Effects of development of host immunity on the biodistribution of xenogeneic MHC non-restricted cytotoxic T cells: implications for adoptive cell therapy of cancer.

1999 ◽  
Author(s):  
A Cesano ◽  
J A Wortman ◽  
M Pourdehnad ◽  
S Visonneau ◽  
D Mozley ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Cytotoxic T Cells ◽  
Adoptive Cell Therapy ◽  
Host Immunity

Combination of gemcitabine and adoptive cell therapy of autologous anti-tumor CTL induces clinical activities in patients with refractory lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3053-3053
Author(s):  
U. Toh ◽  
T. Fujii ◽  
S. Takamori ◽  
M. Fukunaga ◽  
E. Ogo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Cell Therapy ◽  
Tumor Cells ◽  
Cytotoxic T Cells ◽  
Adoptive Cell Therapy ◽  
Autologous Tumor ◽  
Remarkable Change ◽  
Synergistic Enhancement ◽  
Ifn Γ

3053 Background: Cytotoxic T cells selectively kill autologous tumor cells is powerful for adoptive cell therapy of cancer. Gemcitabine (GEM) is able to induce molecular changes in cancer cells that make them to induce an antigen specific CTL response. This study was to evaluate the anti-tumor and the immunological activity using the CTL in combination with GEM. Methods: The 50Gy irradiated autologous tumor cells were cocultured with PBMCs and CTLs was developed with RPMI 1640 and rIL-2 (50 u/ml) for 7–14 days. Nine pts with non small cell lung cancer failed their prior chemotherapy were enrolled this pilot study. GEM regimen [intravenous (iv.) GEM (1000mg/m2) - day 1, 8 and 15 ] was started without CTL administration for 1st cycle. GEM was administered at least 2 cycles with a 1-week interval and combined with iv. CTL therapy (0.9 x 108 - 4.6 x 108 cells/injection + IL-2 0.4 MIU; biweekly for 6 to 12 injections) from 2nd cycle. The mean total administered T cells were reached to 3.9 x 109 - 5.6 x 109. PBMCs were analyzed their surface markers by Flow Cytometry and the cytokine productions of IFN-γ etc. in the serum were measured by ELISA before and after 1st cycle of GEM administration and 3rd cycles of CTL injection. Results: After finishing 2 cycles of GEM and 3 injections of CTL, the ratio of CD4/CD8 in PBMCs increased in 7/9 pts. In contrast, CD3/CD19 decreased in 6/9 pts. The cytokine production of IFN-γ in the serum revealed an increase after treatment, the levels of TGF-β were decreased simultaneously. There was no remarkable change in the levels of NKG2D in the PBMCs and MIG, IP10 in the serum. The clinical response showed PR/SD/PD was 2/5/2. The tumor marker proteins (CEA) were also decreased significantly in 4 of 9 pts. The adverse effects were tolerable with grade <2 fever, nausea and fatigue and no bone marrow suppression was observed. Conclusions: These results suggested the synergistic enhancement of antitumor effect might be induced between CTLs and anti-cancer agent GEM. Marked clinical responses were observed in two pts after the treatment. Thus this chemo-immunotherapy will be applicable for the patients with refractory lung cancer. No significant financial relationships to disclose.

Use of Engineered Exosomes Expressing HLA and Costimulatory Molecules to Generate Antigen-specific CD8+ T Cells for Adoptive Cell Therapy

2017 ◽  
Vol 40 (3) ◽  
pp. 83-93 ◽  
Author(s):  
Sueon Kim ◽  
Hyun-Jung Sohn ◽  
Hyun-Joo Lee ◽  
Dae-Hee Sohn ◽  
Seung-Joo Hyun ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Cd8 T Cells ◽  
Adoptive Cell Therapy ◽  
Costimulatory Molecules

scholarly journals Adoptive cell therapy of prostate cancer using female mice-derived T cells that react with prostate antigens

2010 ◽  
Vol 60 (3) ◽  
pp. 349-360 ◽  
Author(s):  
Huanfa Yi ◽  
Xiaofei Yu ◽  
Chunqing Guo ◽  
Masoud H. Manjili ◽  
Elizabeth A. Repasky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Cell Therapy ◽  
Adoptive Cell Therapy ◽  
Female Mice

scholarly journals Generation of regulable EGFRvIII targeted chimeric antigen receptor T cells for adoptive cell therapy of glioblastoma

