Adoptive cell therapy using tumor‐infiltrating lymphocytes for melanoma refractory to immune‐checkpoint inhibitors

• DOI: 10.1111/cas.15009
• Publication Date: 2021-06-08T22:14:24Z
• Authors: Ikuko Hirai; Takeru Funakoshi; Hajime Kamijuku; Keitaro Fukuda; Mariko Mori; Masatoshi Sakurai; Yuya Koda; Jun Kato; Takehiko Mori; Naohide Watanabe; Shinobu Noji; Tomonori Yaguchi; Takashi Iwata; Shigeki Ohta; Tomonobu Fujita; Ryuji Tanosaki; Makoto Handa; Shinichiro Okamoto; Masayuki Amagai; Yutaka Kawakami
• Keywords: Immune checkpoint; Tumor-infiltrating lymphocytes

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated immunological and genetic factors pretreatment tumor expanded TILs that may be associated clinical response. The treatment protocol comprised preparation TIL culture, lympho-depleting non-myeloablative preconditioning cyclophosphamide fludarabine, infusion, intravenous administration low-dose IL-2. Three subtypes mucosal, superficial spreading, acral underwent TIL-ACT. Most severe adverse events, including fever leukopenia, were manageable supportive regimen specified protocol, suggesting TIL-ACT is suitable for melanoma. One patient showed a short-term partial response, one relatively long-stable disease, experienced disease progression. Whole-exome transcriptional sequencing isolated cells immunohistochemical analyses before revealed various immunostimulatory factors, high mutation burden immune cell-recruiting chemokines, as well immunosuppressive TGF-β, VEGF, Wnt/β-catenin, MAPK signaling epithelial-to-mesenchymal transition, which might influence efficacy Our results imply mechanisms antitumor effect resistance to Further studies immune-resistant are warranted. This registered UMIN Clinical Trial Registry (UMIN 000011431).