 66 (5) ◽  
pp. 593-603 ◽  
Author(s):  
Anchana Rathinasamy ◽  
Christoph Domschke ◽  
Yingzi Ge ◽  
Hans-Henning Böhm ◽  
Steffen Dettling ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Breast Cancer Patients

scholarly journals CTLA-4 blockade increases IFN -producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients

2008 ◽  
Vol 105 (39) ◽  
pp. 14987-14992 ◽  
Author(s):  
C. I. Liakou ◽  
A. Kamat ◽  
D. N. Tang ◽  
H. Chen ◽  
J. Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients

Behavior of Circulating CD4+CD25+Foxp3+ Regulatory T Cells in Colon Cancer Patients Undergoing Surgery

2011 ◽  
Vol 31 (6) ◽  
pp. 1095-1104 ◽  
Author(s):  
Ausilia Sellitto ◽  
Gennaro Galizia ◽  
Umberto De Fanis ◽  
Eva Lieto ◽  
Anna Zamboli ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients

Novel CoupledCAR technology for treating colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2528-2528
Author(s):  
Lei Xiao ◽  
Song Li ◽  
Chengfei Pu ◽  
Zhiyuan Cao ◽  
Xinyi Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Complete Remission ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Tumor Tissue ◽  
Lentiviral Vectors ◽  
Safety And Efficacy ◽  
Pet Ct ◽  
Colorectal Cancer Patients

2528 Background: Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited expansion in vivo. Methods: We designed a CAR lentivirus vector that consisted of a humanized CD19-specific single-chain variable fragment (scFv), a 4-1BB costimulatory domain, and a CD3ζ signaling domain.The lentivirus was produced by transfecting HEK-293T cells with CAR lentiviral vectors and viral packaging plasmids. Patient’s CD3 T cells was cultured in X-VIVO medium containing 125U/mL 1interleukin-2 (IL-2), and transduced with CAR lentivirus at certain MOI 24h after stimulated by anti-CD3/CD28 magnetic beads. Transduction efficiency was evaluated at 7 to 9 days after CAR lentivirus transduction, and quality controls for fungi, bacteria, mycoplasma, chlamydia, and endotoxin were performed. After infusion, serial peripheral blood samples were collected, and the expansion and the cytokine release of CART cells were detected by FACS and QPCR,respectively. The evaluation of response level for patients were performed at month 1,month 3,and month 6 by PET/CT. Results: We engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. To verify the safety and efficacy of CoupledCAR-T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the metastatic colorectal cancer patients were infused with autologous anti-GCC CoupledCAR-T cells range from 4.9×105/kg to 2.9×106/kg. We observed that CoupledCAR-T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, and partial response.) was 57.1% (4/7), complete remission (CR) rate was 14.3% (1/7). Conclusions: In conclusion, the clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers.

Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients

2006 ◽  
Vol 56 (5) ◽  
pp. 641-648 ◽  
Author(s):  
François Ghiringhelli ◽  
Cedric Menard ◽  
Pierre Emmanuel Puig ◽  
Sylvain Ladoire ◽  
Stephan Roux ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Effector Functions ◽  
End Stage ◽  
Metronomic Cyclophosphamide

scholarly journals Infiltration of a Mesothelioma by IFN-γ-Producing Cells and Tumor Rejection after Depletion of Regulatory T Cells

2007 ◽  
Vol 178 (7) ◽  
pp. 4089-4096 ◽  
Author(s):  
Geordie Rudge ◽  
Simon P. Barrett ◽  
Bernadette Scott ◽  
Ian R. van Driel
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Tumor Rejection ◽  
Ifn Γ

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 Anti-tumor effect of CTLA-4 antibody is independent of checkpoint blockade

2021 ◽  
Author(s):  
Han Gao ◽  
Haiyan Cai ◽  
Fei Zhang ◽  
Mingdong Liu ◽  
Xiaoxiao Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Antitumor Activity ◽  
Selective Reduction ◽  
Cancer Therapeutics ◽  
Tumor Rejection ◽  
Binding Property ◽  
Surface Markers ◽  
Important Class ◽  
Anti Tumor Activity ◽  
Targeted Immunotherapy

Abstract Antibodies targeting CTLA-4 are emerging as an important class of cancer therapeutics. It is assumed that these antibodies cause tumor rejection by blocking negative signaling from the CTLA-4-B7 interactions to enhance the priming of naïve T cells in lymphoid organs. However, recent findings have shown that the effectiveness of CTLA-4 antibody critically depends on the Fc domain and the host Fc receptors. It remains unclear if the blocking function of CTLA-4 antibody is required for its anti-tumor activity. To address this, here we have selected a non-blocking anti-CTLA-4 antibody (D138) and assessed its binding property and antitumor activity in comparison with the therapeutic CTLA-4 antibody ipilimumab. Crystal structures of CTLA-4 complexed with these antibodies show that D138 binds to a distinctly different site to that of ipilimumab on the CTLA-4 surface. D138 binding did not block the association of cells expressing CTLA-4 and B7 whereas ipilimumab did. Subsequent antitumor assay revealed that D138 was similarly effective as ipilimumab in inhibiting tumor growth in mice. This antitumor activity required Fc function for efficacy and was correlated with selective reduction of intratumor regulatory T (Treg) cells, resulting in a significant increase in the ratio of CD8+ over Treg cells. Overall these data clearly demonstrate that blocking CTLA-4-B7 interaction is not required for CTLA-4 antibody mediated antitumor activity, opening prospects of developing non-blocking CTLA-4 antibodies or simple binders towards other Treg surface markers for Treg-targeted immunotherapy.

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