T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma

Stromnes, Ingunn M.; Schmitt, Thomas M.; Hulbert, Ayaka; Brockenbrough, J. Scott; Nguyen, Hat; Cuevas, Carlos; Dotson, Ashley M.; Tan, Xiaoxia; Hotes, Jennifer L.; Greenberg, Philip D.; Hingorani, Sunil R.

doi:10.1016/j.ccell.2015.09.022

Cited by 169 publications

(243 citation statements)

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“…CAR-T cells have the ability to gain access to the epithelial cell compartment by invading through the ECM and evading immunosuppressive signals 321 . In preclinical studies CAR-T cells have been reprogrammed to recognize FAP-positive cells and target stromal cells specifically 322 .…”

Section: Tumour-stroma Targeting Strategiesmentioning

confidence: 99%

Targeting the tumour stroma to improve cancer therapy

2018

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Cancers are not merely composed of cancer cells alone and, instead, are complex ‘ecosystems’ comprising many different cell types and noncellular factors. The tumour stroma is a critical component of the tumour microenvironment, where it has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote resistance of cancer cells to such therapies, eventually resulting in fatal disease. Therefore, novel treatment strategies should combine anticancer and antistroma agents. Herein, we provide an overview of the advances in understanding the complex cancer cell–tumour stroma interactions, and discuss how this knowledge can result in more effective therapeutic strategies, which might ultimately improve patient outcomes.

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Section: Tumour-stroma Targeting Strategiesmentioning

confidence: 99%

Targeting the tumour stroma to improve cancer therapy

2018

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“…Robust clinical responses have been observed in a number of cancer types such as chronic lymphocytic leukemia and B-cell lymphoma Kochenderfer and Rosenberg 2013). Although TCRs against mesothelin, a native antigen highly expressed in PDAC, exhibited a promising survival benefit in a Kras-driven PDAC GEMM (Stromnes et al 2015), the effectiveness of these engineered T-cell therapies for human tumors remains to be determined. While multiple clinical trials are ongoing to test the safety and anti-tumor effects of various anti-mesothelin-based CARs in PDAC patients (clinical trial information: NCT01583686, NCT02465983, and NCT02580747), a phase I trial in six PDAC patients indicated that it was well tolerated ( Fig.…”

Section: Prospect Of Pdac Immunotherapymentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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“…Recently, it was shown in an elegant study that T cells engineered to express affinity-enhanced TCR can overcome intratumoural immune suppression and induce pancreatic cancer cell death 158. A similar approach is the adoptive transfer of T cells genetically modified to express a chimeric antigen receptor (CAR).…”

Section: Introductionmentioning

confidence: 99%

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

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et al. 2018

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Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

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T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma

Cited by 169 publications

References 59 publications

Targeting the tumour stroma to improve cancer therapy

Targeting the tumour stroma to improve cancer therapy

Genetics and biology of pancreatic ductal adenocarcinoma

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

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