scholarly journals Safety Strategies of Genetically Engineered T Cells in Cancer Immunotherapy

2018 ◽  
Vol 24 (1) ◽  
pp. 78-83 ◽  
Author(s):  
Yan-Bei Ren ◽  
Shang-Jun Sun ◽  
Shuang-Yin Han
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Suicide Gene ◽  
Cell Receptor ◽  
Genetically Engineered ◽  
Great Promise ◽  
T Cell Therapy ◽  
Treatment Regimens ◽  
Engineered T Cells

T-cell therapy using genetically engineered T cells modified with either T cell receptor or chimeric antigen receptor holds great promise for cancer immunotherapy. The concerns about its toxicities still remain despite recent successes in clinical trials. Temporal and spatial control of the engineered therapeutic T cells may improve the safety profile of these treatment regimens. To achieve these goals, numerous approaches have been tested and utilized including the incorporation of a suicide gene, the switch-mediated activation, the combinatorial antigen recognition, etc. This review will summarize the toxicities caused by engineered T cells and novel strategies to overcome them.

scholarly journals Application of Droplet Digital PCR for the Detection of Vector Copy Number in Clinical CAR/TCR T-Cell Products

2020 ◽  
Author(s):  
Alex Lu ◽  
Hui Liu ◽  
Rongye Shi ◽  
Yihua Cai ◽  
Jinxia Ma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Copy Number ◽  
Cell Receptor ◽  
Digital Pcr ◽  
Retroviral Vectors ◽  
Genetically Engineered ◽  
Hematopoietic Stem ◽  
Engineered T Cells ◽  
Vector Copy Number

Abstract Background : Genetically engineered T cells have become an important therapy for B-cell malignancies. Measuring the efficiency of vector integration into the T cell genome is important for assessing the potency and safety of these cancer immunotherapies. Methods: A digital droplet polymerase chain reaction (ddPCR) assay was developed and evaluated for assessing the average number of lenti- and retroviral vectors integrated into Chimeric Antigen Receptor (CAR) and T-Cell Receptor (TCR)-engineered T cells. Results: The ddPCR assay consistently measured the concentration of an empty vector in solution and the average number of CAR and TCR vectors integrated into T cell populations. There was a linear relationship between the average vector copy number per cell measured by ddPCR and the proportion of cells transduced as measured by flow cytometry. Similar vector copy number measurements were obtained by different staff using the ddPCR assay, highlighting the assays reproducibility among technicians. Analysis of fresh and cryopreserved CAR-T and TCR engineered T cells yielded similar results. Conclusions: ddPCR is a robust tool for accurate quantitation of average vector copy number in CAR and TCR engineered T-cells. The assay is also applicable to other types of genetically engineered cells including Natural Killer cells and hematopoietic stem cells.

Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy

2020 ◽  
Vol 12 (571) ◽  
pp. eaaz6667
Author(s):  
Meixi Hao ◽  
Siyuan Hou ◽  
Weishuo Li ◽  
Kaiming Li ◽  
Lingjing Xue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Therapy ◽  
Solid Tumors ◽  
T Cell Receptor ◽  
Chimeric Antigen Receptor ◽  
Cell Receptor ◽  
T Cell Therapy ◽  
Engineered T Cells

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.

TCR-engineered T-cell therapy through personalized identification of CDR3 clonotypes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15021-e15021
Author(s):  
Zishan Zhou ◽  
Yue Pu ◽  
Shanshan Xiao ◽  
Ping Wang ◽  
Yang Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Single Cell ◽  
Adoptive Cell Therapy ◽  
Cell Receptor ◽  
Illumina Hiseq ◽  
T Cell Therapy ◽  
Engineered T Cells

