Tumor infiltrating lymphocyte (TIL) harvest and ex vivo expansion from primary and metastatic (met) uveal melanoma (UM) tumors.
Authors: Patel Sapna Pradyuman , Forget Marie-Andree , Kreidieh Firas Y. , Pelster Meredith , Davies Michael A. , Amaria Rodabe Navroze , Gombos Dan S. , Bernatchez Chantale 
Published: June 2023

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Background: Adoptively transferred autologous cell therapy using tumor-infiltrating lymphocytes (TIL) is an emerging treatment for met melanoma. Responses have been seen in patients (pts) with checkpoint inhibitor-naïve and -refractory cutaneous melanoma. UM represents a disease subtype that is traditionally less responsive to immune checkpoint blockade (ICB). Preliminary studies have shown clinical utility of TIL in UM pts. However, data describing the success rates of TIL harvest and ex vivo expansion of cells from primary and met UM tumors, and of the treatment of pts with met UM, is limited. Methods: Between 2004 and 2019, we conducted a single-center IRB-approved trial (NCT NCT00338377) for TIL harvest in pts age 18 and older with documented met melanoma, including UM pts. The protocol was amended to allow harvest of primary UM tumors in 2015 if the pt was dispositioned for enucleation as primary treatment. Results: A total of 96 UM pts underwent TIL harvest; 9 underwent treatment with TIL. Median age was 54 years (range: 28 – 86); 56% of the pts were male; 78% were Caucasian, 9% Hispanic, and 13% unknown ethnicity. Overall successful ex vivo expansion of TIL occurred in 34.8% (32/92) of UM tumors in typical tumor fragment culture with IL-2 (TIL 1.0), with higher rates observed with UM mets (29/65; 44.6%) than UM primary tumors (3/27; 11.1%). Better results were observed with a culture method (TIL 3.0) that includes agonistic stimulation of CD3 and 41BB, with 96.8% (30/31 tumors). Expansion using this new method was successful in 9/10 primary UM tumors and 21/21 UM mets. Average number of days in culture for successful initial ex vivo expansion was 33.0 days for TIL 1.0 and 17.9 days for TIL 3.0 ( p-value<0.0001). Overall, the average number of TIL expanded from culture and cryopreserved for clinical use was 130.4 million for TIL 1.0 (range: 34-460) and 326.2 million for TIL 3.0 (range 102-760) ( p-value<0.0001). Nine met UM pts received treatment with up to 150 x 109 post-Rapid Expansion Protocol (REP) TIL (5 TIL 1.0, 4 TIL 3.0). Median age was 53, 44% were male, and all had active liver mets with a median of 3 lines of prior treatment for advanced disease. 8 of the TIL products were from UM mets (4 soft tissue, 3 liver, 1 combination of soft tissue and liver tumors), and 1 was from primary UM tumor, for which TIL could only be expanded with TIL 3.0. Best overall response rate per immune-related response criteria was 22% partial response (PR, duration of response was 22.1 months and 16.5 months), 44% stable disease (SD), and 33% progression of disease (PD) for a disease control rate of 66% (PR + SD). Both responding pts had TIL harvests from mets and had previously progressed on ICB, one was treated with TIL 3.0. Conclusions: TIL harvest and successful ex vivo expansion of cells is possible from both primary and met UM with TIL 3.0 culture method and can be therapeutically effective. Clinical trial information: NCT00338377 .