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Generation of Human Chimeric Antigen Receptor Regulatory T Cells

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Rapamycin-resistant effector T-cell therapy.

Daniel H Fowler¹

¹Experimental Transplantation and Immunology Branch, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA.

Immunological Reviews

|December 17, 2013

Summary

This summary is machine-generated.

Rapamycin-resistant effector T (T-Rapa) cells, generated ex vivo, show enhanced function and balance graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effects. This approach holds promise for improving transplantation therapies.

Keywords:

Th1/Th2/Th17 apoptosis/autophagy cytokines graft versus host disease transplantation

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Area of Science:

Immunology
Pharmacology
Transplantation Biology

Background:

Mechanistic target of rapamycin (mTOR) inhibition stresses tumor and T cells.
Cells employ survival mechanisms like alternative signaling and autophagy.
Rapamycin-resistant effector T (T-Rapa) cells exhibit enhanced function.

Purpose of the Study:

To investigate the therapeutic potential of ex vivo rapamycin-modified T cells (T-Rapa).
To evaluate the ability of T-Rapa cells to modulate immune responses in transplantation.
To assess the balance between graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effects.

Main Methods:

Ex vivo rapamycin treatment of T cells with polarizing cytokines and antigen-presenting-cell-free costimulation.
Generation of T-helper 1 (Th1) or T-helper 2 (Th2)-type effector cells.
Murine models and Phase I/II clinical trials in allogeneic hematopoietic cell transplantation.

Main Results:

Murine Th2-skewed T-Rapa cells potently prevented graft rejection and GVHD while balancing GVHD and GVT.
Human T-Rapa cells in a Phase II trial showed a mixed Th2/Th1 phenotype, promoting donor chimerism and a favorable GVHD/GVT balance.
A Phase I trial evaluating autologous Th1/Tc1-skewed T-Rapa cells is ongoing.

Conclusions:

Ex vivo rapamycin modulation of effector T cells is a flexible therapeutic strategy.
T-Rapa cells offer a promising approach to optimize immune balance in transplantation.
This method may improve outcomes by mitigating GVHD while preserving GVT effects.