Adoptive transfer of T cells genetically modified to express cancer-specific receptors can mediate impressive tumor regression in terminally ill patients. However, T cell function and persistence over time could be hampered by the activation of inhibitory costimulatory pathways, such as programmed death 1 (PD1)/programmed death ligand 1, leading to T cell exhaustion and providing tumor cells with an escape mechanism from immunosurveillance. In addition, the lack of positive costimulation at the tumor site can further dampen T cell response. Thus, as T cell genetic engineering has become clinically relevant, we aimed at enhancing T cell antitumor activity by genetically diverting T cell–negative costimulatory signals into positive ones using chimeric costimulatory retargeting molecules and which are composed of the PD1 extracellular domain fused to the signaling domains of positive costimulatory molecules such as CD28 and 4-1BB. After characterizing the optimal PD1 chimera, we designed and optimized a tripartite retroviral vector that enables the simultaneous expression of this chimeric molecule in conjunction with a cancer-specific TCR. Human T cells, transduced to express a PD1/28 chimeric molecule, exhibited enhanced cytokine secretion and upregulation of activation markers upon coculture with tumor cells. These engineered cells also proliferated better compared with control cells. Finally, we tested the function of these cells in two xenograft models of human melanoma tumors and show that PD1/28-engineered human T cells demonstrated superior antitumor function. Overall, we propose that engineering T cells with a costimulatory retargeting molecule can enhance their function, which bears important implications for the improvement of T cell immunotherapy.
T-cells are central players in the immune response against both pathogens and cancer. Their specificity is solely dictated by the T-cell receptor (TCR) they clonally express. As such, the genetic modification of T lymphocytes using pathogen- or cancer-specific TCRs represents an appealing strategy to generate a desired immune response from peripheral blood lymphocytes. Moreover, notable objective clinical responses were observed in terminally ill cancer patients treated with TCR-gene modified cells in several clinical trials conducted recently. Nevertheless, several key aspects of this approach are the object of intensive research aimed at improving the reliability and efficacy of this strategy. Herein, we will survey recent studies in the field of TCR-gene transfer dealing with the improvement of this approach and its application for the treatment of malignant, autoimmune, and infectious diseases.
Programmed cell death 1 (PDCD1, best known as PD-1) is a central negative regulator of effector T cells that is involved in the etiology of chronic inflammatory conditions, viral diseases, and cancer. We have recently sought to improve T-cell functions by means of a novel chimeric co-stimulatory molecule that could divert the negative signals normally transmitted by PD-1 into positive ones. Human T cells transduced to express a fusion protein encompassing the extracellular domain of PD-1 and the intracellular portion of the co-stimulatory molecule CD28, which we named PD-1/28, exhibited an increase in cytokine secretion, the upregulation of activation markers, an improved proliferative potential and superior antineoplastic activity in xenograft models of human melanoma.
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