Animal models have demonstrated that the passive transfer of immune lymphoid cells can mediate the regression of established metastatic disease and result in systemic immunity. Our approach in isolating immune lymphoid cells has been the use of lymph nodes (LN) draining progressive tumors or inoculation sites of tumor vaccines. In animal models, we have observed that tumor-draining or vaccine-primed LN harbor """"""""pre-effector"""""""" lymphoid cells which are not fully functional in mediating in vivo tumor regression. However, during secondary in vitro activation with anti-CD3 monoclonal antibody (anti-CD3) followed by expansion in IL-2, the LN cells acquire immune competence in mediating specific tumor regression. Based upon our animal models, we have been conducting clinical trials evaluating the antitumor reactivity of vaccine primed LN cells given as adoptive immunotherapy in patients with stage IV malignancies. We have identified the presence of tumor-specific T cells in vaccine-primed draining LN (VPLN) which have been secondarily activated with anti-CD3. Furthermore, we have documented durable tumor responses in patients with stage IV renal cell cancer (RCC) who have received anti-CD3 activated VPLN cells in a phase II trial. In subsequent animal models, we have recently found that the co-stimulation of VPLN cells with anti-CD28 monoclonal antibody (anti-CD28) in conjunction with antiCD3 resulted in significantly enhanced in vitro and in vivo antitumor reactivity. Based upon these recent observations we propose to evaluate the therapeutic efficacy of anti-CD3/anti-CD28 activated VPLN cells in the adoptive immunotherapy of patients with stage IV RCC.
The specific aims of the proposal are: 1. Conduct a phase II trial of anti-CD3/anti-CD28 activated LN cells primed by autologous tumor cell vaccination and adoptively transferred in patients with stage IV RCC. 2. To correlate in vivo tumor responses with in vitro immune responses. 3. To characterize the CD4+ and CD8+ T cell responses in peripheral blood lymphocytes (PBL) and VPLN cells after autologous tumor vaccination. 4. To identify novel tumor associated antigens in RCC. This proposal is being submitted as an Interactive Research Project Grant (IRPG) in conjunction with another RO1 application submitted by Dr. Lloyd Stoolman. Dr. Stoolman plans to examine novel methods to enrich tumor reactive lymphoid cells based upon adhesion marker expansion utilizing samples generated from this proposal.
|Kroon, Hidde M; Li, Qiao; Teitz-Tennenbaum, Seagal et al. (2007) 4-1BB costimulation of effector T cells for adoptive immunotherapy of cancer: involvement of Bcl gene family members. J Immunother 30:406-16|
|Li, Qiao; Carr, Abbey L; Donald, Elizabeth J et al. (2005) Synergistic effects of IL-12 and IL-18 in skewing tumor-reactive T-cell responses towards a type 1 pattern. Cancer Res 65:1063-70|
|Skitzki, Joseph; Craig, Ronald A; Okuyama, Ryugi et al. (2004) Donor cell cycling, trafficking, and accumulation during adoptive immunotherapy for murine lung metastases. Cancer Res 64:2183-91|
|Chang, Alfred E; Li, Qiao; Jiang, Guihua et al. (2003) Phase II trial of autologous tumor vaccination, anti-CD3-activated vaccine-primed lymphocytes, and interleukin-2 in stage IV renal cell cancer. J Clin Oncol 21:884-90|
|Li, Qiao; Carr, Abbey; Ito, Fumito et al. (2003) Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy. Cancer Res 63:2546-52|
|Li, Q; Normolle, D P; Sayre, D M et al. (2000) Immunological effects of BCG as an adjuvant in autologous tumor vaccines. Clin Immunol 94:64-72|
|Li, Q; Furman, S A; Bradford, C R et al. (1999) Expanded tumor-reactive CD4+ T-cell responses to human cancers induced by secondary anti-CD3/anti-CD28 activation. Clin Cancer Res 5:461-9|