The major objective of this application is to develop novel immunotherapeutic strategies to augment the immune destruction of tumors and to define the mechanism of action of these immune responses. The applicant will focus on the impact that tolerance has on modulation of the immune system against tumor antigens. His goal is to characterize the T cell repertoire with antitumor reactivity for self-antigens in a tolerant host and to activate this immune T cell repertoire to induce the eradication of tumors. Toward this end, he will use Her-2/neu transgenic mice (MMTV-neu) that are tolerant to neu antigens. As result of this tolerance these mice have a low avidity T cell repertoire against neu antigens. In addition, the MMTV-neu mice develop spontaneous mammary tumors.
In Aim 1 of this application, the applicant will examine strategies to activate the immune repertoire of the MMTV-neu mice for elimination of the mammary tumors. These studies include the use of anti-Her-2/neu IL-2 and anti-Her-2/neu-GM-CSF fusion proteins to activate and augment the effector function of the low avidity T cells against neu antigens.
In Aim 2, the applicant will evaluate the impact that tolerance has on the development of peptide-vaccines for tumor elimination and how to overcome such tolerance. To this end, he will use the A2/neu mice and examine whether A2-Her-2/neu-restricted peptides can prevent tumor growth in these animals. In addition he will evaluate whether peptide-vaccination can be boosted with anti-Her-2/neu-IL-2 fusion protein.
In Aim 3, he will examine whether self-tolerance may eliminate or prevent T cells from becoming memory T cells. The applicant will assess whether following immunointervention with anti-Her-2/neu-IL-2 plus anti-Her-2/neu-GM-CSF or peptide vaccines plus anti-Her-2/neu-IL-2 would be possible to generate a memory T cell response capable of preventing the growth of recurring tumors in MMTV-neu mice. Overall, this application intends to learn about the requirements for initiation and perpetuation of an effective antitumor response in tolerized hosts. Successful completion of these studies will add new information for understanding of immunological responses involved against self-tumor antigens and how best to use immunotherapeutic strategies for the treatment of cancer against such antigens.
| Lustgarten, Joseph (2009) Cancer, aging and immunotherapy: lessons learned from animal models. Cancer Immunol Immunother 58:1979-89 |
| Dominguez, Ana Lucia; Lustgarten, Joseph (2008) Implications of aging and self-tolerance on the generation of immune and antitumor immune responses. Cancer Res 68:5423-31 |
| Sharma, Sanjay; Dominguez, Ana Lucia; Hoelzinger, Dominique B et al. (2008) CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol Immunother 57:549-61 |
| Sharma, Sanjay; Dominguez, Ana Lucia; Manrique, Soraya Zorro et al. (2008) Systemic targeting of CpG-ODN to the tumor microenvironment with anti-neu-CpG hybrid molecule and T regulatory cell depletion induces memory responses in BALB-neuT tolerant mice. Cancer Res 68:7530-40 |
