Anti-CTLA-4-Based Immunologic Therapy for Prostate Cancer

Principal Investigators - Eric Small, MD | Marcella Fasso, PhD

Laboratory
Knowledge of the targets of the T cell response to prostate cancer is of considerable utility in the development of more highly specific approaches to immunotherapy via specific immunization. In addition, it can allow the production of reagents for the detection and quantification of immune responses in cancer patients. To these ends we applied our efforts to the identification of T cell targets in the TRAMP system taking advantage of the ability of CTLA-4 blockade to potentiate T cell responses. We used T cells from mice immunized with a TRAMP cell vaccine in combination with CTLA-4 blockade to identify and clone a mouse gene encoding an antigen involved in T cell mediated rejection of TRAMP tumors. The mouse gene, which we designated SPAS-1, has a human homologue. We are now repeating this strategy for the identification of two further T cell defined epitope from mouse prostate cancer cells.

With the help of several labs at UCSF, we have preliminary data on the expression of SPAS-1 in human prostate cancer, which suggest that this gene might be overexpressed in high-degree prostate tumors compared to normal prostate tissue, raising the possibility of using the human SPAS-1 gene as a prognostic marker of human prostate cancer.

Clinical Applications
We previously demonstrated that monoclonal antibody-mediated blockade of CTLA-4 augments and prolongs T cell responses. In the first human trial using CTLA-4 blockade in prostate cancer (conducted at UCSF), a single dose of anti-CTLA-4 antibody resulted in PSA reductions in patients with metastatic, androgen-independent prostate cancer without inducing polyclonal T cell activation.

We previously demonstrated that systemic GM-CSF produces PSA declines in patients with androgen-independent and androgen-dependent prostate cancer. While the mechanism by which GM-CSF induces declines in PSA is unknown, it is possible that non-specific activation of antigen-presenting cells by GM-CSF plays a role. This presumed presentation of antigen may be enhanced by the co-administration of anti-CTLA-4 antibody.

We anticipate that repetitive dosing of anti-CTLA-4 antibody combined with GM-CSF-stimulated antigen presentation can be safely administered without the development of polyclonal T cell activation or autoimmunity. To determine this, we are conducting a phase I study of repetitively dosed humanized anti-CTLA-4 antibody in combination with GM-CSF in metastatic, androgen-independent prostate cancer patients.

This work represents the first identification of a T cell defined epitope from mouse prostate cancer cells, and raises the possibility that the human homologue might be useful in the immunotherapy of human prostate cancer. Additionally, our approach offers the possibility of beginning the development of tumor immunotherapy with targets that are already validated immunologically. This approach, first developed in the laboratory, will be undertaken in the context of combination therapy (CTLA blockade combined with antigen presentation) in prostate cancer patients. In particular, we will evaluate the safety, efficacy, and immunologic effects of GM-CSF therapy combined with CTLA-4 blockade.