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

<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>.

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


Clin. Cancer Res., 2017, 23 (23)

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