Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for cancer.
The genetic modification of peripheral blood lymphocytes using retroviral vectors to redirect T cells against tumor cells has been recently used as a means to generate large numbers of antigen-specific T cells for adoptive cell therapy protocols. However, commonly used retroviral vector-based genetic modification requires T cells to be driven into cell division; this potent mitogenic stimulus is associated with the development of an effector phenotype that may adversely impact upon the long-term engraftment potential and subsequent antitumor effects of T cells. To investigate whether the cytokines used during culture impact upon the engraftment potential of gene-modified T cells, a humanized model employing T cells engrafted with a MART-1-specific T cell receptor adoptively transferred into NOD/Shi-scid IL-2rγ(-/-) (NSG) immune-deficient mice bearing established melanoma tumors was used to compare the effects of the common γ chain cytokines IL-2, IL-7, and IL-15 upon gene-modified T cell activity. MART-1-specific T cells cultured in IL-7 and IL-15 demonstrated greater relative in vitro proliferation and viability of T cells compared with the extensively used IL-2. Moreover, the IL-15 culture prolonged the survival of animals bearing melanoma tumors after adoptive transfer. However, the combination of IL-7 and IL-15 produced T cells with improved engraftment potential compared with IL-15 alone; however, a high rate of xenogeneic graft-versus-host disease prevented the identification of a clear improvement in antitumor effect of these T cells. These results clearly demonstrate modulation of gene-modified T cell engraftment in the NSG mouse, which supports the future testing of the combination of IL-7 and IL-15 in adoptive cell therapy protocols; however, this improved engraftment is also associated with the long-term maintenance of xenoreactive T cells, which limits the ultimate usefulness of the NSG mouse model in this situation.
Clinical and Experimental Immunotherapy Group, Department of Medical Oncology, The Institute of Cancer Sciences, Manchester Academic Healthcare Science Centre, The University of Manchester , Manchester M20 4BX, United Kingdom .
Erik M
EM
Alcantar-Orozco
Hannah
H
Gornall
Vania
V
Baldan
Robert E
RE
Hawkins
David E
DE
Gilham
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D058965:MART-1 Antigen / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D023421:Models, Animal; D012878:Skin Neoplasms / Q000628:therapy; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D007378:Interleukins; D058965:MART-1 Antigen