Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology

Watanabe, Keisuke; Kuramitsu, Shunichiro; Posey, Avery D.; June, Carl H.

doi:10.3389/fimmu.2018.02486

Cited by 190 publications

(212 citation statements)

References 101 publications

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“…Armoured CAR T cells that constitutively secrete pro-inflammatory cytokines as a mechanism to overcome local immunosuppression are a novel concept. Similarly, incorporation of immune-checkpoint inhibition into CAR T cell-based strategies, by various combinatorial or built-in approaches, might improve responses 98 ; the findings of several preclinical studies support the effectiveness of this approach, warranting further clinical translation 98,152,159,160 .…”

Section: Car T Cell Strategies Beyond B Cell Targeting Cd19mentioning

confidence: 99%

“…Going beyond haematological tumours, solid tumours present a new set of unique challenges to the development effective CAR T cell therapies, as reviewed elsewhere [150][151][152][153] . One key issue with solid tumours is that the inherent tumour heterogeneity is likely to be a substantial barrier to identifying an optimal target, and relatedly, antigen loss will probably be a key factor precluding curative remissions.…”

Section: Car T Cell Strategies Beyond B Cell Targeting Cd19mentioning

confidence: 99%

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Mechanisms of resistance to CAR T cell therapy

2019

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Section: Car T Cell Strategies Beyond B Cell Targeting Cd19mentioning

confidence: 99%

Section: Car T Cell Strategies Beyond B Cell Targeting Cd19mentioning

confidence: 99%

Mechanisms of resistance to CAR T cell therapy

2019

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“…However, while CAR T cell therapy has yielded remarkable efficacy for haematological malignancies, its effect against solid tumours is unsatisfactory. It is mostly due to the fact that solid tumours lack unique surface tumour-specific antigens (TSAs) and that tumour-associated antigens (TAAs) overexpressed on tumours are also shared with normal tissues [22]. Additional problems include T cell homing to the site of the disease, penetration of T cells into solid masses, overcoming immunosuppressive tumour microenvironment (TME) and limited CAR T cell persistence after infusion [23].…”

Section: Challenges For Car T Cell Therapies Of Solid Tumoursmentioning

confidence: 99%

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

Chruściel

Urban-Wójciuk

Arcimowicz

et al. 2020

Cancers

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In recent years, much research has been focused on the field of adoptive cell therapies (ACT) that use native or genetically modified T cells as therapeutic tools. Immunotherapy with T cells expressing chimeric antigen receptors (CARs) demonstrated great success in the treatment of haematologic malignancies, whereas adoptive transfer of autologous tumour infiltrating lymphocytes (TILs) proved to be highly effective in metastatic melanoma. These encouraging results initiated many studies where ACT was tested as a treatment for various solid tumours. In this review, we provide an overview of the challenges of T cell-based immunotherapies of solid tumours. We describe alternative approaches for choosing the most efficient T cells for cancer treatment in terms of their tumour-specificity and phenotype. Finally, we present strategies for improvement of anti-tumour potential of T cells, including combination therapies.

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“…Taken together, our results indicate eIF3 controls TCRA and TCRB mRNA translation during the first critical hours after TCR stimulation that lead to subsequent T cell commitment to proliferation and differentiation. These results also suggest that eIF3-responsive mRNA 3’-UTR elements could be used to improve chimeric antigen receptor (CAR) expression and CAR-T cell responsiveness 32, 33 .…”

mentioning

confidence: 91%

A burst in T cell receptor translation mediated by eIF3 interactions with T cell receptor mRNAs

Silva

Ferguson

Smith

et al. 2019

Preprint

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39Activation of T cells requires a global surge in cellular protein synthesis, which is 40 accompanied by a large increase in translation initiation [1][2][3][4] . A central component of the 41 translation initiation machinery-the multi-subunit eukaryotic initiation factor 3 (eIF3)-is 42 rapidly turned on when quiescent T cells are stimulated 3 . However, the precise role eIF3 43 plays in activated T cells is not known. Using a global transcriptome cross-linking 44 approach, we show that human eIF3 interacts with a distinct set of mRNAs in activated 45 Jurkat cells. A subset of these mRNAs, including those encoding the T cell receptor (TCR) 46 subunits TCRA and TCRB, crosslink to eIF3 across the entire length of the mRNA. 47Main 55 Several lines of evidence indicate eIF3 serves specialized roles in cellular translation, by 56 recognizing specific RNA structures in the 5'-untranslated regions (5'-UTRs) of target 57 mRNAs 5 , binding the 7-methyl-guanosine (m 7 G) cap 6 or through interactions with N-6-58 methyl-adenosine (m 6 A) post-transcriptional modifications in mRNAs 7 . Binding to these 59 cis-regulatory elements in mRNA can lead to translation activation or repression, 60 depending on the RNA sequence and structural context 5,7,8 . These functions for eIF3 can 61 aid cell proliferation 5 , or allow cells to rapidly adapt to stress such as heat shock 7 . 62 Additionally, eIF3 plays an important role in the development of specific tissues 9-11 . 63 64 In the immune system, T cell activation involves a burst in translation 1-4 and correlates 65 with assembly of subunit EIF3J with the main eIF3 complex 3 . However, whether eIF3 66 serves a general or more specific role in T cell activation is not known. To delineate how 67 eIF3 contributes to T cell activation, we first identified mRNAs that directly interact with 68 eIF3 in Jurkat cells activated for 5 hours with ionomycin and phorbol 12-myristate 13-69 acetate (I+PMA), or in non-activated Jurkat cells as a control, using photoactivatable 70 ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) 5,12,13 (Fig. 71 1a). We used Jurkat cells as a model for T cells, as PAR-CLIP experiments require a 72 large number of cells labeled with 4-thiouridine at a non-toxic concentration 14 . Jurkat cells 73 also have a defined T cell receptor and transcriptome, avoiding the donor-to-donor 74 variability of primary T cells. In the Jurkat PAR-CLIP experiments, RNA crosslinked to 75 eight of the thirteen eIF3 subunits, as identified by mass spectrometry: subunits EIF3A, 76 EIF3B, EIF3D and EIF3G as seen in HEK293T cells 5 , as well as subunits EIF3C, EIF3E, 77 De Silva et al. 4EIF3F, and EIF3L (Fig. 1b, Extended Data Fig. 1, Supplementary Table 1). In activated 78 Jurkat cells, eIF3 crosslinked to a substantially larger number of mRNAs compared to the 79 non-activated cells (Extended Data Figs. 2 and 3, Supplementary Tables 2 and 3). 80 Notably, eIF3 interacted with a completely new suite of mRNAs in activated Jurkat cells, 81 co...

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Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology

Cited by 190 publications

References 101 publications

Mechanisms of resistance to CAR T cell therapy

Mechanisms of resistance to CAR T cell therapy

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

A burst in T cell receptor translation mediated by eIF3 interactions with T cell receptor mRNAs

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