Reprogramming antitumor immunity

Abstract

Regenerative medicine holds great promise in replacing tissues and organs lost to degenerative disease and injury. Applying principles of cellular reprogramming for the treatment of cancer, however, are not well established. Here we present an overview of cell-based reprogramming techniques (i.e. lineage reprogramming and stimulus-triggered acquisition of pluripotency) used in regenerative medicine, and within this context, envision how the scope of regenerative medicine may be expanded to treat metastatic cancer by revitalizing an exhausted and senescent immune system.

Improving therapy of chronic lymphocytic leukemia with chimeric antigen receptor T cells

“…This phenotypic and functional profile of terminally differentiated CD8+ T cells in CLL patients may be the result of chronic stimulation by low-affinity self-peptides. For this reason, long periods of ex vivo expansion for CAR T cell manufacturing may result in an inferior lymphocyte product that has acquired a phenotype associated with senescence, anergy or exhaustion 38 .…”

“…Furthermore, validated and clinically- approved culture systems will be required to isolate and maintain T SCM cells during the genetic modification and ex vivo culture process. Ultimately, improvements in cellular reprogramming methods may potentiate the induction of plasticity in T cells to expand the pool of T CM or T SCM cells 45 , and could perhaps produce a continuous source of effector progeny 38 .…”

CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

“…Yet, elimination of an established tumor is hampered either due to loss of T cell effector function or its survival (Crompton et al, 2014). Therefore, strategies to increase persistence and sustain effector function of the anti-tumor T cells are of immense importance.…”

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

“…Preclinical data show that ACT can be limited when anti-tumor T cells are terminally differentiated effector cells exhibiting poor persistence (Gattinoni et al, 2009), and emerging data from the clinic supports these observations (Rosenberg et al, 2011; Singh et al, 2016). Thus, there is considerable interest in induced pluripotent stem cell (iPSC) technologies that enable the generation of stem cell-like naive and very early memory T cells derived from highly differentiated T cells (Crompton et al, 2014; Gattinoni et al, 2012; Takahashi and Yamanaka, 2006). …”

“…This linear loss of “stemness” is characteristic of most adult cells, and both differentiation and aging of CD8 + T cells cannot be reversed under physiological conditions (Gattinoni et al, 2009, 2011). Thus, there is interest to use iPSC technology to epigenetically reprogram T cells and “turn back the clock” on aging and differentiation (Crompton et al, 2014). …”