Lymphoma is the sixth most common cancer in both sexes and its incidence is steadily increasing. Despite being one of the most successfully cured cancers, treatment failures and refractory disease are still very common, and new therapies are needed. Treatment with anti-CD20 monoclonal antibody, rituximab, is the most successful immune therapy of cancer ever accomplished, and demonstrates that immune therapy is feasible and can be powerful. The candidate is a medical oncologist with extensive laboratory background in molecular and cell biology. She has spent the past few years working under the guidance of Dr. Alan N. Houghton, who is highly recognized as one of the world experts in tumor immunology. The concept recognized by Dr. Houghton and that represents the basis of this proposal is that, while the immune system is normally tolerant toward tumor associated self-antigens, it is possible to break this tolerance via immunization with antigens derived from a different species (xenogeneic immunization). The small amino acid sequence difference between species is sufficient to trigger an immune response directed toward the xenogeneic antigen but also cross-reactive with the native homologue. In a mouse model, the candidate has shown that CD20, a B-cell surface antigen almost universally expressed by B-cell lymphomas, is a feasible target for active immune therapy with DNA vaccination. Plasmids expressing a truncated form of the human CD20 cDNA, administered to mice via particle bombardment and followed by a lethal challenge of A20 murine lymphoma cells, resulted in cellular immune responses against the human and mouse CD20 (therefore breaking tolerance to the self antigen) and a protective effect from a lethal tumor challenge. Based on these observations, the candidate proposes to expand her work on several aspects of the CD20 vaccine in order to augment its potency possibly by broadening the immune response to involve other arms of the immune system. The proposed optimization includes rational modifications of the CD20 sequence to create optimal MHC class I epitopes, modifications of the carrier plasmid vector, co-administration of key cytokines or a combination of the above. Furthermore, she proposes to explore the effect of CD20 immunization in the post-bone marrow transplant settings. Finally, the candidate proposes to carry out a phase I clinical trial of CD20 DNA vaccine in patients with lymphoma.
|Palomba, M Lia; Piersanti, Kelly; Ziegler, Carly G K et al. (2014) Multidimensional single-cell analysis of BCR signaling reveals proximal activation defect as a hallmark of chronic lymphocytic leukemia B cells. PLoS One 9:e79987|