Although it has been well established experimentally that the transfer of sensitized T lymphocytes can mediate potent antitumor effects, extrapolating the principles of adoptive immunotherapy learned from animal studies to clinical therapy will require the development of innovative techniques to identify as well as to propagate antitumor effector T cells from cancer patients. Toward this end, we have established a culture system whereby cells from tumor-draining lymph nodes can be sensitized to acquire therapeutic efficacy. Since, these cells did not demonstrate overt antitumor reactivity before culture, these are functionally referred to as """"""""Pre-effector"""""""" cells. The in vitro sensitization (IVS) method involves the stimulation of pre-effector cells with tumor cells in the presence of IL-2. The requirement of large numbers of autologous tumor cells for IVS may represent an impediment for clinical application. Attempts were made to explore alternative methods of activation. These efforts led to our discovery that anti-CD3 mAb could stimulate the generation of functional effector cells in the absence of tumor cells. Recently, we have further demonstrated that by in vivo priming with a mixture of tumor cells and a bacterial adjuvant followed by IVS or anti-CD3 activation, it was possible to generate potent immune effector T cells with therapeutic reactivity against a defined nonimmunogenic murine tumor; a situation which may be more analogous to human cancers. These observations provide an impetus for the design of a clinical protocol examining the efficacy of similarly generated T lymphocytes for treatment of patients with advanced cancer. In this proposal, patients will be immunized with a vaccine consisting of autologous irradiated tumor cells and BCG. Primed cells derived from the lymph nodes draining the vaccine sites will be further sensitized either by the IVS or anti-CD3 activation method. Sensitized cells will be infused with the concomitant administration of low doses of IL-2. The objectives of the current proposal are:(1) To assess clinical toxicity and antitumor efficacy; (2) To characterize target specificity and phenotype of sensitized cells;(3) To determine optimal sensitization culture conditions; (4) To determine homing patterns of transferred cells; (5) To assess immunologic reactivity of treated patients; (6) To determine the effects of cyclophosphamide on cellular therapy.
| Chang, A E; Aruga, A; Cameron, M J et al. (1997) Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and interleukin-2. J Clin Oncol 15:796-807 |
| Chang, A E; Yoshizawa, H; Sakai, K et al. (1993) Clinical observations on adoptive immunotherapy with vaccine-primed T-lymphocytes secondarily sensitized to tumor in vitro. Cancer Res 53:1043-50 |