e15021 Background: T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancers. Unlike many shared tumor-specific antigens, such as melanoma-associated antigen (MAGE)-A3, MAGE-A4, and New York esophageal squamous cell carcinoma (NY-ESO)-1, neoantigen has garnered much attention as a potential precision immunotherapy. Personalized neoantigen selection serves a broader and more precision future for cancer patients. Methods: Dendritic cells (DCs) derived from adherent monocytes were pulsed with mixed peptides during the maturation phase. CD8+ cells positively selected from PBMCs were incubated with washed DCs. After 21day culture in X-VIVO medium with IL-7 and IL-15, cells were harvested and stimulated with peptides for 6 h. CD137+ cells were sorted by flow cytometric and immediately processed using the 10x Genomic Chromium Single Cell 5' Library & Gel Bead Kit and Chromium Single Cell V(D)J Enrichment Kit. The T-cell TCR libraries were constructed and sequenced on the Illumina HiSeq X Ten platform. The sequencing reads were aligned to the hg38 human reference genome and analyzed using the 10x Genomics Cell Ranger pipeline. The paired TCR α and β chain sequence of each cell was demonstrated with V(D)J analysis. TCR-T cells were constructed using the information of neoantigen specific TCR, and infused to patients. Results: Two patients were treated with the personalized TCR-T treatment. At the first stage, specialized immune cells were harvested and proceeded to single-cell TCR profiling. Then, the single cell sequencing of the first patient's sample revealed the top five neoantigen specific TCR CDR3 clonotypes with the proportion of 25%, 7.67%, 4.81%, 2.79%, and 2.54%, respectively. Similarly, the other patient had the top five TCR CDR3 sequenced with the proportion of 13.38%, 7.04%, 4.21%, 2.83%, and 1.94%, respectively. The results demonstrated that both patients had one or two dominant CDR3 clonotypes, which might reflect the strength of neoantigen in vivo. At the third stage, TCR-T cells were constructed, and infused to the patients. The clinical outcome will be evaluated in the near future. Conclusions: We have generated a pipeline for a highly personalized cancer therapy using TCR-engineered T cells. Although some questions remain to be answered, this novel approach may result in better clinical responses in future treatment.

scholarly journals T-Cell Receptor Gene Therapy for Human Papillomavirus–Associated Epithelial Cancers: A First-in-Human, Phase I/II Study

2019 ◽  
Vol 37 (30) ◽  
pp. 2759-2768 ◽  
Author(s):  
Stacey L. Doran ◽  
Sanja Stevanović ◽  
Sabina Adhikary ◽  
Jared J. Gartner ◽  
Li Jia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Antigen Presentation ◽  
T Cell Receptor ◽  
Interferon Gamma ◽  
Cell Receptor ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Epithelial Cancers

PURPOSE Genetically engineered T-cell therapy is an emerging treatment of hematologic cancers with potential utility in epithelial cancers. We investigated T-cell therapy for the treatment of metastatic human papillomavirus (HPV)–associated epithelial cancers. METHODS This phase I/II, single-center trial enrolled patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy. Treatment consisted of autologous genetically engineered T cells expressing a T-cell receptor directed against HPV16 E6 (E6 T-cell receptor T cells), a conditioning regimen, and systemic aldesleukin. RESULTS Twelve patients were treated in the study. No dose-limiting toxicities were observed in the phase I portion. Two patients, both in the highest-dose cohort, experienced objective tumor responses. A patient with three lung metastases experienced complete regression of one tumor and partial regression of two tumors, which were subsequently resected; she has no evidence of disease 3 years after treatment. All patients demonstrated high levels of peripheral blood engraftment with E6 T-cell receptor T cells 1 month after treatment (median, 30%; range, 4% to 53%). One patient’s resistant tumor demonstrated a frameshift deletion in interferon gamma receptor 1, which mediates response to interferon gamma, an essential molecule for T-cell–mediated antitumor activity. Another patient’s resistant tumor demonstrated loss of HLA-A*02:01, the antigen presentation molecule required for this therapy. A tumor from a patient who responded to treatment did not demonstrate genetic defects in interferon gamma response or antigen presentation. CONCLUSION Engineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed death-1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers.

