Prostate-Specific Membrane Antigen DNA Vaccines

Rational Design of Prostate-Specific Membrane Antigen DNA Vaccines

Introduction

Recognition of self-antigens is emerging as a theme for the immune recognition of human cancer. Recent studies have shown that self-antigens -- and particularly differentiation antigens -- are most frequently recognized on human cancers. However, due to tolerance, self-antigens are poorly immunogenic. T cells with high avidity for self-peptides are deleted or, if they arise, are inactivated by signals present on or secreted by the tumor. Lower avidity T cells remain, but in order to overcome tolerance and develop robust autoimmunity to a self-antigen expressed on prostate cancer, they must be activated, expanded, and maintained in the host. We have extensive experience in breaking tolerance to tumor self-antigens.

PSMA

Prostate-specific membrane antigen (PSMA) is a prostate differentiation antigen, specifically a type II glycoprotein that is not distributed to a wide variety of tissues and is recognized by autoantibodies and T cells in some patients with prostate carcinoma. PSMA was first identified as a surface protein expressed on normal and malignant prostate epithelial cells. The cDNA encoding PSMA was cloned at Memorial Sloan-Kettering and the enzymatic activity of the protein was characterized at our institution and by others. PSMA is also expressed in the vasculature of many solid tumors. A monoclonal antibody specific for PSMA (hJ591) developed at Cornell Medical College has proven to be an effective imaging agent for prostate cancer metastasis in bone and soft tissue, and also localizes to other solid tumors, presumably by virtue of binding to PSMA in the vasculature. Biochemical and objective measurable disease responses were reported in some patients treated with radionuclide conjugates of J591. Current clinical trials are focused on the use of radio and toxin-conjugated hJ591 for therapeutic use. In addition to these studies, clinical trials of active immunotherapy with PSMA protein or peptides have been completed with no evidence of toxicity and some anecdotal declines in serum prostate-specific antigen (PSA) were reported. These observations support PSMA as a candidate target for vaccination.

[Enlarge Image] Figure 1 Two patients in the higher dose levels had a decline in serum PSA during or immediately following vaccination. Pt #25 (top) received 1500 ƒÝg hPSMA followed by mPSMA and Pt #30 (bottom) received 4000 ƒÝg mPSMA followed by hPSMA

Clinical Trial Data

We previously showed that tolerance to PSMA can be overcome by immunization with altered forms of antigen, including xenogeneic (cross-species) and randomly mutated DNA vaccines. This preclinical data lead to a clinical trial of a xenogeneic PSMA DNA vaccine in patients with a rising PSA following primary therapy. We have completed enrollment, and to date, we have observed antibodies to PSMA in several immunized patients. The vaccine was safe with no toxicity. Furthermore, decreases in serum PSA were seen in two patients who received the higher doses of PSMA DNA (see figure 1).

Aims of Current Study

Our current research is focused on increasing cytotoxic T cell responses to PSMA. Starting from basic concepts in immunology, we have significantly improved the CD8 T cell response to self-antigens, by introducing rationally optimized modifications in the vaccine itself and by using specific adjuvants and cytokines. The aims describe a logical extension of our prior work, with an emphasis on generating pre-clinical data to define the most effective second generation PSMA DNA vaccine. We will select the most efficacious of our rationally optimized DNA vaccines using a systematic analysis of immune responses and tumor immunity in animal models (see aim # 1); choose the optimal adjuvant to use with the selected vaccines (see aim #2) conduct the final preclinical testing of the most active vaccines in mice which develop spontaneous, aggressive, locally invasive prostate cancer (see aim # 3); and introduce this highly selected vaccine into clinical trials in men with castrate metastatic prostate cancer (see aim # 4).

The overall aim of this project is to undertake a systematic comparison of vaccines and adjuvants and arrive at the optimal vaccine for use in a pivotal clinical trial:

1. Evaluate strategies to enhance antigen processing and presentation and provide strong CD8 T cell response for optimized PSMA and HER2/neu DNA vaccines.
2. Combine rationally optimized PSMA and HER2/neu DNA vaccines with molecularly defined immune adjuvants to enhance CD8 T cell responses.
3. Evaluate optimized DNA vaccines for prophylaxis and for treatment in mouse models of prostate cancer.
4. Assess the adjuvant effects of IL-12/Fc fusion DNA in combination with an optimized PSMA DNA vaccine in patients with prostate cancer in a phase I clinical trial.

Project Leaders

• Principle Investigator: Polly Gregor, PhD
• Co-Principle Investigator: Susan Slovin, MD, PhD

Collaborators

• Alan Houghton, MD
• Jedd Wolchok MD, PhD
• James Allison PhD