Standard treatment modalities for nasopharyngeal carcinoma fail to cure local-regional bulky disease in a significant number of patients and are accompanied by severe long-term side effects. Since virtually all undifferentiated NPC are associated with Epstein Barr virus (EBV), this type of tumor is an attractive candidate for immunotherapy targeted against tumor-associated EBV antigens. Recently we have demonstrated the feasibility of generating autologous EBV-specific cytotoxic T lymphocytes (CTL) for patients with EBV+ NPC. Adoptive transfer of these CTL has proven safe and induced clinical responses in all 4 patients with refractory/relapsed disease treated. Although these results are promising, not all patients with bulky disease responded completely. Since the size of the T cell compartment is maintained at a steady state by a number of potent homeostatic mechanisms, we believe this failure was due in part to failure of infused T lymphocytes to undergo adequate expansion in vivo. Since these homeostatic mechanisms drive lymphoproliferation during lymphopenia, we now propose to deplete the patient's lymphoid compartment prior to CTL infusion. For this purpose, we will use short-lived CD45 monoclonal antibodies (MAbs), which we have shown can profoundly deplete lymphocytes in peripheral blood and lymphoid organs, whilst sparing hematopoietic progenitor cells. Subsequent adoptive transfer of EBV-specific CTL should result in expansion of the infused cells to restore the T cell compartment. In the phase I study proposed here, escalating doses of autologous EBV-specific CTL will be administered to NPC patients either at high risk for relapse or with refractory or relapsed disease. Each patient will first receive one dose of CTL alone and then 8 weeks later a fixed dose of CD45 MAbs followed by the same dose of CTL. This study design allows us to evaluate the safety of the combination of CTL and CD45 MAbs in NPC patients and the degree and extent of T cell depletion obtained (Aim 1) as well as an intra-patient comparison of the effect of anti-CD45 on the expansion and in vivo function of EBV-specific CTL (Aim 2). All of the technologies and operating procedures needed to implement this clinical study are in place in the applicant's laboratory. Upon completion of this project, both the maximum safe dose of EBV-specific CTL when given after CD45 MAb treatment as well as the effect of CD45 MAb-mediated T cell depletion on the expansion, persistence and function of adoptively transferred CTL should be clear. ? ? ? December 08, 2003 (See review notes) ? ?
| Louis, Chrystal U; Straathof, Karin; Bollard, Catherine M et al. (2009) Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients. Blood 113:2442-50 |
