Abstracts of 4th Annual UKMF Scientific Meeting on 07-Feb-2003
Can we manipulate the immune system to attack myeloma?
Freda K. Stevenson1, Jason Rice1, Jane Watkins1, Francesco Forconi1, Niklas Zojer1, Gianfranco Di Genova1, Nigel H Russell2, Christian H. Ottensmeier1 and Surinder S. Sahota1
1Molecular Immunology Group, Tenovus Laboratory, Southampton
University Hospitals UK.
2Department of Haematology, Nottingham City Hospital, Nottingham
UK.
Strategies to direct the immune system against myeloma cells have to recognize the problem of immunodeficiency in patients due to disease or therapy. One approach is passive immunotherapy with antibody or T cells, possibly followed by vaccination of recovering patients. Vaccination of donors of allogeneic transplants offers the further advantage of activating immunity in healthy non-tolerized subjects with transfer of specific immunity to patients.
For active vaccination, there are many methods for inducing immunity including whole-cell vaccines, proteins and peptides, often combined with non-specific activators or dendritic cell loading. DNA vaccines have the advantage of simplicity of construction and delivery of defined antigens, together with stimulation of innate immunity via CpG sequences. Additional coding sequences for molecules to enhance specific effector pathways can also be incorporated.
Candidate tumor antigens are now emerging for myeloma. Our initial investigations have focused on idiotypic (Id) antigens expressed by the clonal Ig of neoplastic plasma cells. The encoding VH and VL genes are assembled as single chain Fv (scFv) and placed upstream of a sequence encoding the Fragment C of tetanus toxin. FrC provides an activating signal which leads to CD4+ T-cell mediated protective immunity against a sIg-negative myeloma model. In contrast, vaccination with Id protein fails to provide protection even though high levels of anti-Id antibody are generated. DNA scFv-FrC fusion vaccines are in current clinical trial for patients with follicular lymphoma, with encouraging immune responses against Id protein and FrC being detected. For myeloma, we have been permitted to vaccinate donors of allogeneic transplants with DNA scFv-FrC. High levels of Id-specific proliferative T cells have been induced and in one case transferred to the patient.
We have also investigated MUC-1 as a potential target antigen in myeloma. Although surface expression appears variable and subject to loss, transcripts are common in myeloma cells and activation of T-cell attack is an option. In a pre-clinical model, a DNA MUC-1-FrC vaccine has been used to induce specific protective immunity against MUC-1 expressing tumor cells, with depletion experiments indicating involvement of both CD4 and CD8 effector T cells. Cancer testis antigens are additional target antigens under investigation.
For optimizing induction of CD8+ responses, we have designed a DNA vaccine containing only the first domain of FrC linked to a candidate peptide sequence motif for MHC Class I binding. This design leads to rapid induction of high levels of peptide-specific IFNγ-producing T cells able to kill tumor cells in vitro and in vivo. It is applicable to a wide range of tumor epitopes and to viral peptides. A pilot clinical trial of the design incorporating an immunodominant epitope from pp65 of cytomegalovirus will begin shortly. The increasing range of vaccine designs will offer the opportunity to use multiple DNA vaccines to attack distinct molecular targets on myeloma cells.