Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2

Abstract

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vβ chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.)

Rapid recovery of postnivolumab vemurafenib-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome after tocilizumab and infliximab administration

“…This equilibrium allowed to obtain promising results from the clinical therapeutic application of IL-2 in the trial in patients with metastatic melanoma. [28][29][30] Despite the development of new therapeutic approaches, high-dose IL-2 remains an important option for patients with melanoma and has an improved therapeutic window in the current era. 31 Three chemokine proteins that were reproducibly detected in abundance in the T-cell-rich melanoma were MCP-1/ CCL2, MIP-1β/CCL4, and RANTES/CCL5, while most melanoma cell lines showed expression predominantly of IL-8/CXCL8 only.…”

DNT Cell-based Immunotherapy: Progress and Applications

“…In 2018, the Nobel Prize in physiology or medicine was awarded to immunologists for the discovery of treatments that suppress negative immunoregulation, which conferred mainstream status on cancer immunotherapy [3,4]. Currently, tumor immunotherapies mainly include immune checkpoint inhibitors [5][6][7][8], oncolytic viruses [9], antitumor vaccines [10,11] and adoptive cellular immunotherapy (ACI) [12][13][14][15]. ACI has been used in the clinic and has achieved great clinical benefits for malignant tumors [16,17].…”

Overproduction of IL-2 by Cbl-b deficient CD4 + T cells provides resistance against regulatory T cells

“…76 Adoptive T cell therapies using TILs routinely include IL-2. [77][78][79][80][81][82][83] However, controversies surrounding its ability to promote T cell survival versus the detrimental effects of Treg cell expansion has been unclear. Our studies suggest that if patients are treated with TIL and high dose IL-2, it may lead to the expansion of Treg cells due to the presence of high dose IL-2 but this may not necessarily be detrimental if it occurs together with the development of resistance to the inhibitory effects of Treg cells.…”