MaltSci 麦伴科研

Appearance

Curated Papers > High-impact authoritative literature on "CAR-T therapy"

CAR T-cell therapy for pancreatic cancer. ​

Literature Information ​

DOI10.1002/jso.24627
PMID28346697
JournalJournal of surgical oncology
Impact Factor1.9
JCR QuartileQ2
Publication Year2017
Times Cited51
KeywordsCAR T cells, adoptive cell therapy, checkpoint blockade, chimeric antigen receptor, immunotherapy
Literature TypeJournal Article, Review
ISSN0022-4790
Pages63-74
Issue116(1)
AuthorsCarl J DeSelm, Zachary E Tano, Anna M Varghese, Prasad S Adusumilli

TL;DR ​

CAR T-cell therapy, which genetically modifies a patient's T cells to attack cancer cells, has shown success in treating hematological malignancies and is being explored for solid tumors like pancreatic cancer. However, challenges such as the tumor microenvironment, stromal barriers, and T cell checkpoint expression complicate its application, highlighting the need for further research to overcome these obstacles.

Search for more papers on MaltSci.com ​

CAR T cells · adoptive cell therapy · checkpoint blockade · chimeric antigen receptor · immunotherapy

Abstract ​

Chimeric antigen receptor (CAR) T-cell therapy utilizes genetic engineering to redirect a patient's own T cells to target cancer cells. The remarkable results in hematological malignancies prompted investigating this approach in solid tumors such as pancreatic cancer. The complex tumor microenvironment, stromal hindrance in limiting immune response, and expression of checkpoint blockade on T cells pose hurdles. Herein, we summarize the opportunities, challenges, and state of knowledge in targeting pancreatic cancer with CAR T-cell therapy.

MaltSci.com AI Research Service ​

Intelligent ReadingAnswer any question about the paper and explain complex charts and formulas
Locate StatementsFind traces of a specific claim within the paper
Add to KBasePerform data extraction, report drafting, and advanced knowledge mining

Primary Questions Addressed ​

  1. What specific challenges do CAR T-cell therapies face when targeting the unique tumor microenvironment of pancreatic cancer?
  2. How do the stromal components of pancreatic tumors affect the efficacy of CAR T-cell therapy?
  3. What advancements in genetic engineering could enhance the effectiveness of CAR T-cell therapy for solid tumors like pancreatic cancer?
  4. Are there specific biomarkers that could predict the response to CAR T-cell therapy in pancreatic cancer patients?
  5. How does the expression of checkpoint inhibitors on T cells influence the outcomes of CAR T-cell therapy in pancreatic cancer treatment?

Key Findings ​

Research Background and Purpose ​

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death in the United States by 2030. Despite advances in systemic chemotherapy, the median overall survival for patients with metastatic PDAC remains poor, highlighting the urgent need for novel therapeutic strategies. Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable success in hematological malignancies and is being explored for its potential in treating solid tumors like pancreatic cancer. This review summarizes the opportunities and challenges associated with CAR T-cell therapy for PDAC.

Main Methods/Materials/Experimental Design ​

The review outlines the mechanisms of CAR T-cell therapy, focusing on the genetic engineering of T cells to express CARs that target specific tumor antigens. The authors detail the different generations of CARs, particularly the advantages of second- and third-generation CARs, which incorporate costimulatory domains to enhance T-cell activation and persistence.

Key Components of CAR T-cell Therapy for PDAC ​

Mermaid diagram

Key Results and Findings ​

  1. Tumor Antigens: Various antigens, including mesothelin, carcinoembryonic antigen (CEA), MUC1, prostate stem cell antigen (PSCA), and CD24, are being targeted in ongoing clinical trials.
  2. Clinical Trials: Early-phase clinical trials have shown some promise, with evidence of tumor response and stable disease in patients receiving CAR T-cell therapy targeting mesothelin.
  3. Preconditioning Regimens: Lymphodepletion prior to CAR T-cell therapy has been associated with improved T-cell engraftment and therapeutic efficacy.
  4. Challenges: The complex tumor microenvironment of PDAC presents significant hurdles, including stromal barriers and immune checkpoint expression, which can limit the effectiveness of CAR T-cell therapy.

Main Conclusions/Significance/Innovation ​

CAR T-cell therapy holds potential as a treatment for pancreatic cancer, particularly when combined with strategies to enhance T-cell infiltration and activity in the tumor microenvironment. The review emphasizes the importance of selecting appropriate target antigens and the need for innovative approaches to overcome the immunosuppressive nature of pancreatic tumors. The ongoing development of armored CARs that secrete cytokines and target stromal components represents a significant advancement in the field.

Research Limitations and Future Directions ​

The review acknowledges several limitations, including:

  • The early stage of CAR T-cell therapy development for solid tumors, particularly PDAC.
  • The variability in patient responses and the complexity of the tumor microenvironment.

Future research directions include:

  • Continued exploration of optimal preconditioning regimens and combination therapies (e.g., checkpoint inhibitors).
  • Investigating additional tumor-specific antigens and improving CAR T-cell persistence and efficacy.
  • Developing novel strategies to target the stromal components of pancreatic cancer to enhance treatment outcomes.

Overall, while CAR T-cell therapy for pancreatic cancer is still in its infancy, there is significant optimism regarding its potential, particularly as more sophisticated approaches are developed to address the unique challenges posed by solid tumors.

