A novel AXL chimeric antigen receptor endows T cells with anti-tumor effects against triple negative breast cancers

Wei, Jing; Sun, Huiyan; Zhang, Aimei; Wu, Xuejie; Li, Yuxiang; Liu, Jiawei; Duan, Yanran; Xiao, Fengjun; Wang, Hua; Lv, Ming; Wang, Lisheng; Wu, Chu-Tse

doi:10.1016/j.cellimm.2018.05.004

Cited by 75 publications

(63 citation statements)

References 42 publications

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“…Severe allergic reactions, cytokine release syndrome, and neurologic toxicities have been documented with cellular therapies, often requiring inpatient administration and monitoring [61]. Potential targets under investigation for cellular therapy in TNBC include MUC1 [62], NKG2D [63], AXL [64], TEM8/ANTXR1 [65], FRα [66], mesothelin (NCT02892114), and ROR1 (NCT02706392). Preliminary data of 4 TNBC patients treated with ROR1+ CAR-T cells has been presented, with 2 patients demonstrating stable disease (one at 15 weeks, one at 19 weeks), and one patient with partial response after a 2nd infusion [67].…”

Section: Cellular Therapymentioning

confidence: 99%

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

Kim

Sanchez

McArthur

et al. 2019

Curr Breast Cancer Rep

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Purpose of Review Immunotherapy is emerging as an effective treatment option for metastatic triple-negative breast cancer. In this review, we summarize clinical data of immunotherapy in triple-negative breast cancer and comment on future directions in the field. Recent Findings IMpassion130 was a phase III trial that demonstrated progression-free survival benefit, and potentially overall survival benefit, of first-line chemotherapy (nab-paclitaxel) plus anti-programmed death ligand 1 (PD-L1) atezolizumab, among PD-L1-positive metastatic triple-negative breast cancers. Studies are ongoing to evaluate other combination therapies with immune checkpoint blockade in TNBC, and to evaluate efficacy in PD-L1-negative tumors and in later lines of therapy. Summary Immunotherapy is now a standard option in the treatment of triple-negative breast cancer. Ongoing trials may expand the degree of clinical benefit. Further work is ongoing to identify novel predictive biomarkers, which in the future may enable a personalized approach of combination immunotherapy.

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Section: Cellular Therapymentioning

confidence: 99%

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

Kim

Sanchez

McArthur

et al. 2019

Curr Breast Cancer Rep

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“…In such cases of antibody resistance, Chimeric Antigen Receptor (CAR) engineered T cells [16] represent an appealing option for improving the outcome for patients with advanced breast cancer [17][18][19][20]. Several tumor-associated membrane proteins are targeted in clinical trials by CAR T cells, including HER2 (NCT02547961, NCT02713984), CEA (NCT02349724) and mesothelin (NCT02792114).…”

Section: Introductionmentioning

confidence: 99%

A Small Number of HER2 Redirected CAR T Cells Significantly Improves Immune Response of Adoptively Transferred Mouse Lymphocytes against Human Breast Cancer Xenografts

Tóth

Szöllősi

Abken

et al. 2020

IJMS

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HER2 positive JIMT-1 breast tumors are resistant to trastuzumab treatment in vitro and develop resistance to trastuzumab in vivo in SCID mice. We explored whether these resistant tumors could still be eliminated by T cells redirected by a second-generation chimeric antigen receptor (CAR) containing a CD28 costimulatory domain and targeting HER2 with a trastuzumab-derived scFv. In vitro, T cells engineered with this HER2 specific CAR recognized HER2 positive target cells as judged by cytokine production and cytolytic activity. In vivo, the administration of trastuzumab twice weekly had no effect on the growth of JIMT-1 xenografts in SCID mice. At the same time, a single dose of 2.5 million T cells from congenic mice exhibited a moderate xenoimmune response and even stable disease in some cases. In contrast, when the same dose contained 7% (175,000) CAR T cells, complete remission was achieved in 57 days. Even a reduced dose of 250,000 T cells, including only 17,500 CAR T cells, yielded complete remission, although it needed nearly twice the time. We conclude that even a small number of CAR T lymphocytes can evoke a robust anti-tumor response against an antibody resistant xenograft by focusing the activity of xenogenic T cells. This observation may have significance for optimizing the dose of CAR T cells in the therapy of solid tumors.

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“…Pharmacological inhibition of AXL has also been shown to decrease metastasis in breast cancer models (19,41) and improve the efficacy of doxorubicin, BCR-ABL inhibitor, docetaxel, paclitaxel, EGFR inhibitor and nivolumab in breast cancer, chronic myelogenous leukemia, prostate cancer, uterine serous cancer, NSCLC and glioblastoma models, respectively (11,19,(42)(43)(44)(45). (46,47). AXL has also been investigated as a target for antibody drug conjugates in melanoma, lung, pancreatic and cervical cancer models, some of which have advanced to phase 1 clinical testing (48).…”

Section: Discussionmentioning

confidence: 99%

AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer

Huang

Wang

et al. 2020

Preprint

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AbstractPancreatic ductal adenocarcinoma (PDA), a leading cause of cancer-related death in the US, has a high metastatic rate and is associated with persistent immune suppression. AXL, a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family, has been identified as a driver of metastasis and immune suppression in multiple cancer types. Here we use single cell RNA sequencing to reveal that AXL is expressed highly in tumor cells that have a mesenchymal-like phenotype and that AXL expression correlates with classic markers of mesenchymal tumor cells. We demonstrate that AXL-deficiency extends survival, reduces primary and metastatic burden and enhances sensitivity to gemcitabine in an autochthonous model of PDA. PDA in AXL-deficient mice displayed a more differentiated histology, higher nucleoside transporter expression and a more active immune microenvironment compared to PDA in wild-type mice. Finally, we demonstrate that AXL-positive mesenchymal tumor cells are critical for PDA progression and metastasis, emphasizing the potential of AXL as a therapeutic target for PDA patients.

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A novel AXL chimeric antigen receptor endows T cells with anti-tumor effects against triple negative breast cancers

Cited by 75 publications

References 42 publications

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

Immunotherapy in Triple-Negative Breast Cancer: Present and Future

A Small Number of HER2 Redirected CAR T Cells Significantly Improves Immune Response of Adoptively Transferred Mouse Lymphocytes against Human Breast Cancer Xenografts

AXL is a key factor for cell plasticity and promotes metastasis in pancreatic cancer

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