Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

The success of immune system-based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC (TM) molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti-CD3 scFv antibody) were previously shown to redirect CD8(+) and CD4(+) T cells against tumours. Here we present evidence that IMCgp100 (ImmTAC recognizing a peptide derived from the melanoma-specific protein, gp100, presented by HLA-A*0201) efficiently redirects and activates effector and memory cells from both CD8(+) and CD4(+) repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD8(+) T cells redirected by IMCgp100 are potent killers of melanoma cells. Furthermore, CD4(+) effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMCgp100. The majority of T cell subsets belonging to both the CD8(+) and CD4(+) repertoires secrete key pro-inflammatory cytokines (tumour necrosis factor-alpha, interferon-gamma, interleukin-6) and chemokines (macrophage inflammatory protein-1 alpha-beta, interferon-gamma-inducible protein-10, monocyte chemoattractant protein-1). At an individual cell level, IMCgp100-redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti-cancer response. This study demonstrates that IMCgp100 induces broad immune responses that extend beyond the induction of CD8(+) T cell-mediated cytotoxicity. These findings are of particular importance because IMCgp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma.