In murine models, signaling through CD40 on dendritic cells is required for a dendritic cell tumor vaccine to effectively generate anti-tumor immunity. Enhancement of that signal by culture of tumor lysate pulsed dendritic cells (DC) with a CD40 agonist increases the potency of the vaccine. Furthermore, blockade of CTLA-4 mediated inhibition of T cell responses has been shown to augment anti-tumor responses. We now firstly propose to evaluate in a randomized clinical trial whether CD40 activation increases the effectiveness of an intranodally injected, tumor lysate pulsed DC vaccine in colorectal cancer patients. Patients who have undergone resection of metastatic colorectal carcinomas will be randomized to be immunized with a CD40 activated or non-activated tumor lysate pulsed DC vaccine.
Our specific aims are: 1) to determine whether CD40 activation increases the induction of systemic immunity to autologous tumor cells and a neo-antigen (KLH), as measured by changes in T cell proliferation, cytokine secretion and DTH in response to autologous tumor or KLH; 2) to determine whether a DC vaccine pulsed with a """"""""whole cell"""""""" lysate will increase the T cell immune response to colorectal cancer cells or to peptides expressed by colorectal cancer cells; and 3) to determine whether a tumor lysate pulsed, intranodally injected autologous DC vaccine can induce clinical responses in patients with metastatic colorectal cancer. We also propose to evaluate the effectiveness of CTLA-4 blockade in conjunction with a tumor lysate pulsed DC vaccine in a murine model and in a second clinical trial. Using two different murine tumor models, we will examine the effect of addition of a systemically administered CTLA-4 blocking antibody on the ability of a DC vaccine to induce protective and therapeutic immunity. In the context of a clinical trial, patients who have undergone resection of metastatic colorectal carcinomas will be immunized with a DC vaccine and then treated with or without anti-CTLA-4 mAb. Induction of systemic immunity to KLH and to tumor cells will be assessed.
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