The overall goal of this proposal is to develop vaccination methods that effectively stimulate tumor antigen specific T-cells, to provide an effective immunotherapeutic strategy for tumor eradication as an adjunct to chemotherapy in women with high-risk and metastatic breast cancer. Peptides derived from HER-2, CEA and p53, capable of being presented in the context of HLA-A2, an allele present in a high proportion of the population, will be used. Response to this immunization strategy will be monitored and correlated with clinical endpoints. There are four aims: To develop an improved and practical procedure for ex-vivo generation of DCs capable of presenting breast cancer tumor antigens, and importantly, to develop more refined in vitro assessment tests that measure induction and intensity of T-cell responsiveness to tumor associated and control antigens at a clonal and lineage level.
The second aim i nvolves re-infusing the ex-vivo generated DC vaccines to determine in vivo safety and tolerability. Several in vitro tests of altered reactivity to self will also be used to explore the possible development of potentially inappropriate autoreactivity concurrent with the appearance of the expected anti tumor immunity. In the third aim, the development of specific in vivo anti tumor immunity in both CD4 and CD8 T-cell lineages following administration of ex-vivo generated DC vaccines will be monitored and correlated with clinical efficacy and outcome parameters. Because the competency of the immune system is markedly affected by high-dose chemotherapy with peripheral blood progenitor cell support, the last aim will assess the extent of immune reconstitution following sequential high-dose chemotherapy and peripheral blood progenitor cell transplantation in women with breast cancer, to identify the optimal time after completion of chemotherapy to initiate the immunization protocol in this specific group of breast cancer patients. The immunotherapy methodology established will, in principle, be applicable to certain other hematological and solid malignancies, and has the potential for providing benefit where conventional modalities of therapy have thus far proved ineffective.
| Moschella, Federica; Bisikirska, Brygida; Maffei, Antonella et al. (2003) Gene expression profiling and functional activity of human dendritic cells induced with IFN-alpha-2b: implications for cancer immunotherapy. Clin Cancer Res 9:2022-31 |
| Moschella, F; Maffei, A; Catanzaro, R P et al. (2001) Transcript profiling of human dendritic cells maturation-induced under defined culture conditions: comparison of the effects of tumour necrosis factor alpha, soluble CD40 ligand trimer and interferon gamma. Br J Haematol 114:444-57 |