scholarly journals CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Sasan Ghaffari ◽  
Nastaran Khalili ◽  
Nima Rezaei
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
Therapeutic Modality ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

AbstractCancer immunotherapy has gained attention as the supreme therapeutic modality for the treatment of various malignancies. Adoptive T-cell therapy (ACT) is one of the most distinctive modalities of this therapeutic approach, which seeks to harness the potential of combating cancer cells by using autologous or allogenic tumor-specific T-cells. However, a plethora of circumstances must be optimized to produce functional, durable, and efficient T-cells. Recently, the potential of ACT has been further realized by the introduction of novel gene-editing platforms such as the CRISPR/Cas9 system; this technique has been utilized to create T-cells furnished with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR) that have precise tumor antigen recognition, minimal side effects and treatment-related toxicities, robust proliferation and cytotoxicity, and nominal exhaustion. Here, we aim to review and categorize the recent breakthroughs of genetically modified TCR/CAR T-cells through CRISPR/Cas9 technology and address the pearls and pitfalls of each method. In addition, we investigate the latest ongoing clinical trials that are applying CRISPR-associated TCR/CAR T-cells for the treatment of cancers.

scholarly journals Application of Adoptive T-Cell Therapy Using Tumor Antigen-Specific T-Cell Receptor Gene Transfer for the Treatment of Human Leukemia

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Toshiki Ochi ◽  
Hiroshi Fujiwara ◽  
Masaki Yasukawa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Transfer ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
Human Leukemia ◽  
Cancer Antigen ◽  
T Cell Therapy ◽  
Engineered T Cells ◽  
Leukemia Antigen

The last decade has seen great strides in the field of cancer immunotherapy, especially the treatment of melanoma. Beginning with the identification of cancer antigens, followed by the clinical application of anti-cancer peptide vaccination, it has now been proven that adoptive T-cell therapy (ACT) using cancer antigen-specific T cells is the most effective option. Despite the apparent clinical efficacy of ACT, the timely preparation of a sufficient number of cancer antigen-specific T cells for each patient has been recognized as its biggest limitation. Currently, therefore, attention is being focused on ACT with engineered T cells produced using cancer antigen-specific T-cell receptor (TCR) gene transfer. With regard to human leukemia, ACT using engineered T cells bearing the leukemia antigen-specific TCR gene still remains in its infancy. However, several reports have provided preclinical data on TCR gene transfer using Wilms' tumor gene product 1 (WT1), and also preclinical and clinical data on TCR gene transfer involving minor histocompatibility antigen, both of which have been suggested to provide additional clinical benefit. In this review, we examine the current status of anti-leukemia ACT with engineered T cells carrying the leukemia antigen-specific TCR gene, and discuss the existing barriers to progress in this area.

scholarly journals A Comprehensive Review of Recent Advancements in Cancer Immunotherapy and Generation of CAR T Cell by CRISPR-Cas9

Processes ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 16
Author(s):  
Md. Al Saber ◽  
Partha Biswas ◽  
Dipta Dey ◽  
Md. Abu Kaium ◽  
Md. Aminul Islam ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
Engineered T Cells

The mechanisms involved in immune responses to cancer have been extensively studied for several decades, and considerable attention has been paid to harnessing the immune system’s therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell cancer therapy and CAR T-cell therapy have gained prominence through immunotherapy. However, the full potential of cancer immunotherapy remains to be accomplished. In spite of having startling aspects, cancer immunotherapies have some difficulties including the inability to effectively target cancer antigens and the abnormalities in patients’ responses. With the advancement in technology, this system has changed the genome-based immunotherapy process in the human body including the generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR T-cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against cancer. In this review, we have broadly focused on recent immunotherapeutic techniques against cancer and the use of CRISPR-Cas9 technology for the modification of the T cell, which can specifically recognize cancer cells and be used as immune-therapeutics against cancer.

scholarly journals Application of Genome-Editing Technologies for Off-the-Shelf T Cell-Based Cancer Immunotherapy

