4-1BB Agonist Focuses CD8<sup>+</sup> Tumor-Infiltrating T-Cell Growth into a Distinct Repertoire Capable of Tumor Recognition in Pancreatic Cancer.

Abstract

<b>Purpose:</b> 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<sup>+</sup> TILs capable of autologous tumor recognition. In addition, we explored the phenotype and T-cell receptor repertoire of the CD8<sup>+</sup> TILs in the tumor microenvironment.<b>Experimental Design:</b> 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.<b>Results:</b> Increased CD8<sup>+</sup> 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<sup>+</sup> TIL repertoire than IL2 alone. TILs from both culture conditions displayed MHC class I-restricted recognition of autologous tumor targets.<b>Conclusions:</b> 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. <i>Clin Cancer Res; 23(23); 7263-75. ©2017 AACR</i>.

EDRN PI Authors
Medline Author List
  • Alvarez HA
  • Bernard V
  • Bernatchez C
  • Bristow CA
  • Creasy C
  • Fleming JB
  • Forget MA
  • Haymaker C
  • Heffernan TP
  • Hurd MW
  • Hwu P
  • Javle M
  • Kang Y
  • Kim YU
  • Maitra A
  • Overman MJ
  • Parra ER
  • Rodriguez-Canales J
  • Sakellariou-Thompson D
  • Uraoka N
  • Varadhachary G
  • Zhang J
  • Zhao L
PubMed ID
28947567
Appears In
Clin Cancer Res, 2017 Dec, volume 23 (issue 23)