Targeting the Tumor Microenvironment
Over the past few years, our laboratory has studied the immune responses of Her-2/neu transgenic mice (neu mice). Our results confirmed neu mice are tolerant to neu antigens and that multiple immunizations with DCs pulsed with neu-antigens were not able to reject tumors in neu mice. These results indicated that vaccination alone was not sufficient to control tumor growth in these animals. This raises the question of which conditions should be optimized for inducing an antitumor immune response in tolerant hosts. In order to develop a new immunotherapeutic strategy we decided to target the tumor microenvironment. Intratumoral injections of CpG-ODN induced the rejection of tumor in neu mice. Although the results of i.t. injections of CpG-ODN are very encouraging, the drawback of this strategy is that not all tumors will be physically available for performing i.t. injections and it will be difficult to target metastatic lesions. In order to target the CpG-ODN at the tumor site, we generated an antibody-CpG-ODN conjugate. We chemically conjugated an anti-Her-2/neu mAb with CpG-ODN. Our data indicated that injections of anti-neu-CpG-ODN induced the rejection of primary tumors in neu mice in the same manner as CpG-ODN. Another goal is to optimize the use of anti-neu-CpG-ODN in combination with T-reg depletion for the treatment of multiple and metastatic tumors.
Aging and Antitumor Responses
The incidence of cancer has increased over the last years, due mainly to an increase in the elderly population. The age-associated increase in cancer may be due in part to a global decrease in immune function. We have demonstrated that immunotherapeutic intervention could be effective in young animals, but that the same therapy is not effective in old animals. Therefore, a successful vaccine should be customized in order to be effective in both the young and the old. Critical to optimize an immunotherapy for the old is the development of tumor models that closely resemble the human immune-conditions which will accurately predict the clinical outcomes. We have demonstrated that by crossing the Her-2/neu mice with the HLA-A2.1/Kb mice, these animals spontaneous tumors appear when animals are 20-22 months old. Therefore, the A2xneu mouse model provides a unique opportunity to evaluate antitumor immune responses against a self antigen where aging and tolerance are present at the same time. We have also demonstrated that aging drastically altered the immune system of old mice. We have shown that the priming ability of old A2xneu and A2xFVB mice to induce a T cell response is much weaker when compared to the priming ability of young A2xneu and A2xFVB animals. Furthermore, for the first time we have shown that old mice have at least double the amount of T-regs than young mice. This high accumulation of T-regs inhibits the immune responses in the old. Using immunological and genomic analysis our objective is to better understand why there is a deficiency on old CD4 and CD8 T cells, T-regs and in antigen presenting cells. Our ultimate is to customize antitumor vaccination strategies that would be effective in the young and the old.
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