The passive transfer of immune lymphoid cells can mediate the regression of established metastatic disease and result in systemic immunity. In animal models, the applicant has observed that tumor- draining or vaccine- primed lymph nodes (LN) harbor """"""""pre-effector"""""""" cells which are not fully functional in mediating in vivo tumor regression. However, during secondary in vitro activation these pre-effector cells can differentiate and numerically expand into competent effector cells for adoptive immunotherapy. Furthermore, the applicant has demonstrated that the inability of poorly immunogenic tumors to stimulate a pre- effector cell response can be upregulated with the co- inoculation of a bacterial immune adjuvant, or by genetically modifying tumor cells to secrete specific cytokines (ie. GM-CSF). Since human tumors are postulated to be poorly immunogenic, these approaches lend credence for their application in clinical therapy. This groups has a unique experience in the generation of large quantities of human vaccine-primed LN cells for therapy. These cells can be elicited in vivo by the intradermal inoculation of irradiated autologous tumor cells admixed with the bacterial adjuvant, BCG, to stimulate antitumor reactivity in the draining LN. Utilizing an anti-CD3/IL-2 activation procedure which has been defined in animal models, the applicant has reliably activated and expanded these vaccine-primed LN cells into large quantities (1011 cells/treatment) for clinical therapy. Importantly, in patients with advanced renal cell cancer (RCC), the applicant observed significant complete and partial tumor responses.
The aims of this application extend these efforts with specific applications for the treatment of metastatic RCC to include: 1) to define the in vivo antitumor reactivity of anti-CD3/IL-2 activated LN cells primed with autologous tumor plus BCG in the adoptive immunotherapy of RCC; 2) to assess the in vivo antitumor reactivity of anti-CD3/IL-2 activated LN cells primed with GM-CSF gene- modified autologous tumor in the adoptive immunotherapy of RCC; 3) to examine the in vitro immunobiology of vaccine-primed LN cells in order to assess the role of immune adjuvants utilized in the vaccines (ie. BCG and GM-CSF), and to determine if correlates exist to tumor response; and 4) to develop methods that selectively activate vaccine-primed lymphoid cells with respect to TCR- Vbeta usage utilizing bacterial superantigens, and characterize their tumor reactivity.
