Membrane anchored interleukin-18 as an effective genetic adjuvant for adoptive T cell therapy of cancer

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or gene-modified T cells expressing antitumor T cell receptors (TCRs) or chimeric antigen receptors (CARs) often yields a high rate of clinical response in several types of cancer. New approaches for enhancing the functional properties of antitumor T cells could improve the clinical outcome of these treatments. The administration of cytokines can boost T-cell survival, proliferation, and capacity to subvert suppressive mechanisms, but the adverse effects of systemic administration limit their use in patients. To this end, cytokines as integral membrane proteins can both maximize the availability of cytokines to the adoptively transferred T cells and minimize toxicity. Recently we created two classes of genes, each designed to operate autonomously upon expression in T cells: genetically membrane-anchored IL-18 (memIL-18) and memIL-18 fused with the intracellular signaling portions of constitutively active (ca)TLR4 and caCD40 (memIL-18-TLR4-CD40). We confirmed the expression of the genetic adjuvants using different methods in human T cells post-mRNA transfection. Then, in a series of in vitro experiments, we showed that the mere expression of these adjuvants by CD8+ T cells (PBL) or anti-melanoma TILs exhibited enhancement of multiple functional properties upon co-culture with their target tumor cells. In conclusion, linking membrane-anchored IL-18 may offer an effective and safe tool for strongly amplifying T cell functions for adoptive T cell therapy of cancer.