Heretofore it has been difficult to study and periodically monitor the anti-tumor immune response of cancer patients for prolonged periods of time in vivo. The co-engraftment of patients~ tumor and their peripheral blood lymphocytes (PBL) into severe combined immunodeficient (SCID) mice provides an opportunity for the first time to study patients~ anti-tumor response and to evaluate the potential of immunotherapeutic strategies in an in vivo model. The model has two embodiments. In the first model patients~ PBL are co-injected with patient~s tumor cells subcutaneously into SCID mice and the xenograft monitored for changes in tumor volume, mitotic and apoptotic indices. In the second model patients~ PBI (made tolerant to mouse tissue antigens) are inoculated intraperitoneally into SCID mice and subsequently challenged with tumor cells with or without immunotherapy. In both models PBL-mediated anti-tumor responses and enhancement of these responses with cytokines or vaccination have been established. The initial goal of this proposal is to demonstrate, monitor and characterize lung cancer patients~ immune response to their tumor at selected intervals after the surgical removal of the tumor. By titrating the number of PBI required to inhibit the growth of a tumor xenograft it is possible to demonstrate an anti-tumor response and to determine if the response changes wit time after the cytoreduction of the tumor. Cell phenotype and cytokines contributing to the patients~ PBL mediated tumor suppression will be defined. The information obtained from these initial studies (i.e., the optimal cytokine or cytokine combination, time after surgery required for recovery of PBL response to tumors, number and phenotype of PBL required for tumor suppression) will be utilized to design immunotherapeutic strategies that will be evaluated in the chimeric human/scidmouse models. These strategies include cytokine gene therapies and tumor vaccination employing dendritic cells. These studies are expected to contributed substantially to our understanding of lung cancer patients~ anti-tumor immunity and to provide a more rational approach to the design and evaluation of immunotherapy of lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075235-04
Application #
6173281
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Hecht, Toby T
Project Start
1997-07-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
4
Fiscal Year
2000
Total Cost
$136,336
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Hess, Stephen D; Egilmez, Nejat K; Bailey, Nicola et al. (2003) Human CD4+ T cells present within the microenvironment of human lung tumors are mobilized by the local and sustained release of IL-12 to kill tumors in situ by indirect effects of IFN-gamma. J Immunol 170:400-12
Egilmez, Nejat K; Hess, Stephen D; Chen, Fang-An et al. (2002) Human CD4+ effector T cells mediate indirect interleukin-12- and interferon-gamma-dependent suppression of autologous HLA-negative lung tumor xenografts in severe combined immunodeficient mice. Cancer Res 62:2611-7
Hill, Hank C; Conway Jr, Thomas F; Sabel, Michael S et al. (2002) Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. Cancer Res 62:7254-63
Bankert, Richard B; Hess, Stephen D; Egilmez, Nejat K (2002) SCID mouse models to study human cancer pathogenesis and approaches to therapy: potential, limitations, and future directions. Front Biosci 7:c44-62
Bankert, Richard B; Hess, Stephen D; Egilmez, Nejat K (2002) SCID mouse models to study human cancer pathogenesis and approaches to therapy: potential, limitations, and future directions. Front Biosci 7:c44-62
Sugano, M; Conway Jr, T F; Kelleher Jr, R J et al. (2001) Human dendritic cells pulsed with autologous Epstein-Barr virus transformed B-cell lymphoblastoid cell (BCL) lysate elicit a BCL specific MHC-class II restricted T-cell response. J Exp Clin Cancer Res 20:175-82
Bankert, R B; Egilmez, N K; Hess, S D (2001) Human-SCID mouse chimeric models for the evaluation of anti-cancer therapies. Trends Immunol 22:386-93
Yamada, M; Shiroko, T; Kawaguchi, Y et al. (2001) CD40-CD40 ligand (CD154) engagement is required but not sufficient for modulating MHC class I, ICAM-1 and Fas expression and proliferation of human non-small cell lung tumors. Int J Cancer 92:589-99
Sugiyama, Y; Kato, M; Chen, F A et al. (2001) Human inflammatory cells within the tumor microenvironment of lung tumor xenografts mediate tumor growth suppression in situ that depends on and is augmented by interleukin-12. J Immunother 24:37-45
Egilmez, N K; Jong, Y S; Sabel, M S et al. (2000) In situ tumor vaccination with interleukin-12-encapsulated biodegradable microspheres: induction of tumor regression and potent antitumor immunity. Cancer Res 60:3832-7

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