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Zohreh Hakakzadeh ◽  
Vahid Yekehfallah ◽  
Hamidreza Ebrahimiyan ◽  
Ali Sayadmanesh ◽  
Mohsen Basiri
Keyword(s):  
T Cells ◽  
T Cell ◽  
Genome Editing ◽  
Therapeutic Potential ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Graft Versus Host ◽  
Promising Strategy ◽  
Engineered T Cells ◽  
Allogeneic Response

: Genetically, engineered T-cell therapy is a personalized treatment that has demonstrated considerable therapeutic potential for solid tumors and hematopoietic cancers. However, endogenous T-cell receptors (TCRs) on the surface of engineered T cells hamper their application in the allogeneic settings by inducing graft-versus-host disease, where endogenous TCRs on the surface of engineered T cells respond to the recipient’s tissues. Since the cause of this allogeneic response is the TCR complex on the surface of the engineered T cells, preventing the expression of TCR components on the surface of these cells is a promising strategy to address this challenge. This review discusses the production of allogeneic chimeric antigen receptor T cells using genome-editing methods.

scholarly journals Application of Droplet Digital PCR for the Detection of Vector Copy Number in Clinical CAR/TCR T-Cell Products

2020 ◽  
Author(s):  
Alex Lu ◽  
Hui Liu ◽  
Rongye Shi ◽  
Yihua Cai ◽  
Jinxia Ma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Copy Number ◽  
Cell Receptor ◽  
Digital Pcr ◽  
Retroviral Vectors ◽  
Genetically Engineered ◽  
Hematopoietic Stem ◽  
Engineered T Cells ◽  
Vector Copy Number

Abstract Background : Genetically engineered T cells have become an important therapy for B-cell malignancies. Measuring the efficiency of vector integration into the T cell genome is important for assessing the potency and safety of these cancer immunotherapies. Methods: A digital droplet polymerase chain reaction (ddPCR) assay was developed and evaluated for assessing the average number of lenti- and retroviral vectors integrated into Chimeric Antigen Receptor (CAR) and T-Cell Receptor (TCR)-engineered T cells. Results: The ddPCR assay consistently measured the concentration of an empty vector in solution and the average number of CAR and TCR vectors integrated into T cell populations. There was a linear relationship between the average vector copy number per cell measured by ddPCR and the proportion of cells transduced as measured by flow cytometry. Similar vector copy number measurements were obtained by different staff using the ddPCR assay, highlighting the assays reproducibility among technicians. Analysis of fresh and cryopreserved CAR-T and TCR engineered T cells yielded similar results. Conclusions: ddPCR is a robust tool for accurate quantitation of average vector copy number in CAR and TCR engineered T-cells. The assay is also applicable to other types of genetically engineered cells including Natural Killer cells and hematopoietic stem cells.

scholarly journals The Advance Cancer Immunotherapy Techniques and the Future Perspective of Modified T Cell Therapy

2021 ◽  
Author(s):  
Md. Al Saber ◽  
Partha Biswas ◽  
Dipta Dey ◽  
Md. Abu Kaium ◽  
Md. Aminul Islam ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cancer Immunotherapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
Engineered T Cells

The mechanisms involved in immune responses to cancer have been extensively studied for several decades and, considerable attention has been paid to harnessing the immune system's therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell-cancer therapy and immune test therapy have gained prominence through immunotherapy. However, it remains to be accomplished the full potential of cancer immunotherapy. In spite of having startling aspects, the cancer immunotherapies have some difficulties including the inability to effectively targeting the cancer antigens and the abnormalities in patient response. With the advancement of technology, this system has changed the genome-based immunotherapy process in the human body including generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome-editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR-T cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR-T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against the cancer. In this review, we have broadly focused on the use of CRISPR-Cas9 technology for the modification of the T-cell, which can specifically recognize cancer cells and be used as immune therapeutics against cancer. We have also demonstrated the other potential strategies for the treatment of cancer.

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