The research group of Dr. Harry Dolstra, Department of Laboratory Medicine - Laboratory of Hematology, published an article in the prestigious journal Blood entitled "Inhibition of Akt-signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy".
Effective T cell therapy against cancer is dependent on the formation of long-lived, stem cell-like T cells with the ability to self-renew and differentiate into potent effector cells. Here, we investigated the in vivo existence of stem cell-like antigen-specific T cells in allogeneic stem cell transplantation (allo-SCT) patients, and their ex vivo-generation for additive treatment post-transplant. Early after allo-SCT, CD8+ Tscm cells targeting minor histocompatibility antigens (MiHAs) expressed by recipient tumor cells were non-detectable, emphasizing the need for improved additive MiHA-specific T cell therapy. Importantly, MiHA-specific CD8+ T cells with an early CCR7+CD62L+CD45RO+CD27+CD28+CD95+ memory-like phenotype and gene signature could be expanded from naive precursors by inhibiting Akt-signaling during ex vivo-priming and expansion.
This resulted in a MiHA-specific CD8+ T cell population containing a high proportion of stem cell-like T cells, compared to terminally differentiated effector T cells in control cultures. Importantly, these Akt-inhibited MiHA-specific CD8+ T cells showed a superior expansion capacity both in vitro as well as in immunodeficient mice, and induced a superior anti-tumor effect in intrafemural multiple myeloma-bearing mice. These findings provide a rationale for clinical exploitation of ex vivo generated Akt-inhibited MiHA-specific CD8+ T cells in additive immunotherapy to prevent or treat relapse in allo-SCT patients.
Inhibition of Akt-signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy van der Waart AB, van de Weem NM, Maas F, Kramer CS, Kester MG, Falkenburg JH, Schaap N, Jansen JH, van der Voort R, Gattinoni L, Hobo W, Dolstra H. Blood 2014
Willemijn Hobo Anniek van der Waart Harry Dolstra
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