Adoptive cellular therapies: the current landscape

Rohaan, Maartje W.; Wilgenhof, Sofie; Haanen, John B.A.G.

doi:10.1007/s00428-018-2484-0

Cited by 317 publications

(250 citation statements)

References 125 publications

(163 reference statements)

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“…The second approach of ACT uses T-cells extracted from the peripheral blood via leukapheresis, which are then genetically modified to improve tumour cell recognition. This is done by transducing T-cells with retroviral or lentiviral vectors to highly express novel TCRs that target specific TAAs [25,26]. To circumvent immune evasion in cancer cells by MHC aberrant expression or reduction, T-cells can be alternatively modified to express chimeric antigen receptors (CAR) [27].…”

Section: Cancer Vaccinesmentioning

confidence: 99%

“…To circumvent immune evasion in cancer cells by MHC aberrant expression or reduction, T-cells can be alternatively modified to express chimeric antigen receptors (CAR) [27]. CAR T-cells function similarly to TCR-modified T-cells but can recognise TAA in an MHC-independent manner [26]. CAR T-cell therapy has reported significant clinical response, with up to 90% complete remission rates in acute lymphoblastic leukemia targeting the B-cell antigen CD19 [28]; it has also shown high efficacy in the treatment of leukemia using CD22-directed CAR T-cells [29].…”

Section: Cancer Vaccinesmentioning

confidence: 99%

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Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Law

Valdés-Mora

Gallego‐Ortega

2020

Cells

354

272

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The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.

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Section: Cancer Vaccinesmentioning

confidence: 99%

Section: Cancer Vaccinesmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Law

Valdés-Mora

Gallego‐Ortega

2020

Cells

354

272

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“…Most clinical protocols with TCR gene therapy have incorporated preconditioning of the patient with a lymphodepleting regimen prior to T cell infusion 50 . This aims at both facilitating engraftment and homeostatic expansion and thus improving persistence of the modified T cells.…”

Section: Lymphoproliferative Preparation Regimenmentioning

confidence: 99%

“…ACT using CAR-modified T cells holds the capacity of the same effector function as TCR-modified T cells, but independently of MHC-I expression 119 . However, whilst impressive clinical responses have already been seen in haematological malignancies with CD19-specific CAR T cells 120 , which has since led to the exploration of using CAR therapy in solid tumours (reviewed in 121,122 ), TCR-modified T cells still feature a number of specific advantages that would prove beneficial in the context of cancer immunotherapy. As mentioned above, TCRs recognise processed peptides presented by MHC molecules, which means that they can target antigens from the entire protein composition of tumour cells.…”

Section: Mhc-i Downregulationmentioning

confidence: 99%

T-cell receptor gene-modified cells: past promises, present methodologies and future challenges

Rego

Morris²,

Lowdell

2019

Cytotherapy

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Immunotherapy constitutes an exciting and rapidly evolving field, and the demonstration that genetically-modified T cell receptors (TCRs) can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy.Overall, TCR-modified T cells have the ability to target a wide variety of self and non-self targets through the normal biology of a T cell. Although MHC-restricted and dependent on co-receptors, genetically engineered TCRs still present a number of characteristics that ensure they are an important alternative strategy to chimeric antigen receptors (CARs), and high affinity TCRs can now be successfully engineered with the potential to enhance therapeutic efficacy while minimising adverse events.This review will focus on the main characteristics of TCR gene-modified cells, their potential clinical application and promise to the field of adoptive cell transfer (ACT), basic manufacturing procedures and characterisation protocols, and overall challenges that need to be overcome so that redirection of TCR specificity may be successfully translated into clinical practice, beyond early phase clinical trials. BackgroundWith roots in the principles of basic immunology, synthetic biology and genetic engineering, the field of adoptive cell transfer (ACT) has become one of the most promising and innovative approaches to treat cancer, viral infections and other immune-modulated diseases.There are currently three main types of ACT using effector T cells 1 : administration of tumour infiltrating lymphocytes (TILs), and gene transfer-based strategies relying on genetic engineering to express either chimeric antigen (Ag) receptors (CARs) -composed of antibody (Ab)-binding domains fused to T cell signalling domains -or engineered T cell receptor (TCR) α/β heterodimers.Genetic modification of autologous T cells to target specific tumour antigens has been developed to overcome the consequences of immune tolerance and offers the possibility to endow the immune system with reactivities not naturally present. This approach has the additional benefit of rapid tumour eradication, which is usually observed with cytotoxic chemotherapy or other targeted therapies rather than the delayed responses that are commonly observed with vaccines and T cell checkpoint therapies. Page 2 of 33Durable anticancer responses have been extensively reported for CARs targeting CD19 in the treatment of acute lymphoblastic leukaemia (ALL), B-cell lymphomas 2 and chronic lymphocytic leukaemia (CLL), and the US Food and Drug Administration (FDA) has recently approved two genetically engineered CD19 CAR T cell products, tisagenlecleucel (Kymriah) 3 and axicabtagene ciloleucel (Yescarta) 4 , for clinical application. Therapeutic TCR gene-modified T cells have demonstrated clinical activity in earlier phase clinical trials but their development currently lags behind CAR T cells 2 . The unique biology of TCR-peptide/MHC recognition may render TCR-modified T cells a more suitable approach for specific t...

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“…Adoptive cellular immunotherapy (ACT) is the process of transferring effector immune cells, such as T lymphocytes, to cancer patients, including modifying and expanding these immune cells ex vivo to target specific cancer cells [22,23]. The transferred immune cells can have autologous or allogeneic origin.…”

Section: Adoptive Cellular Immunotherapymentioning

confidence: 99%