Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells.

Journal: 
Proc Natl Acad Sci U S A
Publication Year: 
2011
Authors: 
D N Vatakis
R C Koya
C C Nixon
L Wei
S G Kim
P Avancena
G Bristol
D Baltimore
D B Kohn
A Ribas
C G Radu
Z Galic
J A Zack
PubMed link: 
22123951
Public Summary: 
The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves introducing cancer-specific T-cell receptors into a patient’s T cells using gene-therapy. In this study, we have genetically modified human hematopoietic stem cells (hHSC) to express a melanoma-specific T-cell receptor and introduced these cells into a human/mouse chimera model. In these mice, the stem cells will produce T cells which will express this receptor. These melanoma-specific T cell receptors only function in the presence of specific blood antigen (HLA-A*0201). These mice express this specific human antigen. When these hHSC expressing an HLA-A*0201-restricted melanoma-specific T-cell receptor were introduced into humanized mice, a large melanoma-specific naive CD8(+) T-cell population was generated in the mice. When tumors were introduced into the mice, these transgenic CD8(+) T cells eliminated the human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non-HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the hHSC population established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.
Scientific Abstract: 
The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201-restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific naive CD8(+) T-cell population. Following tumor challenge, these transgenic CD8(+) T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non-HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.
PNAS Lens Free Article Link: