Isolation of T_CM cells for tumour immunotherapy

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Reporting in Science Translational Medicine, Wang et al. describe a method to prospectively identify rare human melanoma-specific CD8⁺ central memory T cells (T_CM cells) based on cytokine production.

a method to identify and isolate rare tumour-specific T_CM cells that can persist following... adoptive transfer

Animal studies have suggested that T_CM cells can survive long-term after adoptive transfer. Human T_CM cells have been reported to produce more interleukin-2 (IL-2) and less interferon-γ (IFNγ) than effector memory T cells (T_EM cells), and therefore the authors hypothesized that these cell populations could be identified based on their relative production of these cytokines. Indeed, a high IL2/IFNG mRNA ratio in peripheral blood cells following short-term T cell stimulation correlated with the T_CM cell phenotype.

Using a previously described high-throughput method to screen for tumour-specific CD8⁺ T cells, rare tumour-specific T_CM cells were isolated from patients with melanoma based on their high IL2/IFNG mRNA ratio. Effector T cell clones generated from tumour-specific T_EM cells (which have a low IL2/IFNG mRNA ratio) or T_CM cells had similar cytolytic activities, but T_CM cell-derived T cell clones had a distinct gene expression profile associated with cell survival.

In a pilot clinical trial, T_CM cells specific for gp100 (also known as PMEL) were isolated from five patients with metastatic melanoma. Effector T cell clones were then derived from these cells and adoptively transferred back into the same patients. Five days after infusion, the effector T cells were found to be targeting gp100-expressing melanocytes, resulting in the induction of autoimmune dermatitis. These data indicate that the transferred T cells were functional in vivo.

Importantly, the transferred cells were present in the blood at considerable frequencies in four of the five patients 1 month after transfer, and beyond 100 days in the one patient who was assessed for this time period. Furthermore, a subset of the persisting clones had regained a T_CM cell phenotype and the ability to produce IL-2. However, no tumour regression was observed in these patients. This may have been due to the high expression levels of negative regulatory molecules (namely CTLA4, PD1 and TIM3) on the effector T cell clones.

So, this study describes a method to identify and isolate rare tumour-specific T_CM cells that can persist following the adoptive transfer of the derived T cell clones. But, further work is needed to improve their antitumour efficacy, which may be achieved by combining this approach with drugs that block the negative regulatory molecules or by modulating the immunosuppressive tumour microenvironment.