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.
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