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CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation

Overview of attention for article published in Journal for Immunotherapy of Cancer, May 2018
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (89th percentile)

Mentioned by

twitter
35 tweeters
patent
4 patents
googleplus
1 Google+ user

Citations

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62 Dimensions

Readers on

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132 Mendeley
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Title
CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation
Published in
Journal for Immunotherapy of Cancer, May 2018
DOI 10.1186/s40425-018-0347-5
Pubmed ID
Authors

Pradip Bajgain, Supannikar Tawinwung, Lindsey D’Elia, Sujita Sukumaran, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Malcolm K. Brenner, Ann M. Leen, Juan F. Vera

Abstract

The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site. First (1G - CD3ζ) and second generation (2G - 41BB.CD3ζ) MUC1-specific CARs were constructed using the HMFG2 scFv. Following retroviral transduction transgenic expression of the CAR±ICR was assessed by flow cytometry. In vitro CAR/ICR T cell function was measured by assessing cell proliferation and short- and long-term cytotoxic activity using MUC1+ MDA MB 468 cells as targets. In vivo anti-tumor activity was assessed using IL4-producing MDA MB 468 tumor-bearing mice using calipers to assess tumor volume and bioluminescence imaging to track T cells. In the IL4-rich tumor milieu, 1G CAR.MUC1 T cells failed to expand or kill MUC1+ tumors and while co-expression of the 4/7ICR promoted T cell expansion, in the absence of co-stimulatory signals the outgrowing cells exhibited an exhausted phenotype characterized by PD-1 and TIM3 upregulation and failed to control tumor growth. However, by co-expressing 2G CAR.MUC1 (signal 1 - activation + signal 2 - co-stimulation) and 4/7ICR (signal 3 - cytokine), transgenic T cells selectively expanded at the tumor site and produced potent and durable tumor control in vitro and in vivo. Our findings demonstrate the feasibility of targeting breast cancer using transgenic T cells equipped to thrive in the suppressive tumor milieu and highlight the importance of providing transgenic T cells with signals that recapitulate physiologic TCR signaling - [activation (signal 1), co-stimulation (signal 2) and cytokine support (signal 3)] - to promote in vivo persistence and memory formation.

Twitter Demographics

The data shown below were collected from the profiles of 35 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 132 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 132 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 23 17%
Researcher 21 16%
Student > Master 15 11%
Student > Bachelor 14 11%
Other 8 6%
Other 13 10%
Unknown 38 29%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 28 21%
Immunology and Microbiology 20 15%
Agricultural and Biological Sciences 16 12%
Medicine and Dentistry 14 11%
Pharmacology, Toxicology and Pharmaceutical Science 5 4%
Other 11 8%
Unknown 38 29%

Attention Score in Context

This research output has an Altmetric Attention Score of 22. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 12 August 2021.
All research outputs
#1,365,625
of 21,784,478 outputs
Outputs from Journal for Immunotherapy of Cancer
#331
of 2,685 outputs
Outputs of similar age
#31,388
of 298,224 outputs
Outputs of similar age from Journal for Immunotherapy of Cancer
#1
of 1 outputs
Altmetric has tracked 21,784,478 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 93rd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,685 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 14.4. This one has done well, scoring higher than 87% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 298,224 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 89% of its contemporaries.
We're also able to compare this research output to 1 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them