Rapamycin‐resistant effector T‐cell therapy

Summary Pharmacologic inhibition of the mechanistic target of rapamycin ( mTOR ) represents a stress test for tumor cells and T cells. Mechanisms exist that allow cells to survive this stress, including suboptimal target block, alternative signaling pathways, and autophagy. Rapamycin‐resistant effector T (T‐Rapa) cells have an altered phenotype that associates with increased function. Ex vivo rapamycin, when used in combination with polarizing cytokines and antigen‐presenting‐cell free costimulation, is a flexible therapeutic approach as polarization to T‐helper 1 (Th1)‐ or Th2‐type effectors is possible. Murine T‐Rapa cells skewed toward a Th2‐type prevented graft rejection and graft‐versus‐host disease ( GVHD ) more potently than control Th2 cells and effectively balanced GVHD and graft‐versus‐tumor ( GVT ) effects. A phase II clinical trial using low‐intensity allogeneic hematopoietic cell transplantation demonstrated that interleukin‐4 polarized human T‐Rapa cells had a mixed Th2/Th1 phenotype; T‐Rapa cell recipients had a balanced Th2/Th1 cytokine profile, conversion of mixed chimerism toward full donor chimerism, and a potentially favorable balance between GVHD and GVT effects. In addition, a phase I clinical trial evaluating autologous T‐Rapa cells skewed toward a Th1‐ and Tc1‐type is underway. Use of ex vivo rapamycin to modulate effector T‐cell function represents a promising new approach to transplantation therapy.