4-1BB agonist focuses CD8+ tumor-infiltrating T-Cell growth into a distinct repertoire capable of tumor recognition in pancreatic cancer

Donastas Sakellariou-Thompson, Marie Andrée Forget, Caitlin Creasy, Vincent Bernard, Li Zhao, Young Uk Kim, Mark W. Hurd, Naohiro Uraoka, Edwin Roger Parra, Ya'an Kang, Christopher A. Bristow, Jaime Rodriguez-Canales, Jason B. Fleming, Gauri Varadhachary, Milind Javle, Michael J. Overman, Hector A. Alvarez, Timothy P. Heffernan, Jianhua Zhang, Patrick HwuAnirban Maitra, Cara Haymaker, Chantale Bernatchez

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Purpose: Survival for pancreatic ductal adenocarcinoma (PDAC) patients is extremely poor and improved therapies are urgently needed. Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) has shown great promise in other tumor types, such as metastatic melanoma where overall response rates of 50% have been seen. Given this success and the evidence showing that T-cell presence positively correlates with overall survival in PDAC, we sought to enrich for CD8+ TILs capable of autologous tumor recognition. In addition, we explored the phenotype and T-cell receptor repertoire of the CD8+ TILs in the tumor microenvironment. Experimental Design: We used an agonistic 4-1BB mAb during the initial tumor fragment culture to provide 4-1BB costimulation and assessed changes in TIL growth, phenotype, repertoire, and antitumor function. Results: Increased CD8+ TIL growth from PDAC tumors was achieved with the aid of an agonistic 4-1BB mAb. Expanded TILs were characterized by an activated but not terminally differentiated phenotype. Moreover, 4-1BB stimulation expanded a more clonal and distinct CD8+ TIL repertoire than IL2 alone. TILs from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets. Conclusions: Costimulation with an anti-4-1BB mAb increases the feasibility of TIL therapy by producing greater numbers of these tumor-reactive T cells. These results suggest that TIL ACT for PDAC is a potential treatment avenue worth further investigation for a patient population in dire need of improved therapy.

Original languageEnglish (US)
Pages (from-to)7263-7275
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

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  • Tissue Biospecimen and Pathology Resource
  • Cytogenetics and Cell Authentication Core
  • Clinical Trials Office

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