4 years ago

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

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells
Caroline Boudousquie, Namir J. Hassan, Bent K. Jakobsen, Jacob M. Hurst, Giovanna Bossi, Karolina A. Rygiel
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™ 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-α, interferon-γ, interleukin-6) and chemokines (macrophage inflammatory protein-1α-β, interferon-γ-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. Immune mobilizing monoclonal T cell receptor against cancer (ImmTAC) recognizing melanoma-associated protein gp100 redirects and activates T cells from CD8+ and CD4+ repertoires to kill tumour cells. The most potent killers are CD8+ terminally differentiated effector T cells / effector memory T cells (Tem) and CD4+ Tem subpopulations. In addition to their cytotoxic properties, activated T lymphocytes secrete a broad array of cytokines/chemokines and display a polyfunctional phenotype – hallmarks of a durable anti-cancer response.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/imm.12779

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