Genetic Redirection of T Cells for the Treatment of Pancreatic Cancer.

Aesha I Ali,Jack D Chan,Tinaz Samiei,Clare Y Slaney,Amanda J Oliver,Michael H Kershaw

doi:10.3389/fonc.2019.00056

Aesha I Ali, Jack D Chan + Show 4 more

Open Access

https://doi.org/10.3389/fonc.2019.00056

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Abstract

Conventional treatments for pancreatic cancer are largely ineffective, and the prognosis for the vast majority of patients is poor. Clearly, new treatment options are desperately needed. Immunotherapy offers hope for the development of treatments for pancreatic cancer. A central requirement for the efficacy of this approach is the existence of cancer antigen-specific T cells, but these are often not present or difficult to isolate for most pancreatic tumors. Nevertheless, specific T cells can be generated using genetic modification to express chimeric antigen receptors (CAR), which can enable T cell responses against pancreatic tumor cells. CAR T cells can be produced ex vivo and expanded in vitro for infusion into patients. Remarkable responses have been documented using CAR T cells against several malignancies, including leukemias and lymphomas. Based on these successes, the extension of CAR T cell therapy for pancreatic cancer holds great promise. However, there are a number of challenges that limit the full potential of CAR T cell therapies for pancreatic cancer, including the highly immunosuppressive tumor microenvironment (TME). In this article, we will review the recent progress in using CAR T cells in pancreatic cancer preclinical and clinical settings, discuss hurdles for utilizing the full potential of CAR T cell therapy and propose research strategies and future perspectives. Research into the use of CAR T cell therapy in pancreatic cancer setting is rapidly gaining momentum and understanding strategies to overcome the current challenges in the pancreatic cancer setting will allow the development of effective CAR T cell therapies, either alone or in combination with other treatments to benefit pancreatic cancer patients.

Highlights

Pancreatic cancer presents a major challenge in the clinic and is one of the most aggressive tumor types
This review aims to summarize the recent development of cellular therapies and clinical data in chimeric antigen receptors (CAR) T cell trials for pancreatic cancer
Surviving mice that received adoptive cell transfer incorporating vaccination” (ACTIV) therapy developed potent immune memory responses against pre-existing tumor cells. These results provide encouraging evidence for the investigation and development of dual-specific T cells for the treatment of difficult cancers including pancreatic cancer

Summary

Introduction

Pancreatic cancer presents a major challenge in the clinic and is one of the most aggressive tumor types. The most common clinical therapeutic approaches against pancreatic cancer include surgical resection, radiotherapy, chemotherapy, and combination of these treatments [5]. CAR T Cell Strategies for Pancreatic Cancer [6,7,8] because most patients that present to the clinic are with advanced or metastatic disease [9]. In the last two decades, chemotherapy and targeted therapy (such as Erlotinib targeting epidermal growth factor receptor, Sunitinib targeting multiple receptor tyrosine kinases, and Everolimus targeting mTOR kinase) have been used for patients with unresectable locally advanced or metastatic pancreatic cancer [11], these have only generated modest improvements in survival [12, 13]. The need to develop alternative effective therapies for pancreatic cancer is urgent

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