2018 ◽  
Vol 507 (1-4) ◽  
pp. 59-66 ◽  
Author(s):  
Yan Zheng ◽  
Ning Gao ◽  
Yu-Long Fu ◽  
Bing-Yong Zhang ◽  
Xiu-Ling Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor

scholarly journals 151 Potentiating the Large-Scale Expansion and Engineering of Peripheral Blood-Derived CAR NK Cells for Off-the-Shelf Application

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A159-A159
Author(s):  
Michael Whang ◽  
Ming-Hong Xie ◽  
Kate Jamboretz ◽  
Hadia Lemar ◽  
Chao Guo ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Adoptive Cell Therapy ◽  
Therapeutic Window ◽  
Target Cells ◽  
Healthy Donors ◽  
Custom Made

BackgroundPeripheral blood natural killer (NK) cells are mature cytotoxic innate lymphocytes possessing an inherent capacity for tumor cell killing, thus making them attractive candidates for adoptive cell therapy. These NK cells are also amenable to CRISPR and chimeric antigen receptor (CAR) genomic engineering for enhanced functions. Moreover, NK cells possess an inherent capacity for off-the-shelf therapy since they are not known to cause graft-versus-host disease, unlike T cells. Presently, approved CAR cell therapy is custom-made from each patient‘s own T cells, a process that can limit patient pool, narrow therapeutic window, and contribute to product variability. In this study, we investigate whether peripheral blood NK cells from a selected donor can be edited, engineered, and expanded sufficiently for off-the-shelf use in a wide patient population.MethodsUsing the CRISPR/Cas9 system, we knocked out CISH expression in isolated peripheral blood NK cells from 3 healthy donors. Subsequently, we expanded edited NK cells by using IL-2 and sequential stimulations using NKSTIM, a modified K562 stimulatory cell line expressing membrane-bound form of IL-15 (mbIL-15) and 4-1BBL. IL-12 and IL-18 were added twice during expansion to drive memory-like NK cell differentiation. We transduced the expanded NK cells to express engineered CD19-targeted CAR and mbIL-15 during an interval between the first and second NKSTIM pulses. We assessed NK cell cytotoxicity against Nalm6 target cells by IncuCyte.ResultsIsolated peripheral blood NK cells from 3 healthy donors were successfully edited using CRISPR/Cas9, engineered to express high levels of CAR, extensively expanded using a series of NKSTIM pulses in the presence of IL-2, and differentiated into memory-like NK cells using IL-12 and IL-18. Interestingly, NK cells from the 3 donors exhibited distinct outcomes. NK cells from one donor reached a peak expansion limit of approximately 7-million-fold before undergoing contraction whereas NK cells from two donors continued to expand over the length of the study surpassing 100-million-fold expansion, without appearing to have reached a terminal expansion limit. At the end of the study, NK cells from one donor exceeded 1-billion-fold expansion and maintained 88% cytolytic activity compared to Nkarta’s standard process control in a 72-hour IncuCyte assay.ConclusionsIn this study, we demonstrate that healthy donor-derived peripheral blood NK cells are capable of expanding over billion-fold while maintaining potency. These results provide a rationale for the development of off-the-shelf CAR NK cell therapies using NK cells from donors selected to provide optimal product characteristics.Ethics ApprovalHuman samples were collected with written informed consent by an approved vendor.

scholarly journals Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Ratchapong Netsrithong ◽  
Methichit Wattanapanitch
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Biology ◽  
Ex Vivo ◽  
Adoptive Cell Therapy ◽  
Basic Knowledge ◽  
Car T Cells ◽  
Car T ◽  
Induced Pluripotent

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells holds impressive clinical outcomes especially in patients who are refractory to other kinds of therapy. However, many challenges hinder its clinical applications. For example, patients who undergo chemotherapy usually have an insufficient number of autologous T cells due to lymphopenia. Long-term ex vivo expansion can result in T cell exhaustion, which reduces the effector function. There is also a batch-to-batch variation during the manufacturing process, making it difficult to standardize and validate the cell products. In addition, the process is labor-intensive and costly. Generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective. Human induced pluripotent stem cells (iPSCs) provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. This review describes basic knowledge of T cell biology, applications in ACT, the use of iPSCs as a new source of T cells and current differentiation strategies used to generate T cells as well as recent advances in genome engineering to produce next-generation off-the-shelf T cells with improved effector functions. We also discuss challenges in the field and future perspectives toward the final universal off-the-shelf immunotherapeutic products.

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