LTX-315 and adoptive cell therapy using tumor-infiltrating lymphocytes in patients with metastatic soft tissue sarcoma.
Authors: Nielsen Morten , Monberg Tine , Albieri Benedetta , Sundvold Vibeke , Rekdal Oystein , Junker Niels , Svane Inge Marie 
Published: June 2022

11567

Background: Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) is a potent treatment that can induce complete and durable tumor regression as documented in patients with metastatic melanoma. To our knowledge, ACT has not been utilized for patients with metastatic soft-tissue sarcoma (STS). LTX-315 is an oncolytic peptide that has been shown to increase TILs in malignant tumors after intratumoral injection. In this trial, patients with metastatic sarcoma were treated with the combination of LTX-315 and TIL - based ACT. Methods: Patients with progressive metastatic STS after a minimum of one systemic treatment were eligible for inclusion. In step 1, patients received up to five treatments over 2-3 weeks with LTX-315 injections. Afterwards, the injected tumor was surgically removed, and TILs were expanded in vitro. In step 2, patients received preparative chemotherapy followed by infusion of the expanded TILs, and follow-up treatment with subcutaneous IL-2. The impact of LTX-315 on tumor microenvironment was assessed by immunohistochemistry (IHC) on biopsies collected before and after injections. Clinical effect of the treatment was assessed by follow-up CT-scans using RECIST 1.1. Exploratory analyses aimed at identifying tumor reactive T cells in the expanded TILs and in peripheral blood (PBMC) in the patients before and after treatment. Expanded TILs or PBMC were cocultured with autologous tumor or selected neo-peptides and reactivity was assessed by measurement by Elispot or flow cytometry. Results: Six patients received intratumoral injections with LTX-315. In 3 out of 5 samples available for IHC, increased infiltration of CD4+ cells following LTX-315 injections was observed. Four patients received the full treatment with both LTX-315 injections and ACT. Total number of infused cells was 44-63x109, comprising 0,4-52% CD8+ T cells. Treatment was tolerated with manageable toxicity. After completed treatment, all four patients had stable disease as best overall response. Two patients with leiomyosarcoma and solitary fibrous tumor had stable disease for 25 and 20 weeks, respectively. In these two patients, and one additional patient, Elispot analyses showed presence of tumor-reactive cells in the PBMC following treatment. Conclusions: This trial demonstrates that the combination of LTX-315 and ACT is feasible and tolerable with manageable toxicity. CD4+ and CD8+ TILs can be expanded in vitro from sarcomas that have been pretreated with the oncolytic peptide LTX-315. Furthermore, the data suggest that LTX-315 can modulate the tumor microenvironment in sarcomas, thus potentially affect the expanded TILs that can be used for ACT. Further optimization of the treatment schedule will position LTX-315 as technology to invoke tumor specific T cells that can be cultured and infused as part of an adoptive transfer regimen for several subtypes of soft tissue sarcoma. Clinical trial information: NCT03725605.