High-dose chemotherapy followed by autologous stem cell transplantation is considered to be the most effective therapy for multiple myeloma but produces complete remissions in only about a third of patients and very few cures. The long-term objective of our clinical research is to learn how to re-establish anti-myeloma T-cell responses in the setting of autologous stem cell transplantation in order to improve upon the outcomes from this procedure. A key hypothesis behind this work is that ex-vivo costimulation of autologous T-cells using anti-CD3/anti-CD28 - conjugated magnetic beads may help to restore T-cell recognition and responsiveness toward myeloma tumor targets. We have developed and implemented a clinical trial in which patients with myeloma receive infusions of ex-vivo costimulated autologous T-cells after autotransplantation. In this trial, patients are also immunized with the T-cell dependent pneumococcal conjugate vaccine (PCV) in order to provide a reliable """"""""readout"""""""" of immune function and to test whether administration of the ex-vivo expanded T-cells will enhance cellular or humoral responses post-transplantation. Using a randomized design, we plan to analyze the specific contributions of the vaccine and the """"""""vaccine-primed"""""""" costimulated T-cells to the overall pneumococcal immune responses. Under this application, we specifically plan to i) analyze the phenotypic pattern and mechanism of immune cell reconstitution after infusion of costimulated T-cells; ii) measure the cellular immune responses that are directed against the conjugate vaccine and the protein carrier component of the PCV (CRM-197); iii) measure T-cell responses against VZV, CMV, and EBV antigens. Peripheral blood mononuclear cells will be incubated with PCV-vaccine, CRM-197 carrier protein, or CMV/VZV/EBV viral antigens and interferon gamma secreting T-cell responders will be detected by proliferation or ELISPOT assays. Knowledge gained from these studies will provide a platform on which to base the development of combined immunotherapy strategies for multiple myeloma and other immunoresponsive hematologic neoplasms as well as novel approaches to the immunization of immunocompromised hosts.
| Rapoport, Aaron P; Stadtmauer, Edward A; Aqui, Nicole et al. (2005) Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 11:1230-7 |
