TCR Redirected T Cells for Cancer Treatment: Achievements, Hurdles, and Goals

Manfredi, Francesco; Cianciotti, Beatrice Claudia; Potenza, Alessia; Tassi, Elena; Noviello, Maddalena; Biondi, Andrea; Ciceri, Fabio; Bonini, Chiara; Ruggiero, Eliana

doi:10.3389/fimmu.2020.01689

Cited by 73 publications

(56 citation statements)

References 400 publications

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“…T cells are essential adaptive immune cells that mediate tumor immunity. The promising immune checkpoint blockade (ICB) therapies mainly target T cells and recover T cell immunity through disrupting PD-1/PD-L1 and CTLA-4/CD80 or CD86 interactions or specifically activating tumor-antigen-specific T cell clones ( 102 , 103 ). Unfortunately, only a small part of patients has beneficial responses with recovered anti-tumor T cell responses.…”

Section: Application Of Single-cell Omics In Tumor Immunologymentioning

confidence: 99%

Applications of Single-Cell Omics in Tumor Immunology

Liu

Zhang

et al. 2021

Front. Immunol.

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The tumor microenvironment (TME) is an ecosystem that contains various cell types, including cancer cells, immune cells, stromal cells, and many others. In the TME, cancer cells aggressively proliferate, evolve, transmigrate to the circulation system and other organs, and frequently communicate with adjacent immune cells to suppress local tumor immunity. It is essential to delineate this ecosystem’s complex cellular compositions and their dynamic intercellular interactions to understand cancer biology and tumor immunology and to benefit tumor immunotherapy. But technically, this is extremely challenging due to the high complexities of the TME. The rapid developments of single-cell techniques provide us powerful means to systemically profile the multiple omics status of the TME at a single-cell resolution, shedding light on the pathogenic mechanisms of cancers and dysfunctions of tumor immunity in an unprecedently resolution. Furthermore, more advanced techniques have been developed to simultaneously characterize multi-omics and even spatial information at the single-cell level, helping us reveal the phenotypes and functionalities of disease-specific cell populations more comprehensively. Meanwhile, the connections between single-cell data and clinical characteristics are also intensively interrogated to achieve better clinical diagnosis and prognosis. In this review, we summarize recent progress in single-cell techniques, discuss their technical advantages, limitations, and applications, particularly in tumor biology and immunology, aiming to promote the research of cancer pathogenesis, clinically relevant cancer diagnosis, prognosis, and immunotherapy design with the help of single-cell techniques.

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Section: Application Of Single-cell Omics In Tumor Immunologymentioning

confidence: 99%

Applications of Single-Cell Omics in Tumor Immunology

Liu

Zhang

et al. 2021

Front. Immunol.

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“…Apart from CAR-T therapies, the specificity of T cells can be redirected toward selected tumor antigens by transduction with an exogenous T cell receptor (TCR) targeting the specific antigen, and this forms the basis of TCR-engineered T cell (TCR-T) therapy ( 145 , 146 ). TCR-T cells specifically targeting Wilms’ tumor 1 (WT1; overexpressed in AML and MDS cells) demonstrated HLA-A*24:02-restricted cytotoxicity against WT1-expressing myeloid leukemias ( 147 ).…”

Section: Synergism With Chimeric Antigen Receptor-engineered-t (Car-tmentioning

confidence: 99%

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes

2021

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Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4+ and CD8+ T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.

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“…Issues with T cell homing is also one of the factors affecting adoptive immunotherapy. The nitration of CCL2 chemokines and the change of glycosylation of T cell surface glycoprotein are the factors that weaken T cell homing ( 70 ). Further, in some cases, despite the large number of specific CD8+ T cells, the tumor continues to grow ( 71 ).…”

Section: Potential and Challenges Of Tcr-t Cell Induced By T-ipscs Fomentioning

confidence: 99%

Neoantigen Specific T Cells Derived From T Cell-Derived Induced Pluripotent Stem Cells for the Treatment of Hepatocellular Carcinoma: Potential and Challenges

Jin

et al. 2021

Front. Immunol.

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Immunotherapy has become an indispensable part of the comprehensive treatment of hepatocellular carcinoma (HCC). Immunotherapy has proven effective in patients with early HCC, advanced HCC, or HCC recurrence after liver transplantation. Clinically, the most commonly used immunotherapy is immune checkpoint inhibition using monoclonal antibodies, such as CTLA-4 and PD-1. However, it cannot fundamentally solve the problems of a weakened immune system and inactivation of immune cells involved in killing tumor cells. T cells can express tumor antigen-recognizing T cell receptors (TCRs) or chimeric antigen receptors (CARs) on the cell surface through gene editing to improve the specificity and responsiveness of immune cells. According to previous studies, TCR-T cell therapy is significantly better than CAR-T cell therapy in the treatment of solid tumors and is one of the most promising immune cell therapies for solid tumors so far. However, its application in the treatment of HCC is still being researched. Technological advancements in induction and redifferentiation of induced pluripotent stem cells (iPSCs) allow us to use T cells to induce T cell-derived iPSCs (T-iPSCs) and then differentiate them into TCR-T cells. This has allowed a convenient strategy to study HCC models and explore optimal treatment strategies. This review gives an overview of the major advances in the development of protocols to generate neoantigen-specific TCR-T cells from T-iPSCs. We will also discuss their potential and challenges in the treatment of HCC.

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TCR Redirected T Cells for Cancer Treatment: Achievements, Hurdles, and Goals

Cited by 73 publications

References 400 publications

Applications of Single-Cell Omics in Tumor Immunology

Applications of Single-Cell Omics in Tumor Immunology

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Neoantigen Specific T Cells Derived From T Cell-Derived Induced Pluripotent Stem Cells for the Treatment of Hepatocellular Carcinoma: Potential and Challenges

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