References ​

  1. Immunohistochemistry of CEA in the human pancreas during development, in the adult, chronic pancreatitis, and pancreatic adenocarcinoma. - G H Albers;G Fleuren;M J Escribano;M Nap - American journal of clinical pathology (1988)
  2. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. - Daniel D Von Hoff;Thomas Ervin;Francis P Arena;E Gabriela Chiorean;Jeffrey Infante;Malcolm Moore;Thomas Seay;Sergei A Tjulandin;Wen Wee Ma;Mansoor N Saleh;Marion Harris;Michele Reni;Scot Dowden;Daniel Laheru;Nathan Bahary;Ramesh K Ramanathan;Josep Tabernero;Manuel Hidalgo;David Goldstein;Eric Van Cutsem;Xinyu Wei;Jose Iglesias;Markus F Renschler - The New England journal of medicine (2013)
  3. The dual adverse effects of TGF-beta secretion on tumor progression. - Joseph A Trapani - Cancer cell (2005)
  4. Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. - Elliot L Servais;Christos Colovos;Luis Rodriguez;Adam J Bograd;Jun-ichi Nitadori;Camelia Sima;Valerie W Rusch;Michel Sadelain;Prasad S Adusumilli - Clinical cancer research : an official journal of the American Association for Cancer Research (2012)
  5. Prostate stem cell antigen: a Jekyll and Hyde molecule? - Norihisa Saeki;Jian Gu;Teruhiko Yoshida;Xifeng Wu - Clinical cancer research : an official journal of the American Association for Cancer Research (2010)
  6. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. - Nobuyoshi Hiraoka;Kaoru Onozato;Tomoo Kosuge;Setsuo Hirohashi - Clinical cancer research : an official journal of the American Association for Cancer Research (2006)
  7. Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer. - Kouichirou Aida;Reina Miyakawa;Koji Suzuki;Kenta Narumi;Takeshi Udagawa;Yuki Yamamoto;Tatsuya Chikaraishi;Teruhiko Yoshida;Kazunori Aoki - Cancer science (2014)
  8. Changing the course of pancreatic cancer--Focus on recent translational advances. - Milind Javle;Talia Golan;Anirban Maitra - Cancer treatment reviews (2016)
  9. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. - Mark E Dudley;John R Wunderlich;Paul F Robbins;James C Yang;Patrick Hwu;Douglas J Schwartzentruber;Suzanne L Topalian;Richard Sherry;Nicholas P Restifo;Amy M Hubicki;Michael R Robinson;Mark Raffeld;Paul Duray;Claudia A Seipp;Linda Rogers-Freezer;Kathleen E Morton;Sharon A Mavroukakis;Donald E White;Steven A Rosenberg - Science (New York, N.Y.) (2002)
  10. CAR therapy: the CD19 paradigm. - Michel Sadelain - The Journal of clinical investigation (2015)

Literatures Citing This Work ​

  1. Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes. - Marie Rouanet;Marine Lebrin;Fabian Gross;Barbara Bournet;Pierre Cordelier;Louis Buscail - International journal of molecular sciences (2017)
  2. Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy. - Neus Martinez-Bosch;Judith Vinaixa;Pilar Navarro - Cancers (2018)
  3. Driving CARs on the uneven road of antigen heterogeneity in solid tumors. - Nan Chen;Xiaoyu Li;Navin K Chintala;Zachary E Tano;Prasad S Adusumilli - Current opinion in immunology (2018)
  4. The Role of Mesothelin as a Diagnostic and Therapeutic Target in Pancreatic Ductal Adenocarcinoma: A Comprehensive Review. - Federico Nichetti;Antonio Marra;Francesca Corti;Alessandro Guidi;Alessandra Raimondi;Natalie Prinzi;Filippo de Braud;Sara Pusceddu - Targeted oncology (2018)
  5. Immunotherapy and Prevention of Pancreatic Cancer. - Alexander H Morrison;Katelyn T Byrne;Robert H Vonderheide - Trends in cancer (2018)
  6. Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options. - Derya Kabacaoglu;Katrin J Ciecielski;Dietrich A Ruess;Hana Algül - Frontiers in immunology (2018)
  7. Gene Therapy for Pancreatic Diseases: Current Status. - Kenya Kamimura;Takeshi Yokoo;Shuji Terai - International journal of molecular sciences (2018)
  8. Low-Dose Radiation Conditioning Enables CAR T Cells to Mitigate Antigen Escape. - Carl DeSelm;M Lia Palomba;Joachim Yahalom;Mohamad Hamieh;Justin Eyquem;Vinagolu K Rajasekhar;Michel Sadelain - Molecular therapy : the journal of the American Society of Gene Therapy (2018)
  9. Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment. - Chin-King Looi;Felicia Fei-Lei Chung;Chee-Onn Leong;Shew-Fung Wong;Rozita Rosli;Chun-Wai Mai - Journal of experimental & clinical cancer research : CR (2019)
  10. A long way to the battlefront: CAR T cell therapy against solid cancers. - Zhicai Wang;Wei Chen;Xing Zhang;Zhiming Cai;Weiren Huang - Journal of Cancer (2019)

... (41 more literatures)

© 2025 MaltSci - We reshape scientific research with AI technology