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Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion

The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma

Tavera, René J.*; Forget, Marie-Andrée*; Kim, Young Uk*; Sakellariou-Thompson, Donastas*; Creasy, Caitlin A.*; Bhatta, Ankit*; Fulbright, Orenthial J.*; Ramachandran, Renjith*; Thorsen, Shawne T.*; Flores, Esteban*; Wahl, Arely*; Gonzalez, Audrey M.*; Toth, Christopher*; Wardell, Seth*; Mansaray, Rahmatu*; Radvanyi, Laszlo G.*; Gombos, Dan S.; Patel, Sapna P.*; Hwu, Patrick*; Amaria, Rodabe N.*; Bernatchez, Chantale*; Haymaker, Cara*

doi: 10.1097/CJI.0000000000000230
Basic Studies

In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy—the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8+ TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8+CD3+ TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks. Finally, providing the 3 signals attributed to optimal T-cell activation led to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma. This new methodology for the initial phase of TIL expansion brings a new opportunity for translation of TIL therapy in challenging malignancies such as uveal melanoma.

Departments of *Melanoma Medical Oncology

Head and Neck Surgery, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX

R.J.T. and M.-A.F. contributed equally.

Reprints: Cara Haymaker, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Unit 904, 7455 Fannin, Houston, TX 77054 (e-mail:

Received February 28, 2018

Accepted April 8, 2018

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