CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30− Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions

Hong, Lee K.; Chen, Yuhui; Smith, Christof C.; Montgomery, Stephanie A.; Vincent, Benjamin G.; Dotti, Gianpietro; Savoldo, Barbara

doi:10.1158/2326-6066.cir-18-0065

Cited by 60 publications

(56 citation statements)

References 50 publications

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“…More recently, FasL on CAR T cells has been shown to induce embryonal carcinoma death independent of target antigen expression, especially after Fas was ectopically expressed in the tumor. 31 We found that another death-inducing ligand, Figure 3. Sensitizing RT Transcriptionally Primes Pancreatic Cancer Cells for TRAIL-Induced Death (A) RNA expression levels of signaling molecules known to mediate various TRAIL responses, including survival and migration, tumor-supportive inflammation, necroptosis, apoptosis, and death receptor endocytosis, were quantified by RNA-seq before and after RT exposure to Capan2 pancreatic cancer cells in three biologic replicates.…”

Section: Discussionmentioning

confidence: 89%

Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape

et al. 2018

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CD19 chimeric antigen receptors (CARs) have demonstrated great efficacy against a range of B cell malignancies. However, antigen escape and, more generally, heterogeneous antigen expression pose a challenge to applying CAR therapy to a wide range of cancers. We find that low-dose radiation sensitizes tumor cells to immune rejection by locally activated CAR T cells. In a model of pancreatic adenocarcinoma heterogeneously expressing sialyl Lewis-A (sLeA), we show that not only sLeA + but also sLeAtumor cells exposed to low-dose radiation become susceptible to CAR therapy, reducing antigennegative tumor relapse. RNA sequencing analysis of low-dose radiation-exposed tumors reveals the transcriptional signature of cells highly sensitive to TRAIL-mediated death. We find that sLeA-targeted CAR T cells produce TRAIL upon engaging sLeA + tumor cells, and eliminate sLeA À tumor cells previously exposed to systemic or local low-dose radiation in a TRAILdependent manner. These findings enhance the prospects for successfully applying CAR therapy to heterogeneous solid tumors. Local radiation is integral to many tumors' standard of care and can be easily implemented as a CAR conditioning regimen.

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Section: Discussionmentioning

confidence: 89%

Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape

et al. 2018

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“…To detect the side population (SP) cells, Hoechst 33342 samples were excited using a 355 nm UV laser on a LSRII/Fortessa flow cytometer (BD Biosciences; refs. 21,22).…”

Section: Side Population Staining By Hoechst Dyementioning

confidence: 99%

Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15

Chen

Sun

Landoni

et al. 2019

Clinical Cancer Research

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144

124

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Purpose: A delay in encountering the cognate antigen while in the circulation, and the suboptimal costimulation received at the tumor site are key reasons for the limited activity of chimeric antigen receptor-redirected T cells (CAR-T) in solid tumors. We have explored the benefits of incorporating the IL15 cytokine within the CAR cassette to provide both a survival signal before antigen encounter, and an additional cytokine signaling at the tumor site using a neuroblastoma tumor model. Experimental Design: We optimized the construct for the CAR specific for the NB-antigen GD2 without (GD2.CAR) or with IL15 (GD2.CAR.15). We then compared the expansion, phenotype, and antitumor activity of T cells transduced with these constructs against an array of neuroblastoma cell lines in vitro and in vivo using a xenogeneic metastatic model of neuroblastoma. Results: We observed that optimized GD2.CAR.15-Ts have reduced expression of the PD-1 receptor, are enriched in stem cell-like cells, and have superior antitumor activity upon repetitive tumor exposures in vitro and in vivo as compared with GD2.CAR-Ts. Tumor rechallenge experiments in vivo further highlighted the role of IL15 in promoting enhanced CART antitumor activity and survival, both in the peripheral blood and tissues. Finally, the inclusion of the inducible caspase-9 gene (iC9) safety switch warranted effective on demand elimination of the engineered GD2. CAR.15-Ts. Conclusions: Our results guide new therapeutic options for GD2.CAR-Ts in patients with neuroblastoma, and CART development for a broad range of solid tumors.

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“…Further investigation of CDK4/6 inhibition for the treatment of teratoma is required based on the preliminary results indicating the safety and potential clinical benefit [ 115 ]. Similarly, immune checkpoint inhibitors in MOGCTs need to be unraveled [ 115 , 116 ].…”

Section: Management Of Malignant Ovarian Germ Cell Tumors (Mogcts)mentioning

confidence: 99%

Wise Management of Ovarian Cancer: On the Cutting Edge

Boussios

Mikropoulos

Samartzis

et al. 2020

JPM

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Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20–40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.

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CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30− Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions

Cited by 60 publications

References 50 publications

Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape

Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape

Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15

Wise Management of Ovarian Cancer: On the Cutting Edge

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