Abstract LB-069: Persistence of cryopreserved tumor-infiltrating lymphocyte product lifileucel (LN-144) in C-144-01 study of advanced metastatic melanoma
Authors: Viktoria Gontcharova, Sam Suzuki, Michelle R. Simpson-Abelson, Michelle Blaskovich, Cécile Chartier
Journal: Cancer Research (2019)

Abstract Adoptive cell transfer utilizing tumor-infiltrating lymphocytes (TIL) is recognized as an effective treatment in metastatic melanoma and other solid tumors eliciting durable and complete responses in heavily pretreated patients, presumably by targeting somatic mutations specific to each tumor1. We have treated patients with anti-PD-1-refractory advanced melanoma with lifileucel and reported an overall response rate of 38%2. Here, we analyzed the composition of the initial TIL products and the T cells circulating 42 days post-infusion (D42) to uncover a potential link between clonal diversity, TIL in vivo persistence, and anti-tumor activity. Since TIL products are preparations of polyclonal autologous T cells, each T cell clone expresses a unique T cell receptor (TCR) that can be identified by its complementary determining region 3 (CDR3). CDR3 of TIL products and corresponding post-infusion peripheral blood samples were subjected to RNA-seq, using iRepertoire technology (Huntsville, AL). The average number of unique TCR CDR3 sequences (uCDR3) was 17511 [3574-110797] across TIL products, with Shannon diversity indexes varying from 2.7 to 10.8. Correlation analyses revealed no association between either parameter and clinical response, suggesting that tumor-reactive T cells may be present in low and high diversity bulk TIL products. At D42, TIL clones could be detected in the circulation of all treated patients. Numbers of Shared uCDR3 ranged from 28 to 6964 unique clonotypes and represented highly variable fractions of both the TIL product and the D42 circulating T cells. A link between Shared T cell clones and clinical response was previously hypothesized3. In this study, comparable percentages of Shared uCDR3 were detected in responders and non-responders. Importantly, the majority of Shared uCDR3 were not detected in the patients’ peripheral blood at the time of enrollment, indicating that they represented intratumoral clonotypes that persisted after TIL administration. In addition, Shared uCDR3 clones represented at either high or low frequencies in the TIL product could persist for at least 6 weeks post-infusion. Finally, more than 97% of persisting clones were uniquely present in individual responding and non-responding patients, indicating a unique repertoire in each TIL preparation. Overall, the data demonstrate that a fraction of TIL clones persisted in all patients. The uniqueness of the clonal profiles associated with response highlights the challenge of identifying a single TCR as mediator of activity and supports using a polyclonal product such as bulk TILs to treat solid tumors with their associated unique, patient-specific, mutational and neoantigen spectra. 1 Rosenberg et al. CCR 2011; 2 SITC Nov2018; 3 Robbins et al. J Immunol 2004 Citation Format: Viktoria Gontcharova, Sam Suzuki, Michelle R. Simpson-Abelson, Michelle Blaskovich, Cécile Chartier. Persistence of cryopreserved tumor-infiltrating lymphocyte product lifileucel (LN-144) in C-144-01 study of advanced metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-069.