It has been postulated that the immune response to progressive tumors is insufficient due to a deficiency in afferent mechanisms responsible for the development of tumor reactive T cells. The purpose of this project is to harness the antigen presenting and processing capacity of dendritic cells (DC) to elicit tumor rejection T cell responses in the tumor bearing host. Conceptually this will be accomplished with the use of tumor lysate- pulsed DC as an adjunct to adoptive T cell immunotherapy. Our laboratory has developed methodologies to isolate, culture and pulse DC capable of priming T cells to tumor antigen. These methods have allowed us to utilize tumor lysates as a source of antigen to generate primary immune responses to murine and human tumors. A major advantage of utilizing tumor lysate is the ability to sensitize T cells to unknown tumor antigens that can serve as targets for immune T cells to unknown tumor antigens that can serve as targets for immune T cells, and is therefore applicable to human tumors where defined tumor-associated antigens are not fully characterized. We have extensive pre-clinical and clinical experience in characterizing antitumor immunity induced by whole autologous tumor cell vaccines in vaccine-primed lymphonodes (VPLN) and subsequently activated ex vivo to generate large quantities of effector T cells for adoptive immunotherapy. This approach has been translated into on-going clinical trials of adoptive immunotherapy in advanced cancers where significant clinical responses have been observed. We proposed to evaluate the efficacy of tumor lysate-pulsed DC (TP-DC) in the induction of VPLN cells in pre-clinical studies. In clinical studies we plan to evaluate the cellular immune responses induced by TP-DC in the peripheral blood, VPLN and within the tumor. Based on our findings, we plan to conduct clinical study to evaluate the therapeutic efficacy of TP-DC VPLN cells in adoptive immunotherapy.
These aims are summarized below:
Aim 1 : Assess the role of TP-DC in the induction and maintenance of effector T cells for adoptive immunotherapy in animal models.
Aim 2 : Assess the T cell responses induced by TP-DC vaccinations in clinical studies.
Aim 3 : Enrich for tumor reactive T cells using adhesion receptors from clinical material derived in Aims 2 and 4.
Aim 4 : Conduct an adoptive immunotherapy trial of DC-primed lymph node cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA059327-10
Application #
6579878
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
10
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Teitz-Tennenbaum, Seagal; Li, Qiao; Davis, Mary A et al. (2009) Radiotherapy combined with intratumoral dendritic cell vaccination enhances the therapeutic efficacy of adoptive T-cell transfer. J Immunother 32:602-12
Redman, Bruce G; Chang, Alfred E; Whitfield, Joel et al. (2008) Phase Ib trial assessing autologous, tumor-pulsed dendritic cells as a vaccine administered with or without IL-2 in patients with metastatic melanoma. J Immunother 31:591-8
Teitz-Tennenbaum, Seagal; Li, Qiao; Davis, Mary A et al. (2008) Dendritic cells pulsed with keyhole limpet hemocyanin and cryopreserved maintain anti-tumor activity in a murine melanoma model. Clin Immunol 129:482-91
Teitz-Tennenbaum, Seagal; Li, Qiao; Okuyama, Ryuji et al. (2008) Mechanisms involved in radiation enhancement of intratumoral dendritic cell therapy. J Immunother 31:345-58
Pinnix, Chelsea C; Herlyn, Meenhard (2007) The many faces of Notch signaling in skin-derived cells. Pigment Cell Res 20:458-65
Govindarajan, Baskaran; Sligh, James E; Vincent, Bethaney J et al. (2007) Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest 117:719-29
Topczewska, Jolanta M; Postovit, Lynne-Marie; Margaryan, Naira V et al. (2006) Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nat Med 12:925-32
Pilon-Thomas, Shari; Verhaegen, Monique; Kuhn, Lisa et al. (2006) Induction of anti-tumor immunity by vaccination with dendritic cells pulsed with anti-CD44 IgG opsonized tumor cells. Cancer Immunol Immunother 55:1238-46
Qin, Jian-Zhong; Xin, Hong; Sitailo, Leonid A et al. (2006) Enhanced killing of melanoma cells by simultaneously targeting Mcl-1 and NOXA. Cancer Res 66:9636-45
Pilon-Thomas, Shari; Li, Wenbin; Briggs, Jon J et al. (2006) Immunostimulatory effects of CpG-ODN upon dendritic cell-based immunotherapy in a murine melanoma model. J Immunother 29:381-7

Showing the most recent 10 out of 103 publications