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 |