CAR T‐cell therapy for pancreatic cancer

DeSelm, Carl J.; Tano, Zachary E.; Varghese, Anna M.; Adusumilli, Prasad S.

doi:10.1002/jso.24627

Cited by 70 publications

(49 citation statements)

References 143 publications

(242 reference statements)

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“…ACT with genetically engineered cells CAR-engineered T cell (CAR-T) ACT for PDAC was very recently thoroughly reviewed [127][128][129][130][131]. Various artificial gene-design strategies targeting the cancer stroma and overcoming immunosuppressive factors have been explored to improve the effect of CAR-T ACT on PDAC.…”

Section: Actmentioning

confidence: 99%

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer resistant to traditional treatments, although a limited number of early-stage patients can undergo radical resection. Immunotherapies for the treatment of haematological malignancies as well as solid tumours have been substantially improved over the past decades, and impressive results have been obtained in recent preclinical and clinical trials. However, PDAC is likely the exception because of its unique tumour microenvironment (TME). In this review, we summarize the characteristics of the PDAC TME and focus on the network of various tumour-infiltrating immune cells, outlining the current advances in PDAC immunotherapy and addressing the effect of the PDAC TME on immunotherapy. This review further explores the combinations of different therapies used to enhance antitumour efficacy or reverse immunodeficiencies and describes optimizable immunotherapeutic strategies for PDAC. The concordant combination of various treatments, such as targeting cancer cells and the stroma, reversing suppressive immune reactions and enhancing antitumour reactivity, may be the most promising approach for the treatment of PDAC. Traditional treatments, especially chemotherapy, may also be optimized for individual patients to remodel the immunosuppressive microenvironment for enhanced therapy.

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Section: Actmentioning

confidence: 99%

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

et al. 2020

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“…Pancreatic cancer exemplifies this problem, with a number of attractive targets; however, none of these are clearly expressed on all tumor cells. 12 Sialyl Lewis A (sLeA), a surface antigen expressed on 75%-90% of pancreatic tumors 13 with low expression on normal human tissues 13 is an active antibody target in clinical trials (NCT03118349, NCT02672917, and NCT02687230). The human monoclonal 5B1 antibody targeting sLeA has demonstrated specificity for pancreatic cancer in vitro and in vivo 13 as well as safety and tolerability in pancreatic cancer patients at biologically active doses.…”

Section: Slea-specific Car T Cells Are Active Against Pancreatic Tumomentioning

confidence: 99%

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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“…In current clinical practice, CRS is more common in CAR‐T therapy for hematologic tumors. CRS is sometimes observed in CAR‐T therapy of solid tumors and can usually be rescued by treatment with high dose of glucocorticoids and vasopressors, organ function support, and the IL‐6 receptor antibodies …”

Section: Principal Challenges Of Car‐t Therapy For Solid Tumors Inclumentioning

confidence: 99%

Research progress and design optimization of CAR‐T therapy for pancreatic ductal adenocarcinoma

et al. 2019

Cancer Medicine

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Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer with limited treatment options. Chimeric antigen receptor T cells (CAR‐T) are genetically engineered T cells that can specifically kill tumor cells without major histocompatibility complex restriction. Encouraging progress in CAR‐T therapy for PDAC has been made in preclinical and early phase clinical trials. Challenges in CAR‐T therapy for solid tumors still exist, including immunosuppressive microenvironment, interstitial barrier, poor chemotaxis, and the “on‐target, off‐tumor” effect. Applying neoantigens of PDAC as targets for CAR‐T therapy, recognizing the CAR‐T subgroup with better antitumor effect, and designing a CAR‐T system targeting stroma of PDAC may contribute to develop a powerful CAR‐T therapy for PDAC in the future.

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CAR T‐cell therapy for pancreatic cancer

Cited by 70 publications

References 143 publications

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

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

Research progress and design optimization of CAR‐T therapy for pancreatic ductal adenocarcinoma

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