Enhancing Anti-CTLA4 Immunology Therapy for Prostate Cancer with Cotargeting Soluble NKG2D Ligand
Abstract
Prostate cancer remains the most common cancer in men in the United States, with an estimated incidence of 240,890 new cases (29% of all new cancer cases) in 2011, and it is the second most common cause of death from cancer in men, with 33,720 estimated deaths (11% of all estimated deaths) in 2011. First-line therapies for early stage localized prostate cancer are surgery and radiotherapy, and the 5-year relative survival rate is essentially 100% based on 2001-2007 statistics. However, for patients with prostate cancer that has metastasized, the 5-year relative survival rate is 28.8%. Androgen ablation by surgical or chemical castration is used to treat men with recurrent prostate cancer. Initially, prostate cancer cells respond to androgen deprivation, but they eventually become resistant. There have been numerous clinical trials examining androgen deprivation combined with other treatments in men with metastatic prostate cancer, but most of these trials have shown no significant improvement in the survival rate. Cancer immunotherapy, whereby a patient s immune system is stimulated to create an anti-tumor effect, has emerged as a novel form of therapy for men with metastatic, castration-resistant prostate cancer (mCRPC). One of the most desirable immunotherapies for prostate cancer is the immunomodulatory therapy, where the immune system itself is targeted for modulation. One example of immunomodulatory therapy is to use antibody to block the activity of the immune checkpoint proteins, such as CTLA4 and PD-1, to remove the crucial "brakes" on the immune system, thus activating the immune system to fight cancer. Due to the effectiveness in clinical trials, antibodies blocking CTLA4 and PD-1 have won Food and Drug Adminstration approval for treating metastatic melanoma. In clinical trials with mCRPC, only the antibody to CTLA4 showed limited effect in mCRPC after failure of all standard treatment, however, with high autoimmune toxicity. The toxicity is due to non-specific uncontrolled release of the "immune brake." During the last decade, a new negative immune modulatory factor (soluble MIC, sMIC) that is specifically released by cancer cells has been uncovered. We are the only laboratory that has extensively studied the impact of sMIC on prostate cancer metastasis, using clinical patients samples and also "human-like" animal models. We found that high level of serum sMIC is detrimental to the patient s immune system. Using a preclinical "human-like" animal model we created, we show that removal of serum sMIC with an antibody effectively revives the host s own immune system, induces tumor shrinkage, and reduces cancer metastasis. However, during the treatment course, we found that the check point protein CTLA4 was increased on immune cells, presumably a feedback response to the riving of the immune system. Based on these scientific understandings, we propose to explore the combinatory therapy of antibodies to sMIC and CTLA4 for mCRPC, with the goals to enhance the therapeutic effect of anti-CTLA4 and concurrently to reduce the autoimmune toxicity of anti-CTLA4 therapy. We hope that, in the combinatory therapy, a significantly lower dose of anti-CTLA4 would be needed to achieve the desired therapeutic effect. We will also investigate whether serum levels of sMIC can predict who will benefit from the combinatory therapy. Since the antibody to sMIC has been formulated for human application, if our proposed study is successful, we anticipate that our proposed therapy will be used in a clinical trial for men with mCRPC within 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510406
Entities
People
- Jennifer Wu
Organizations
- Medical University of South Carolina
- United States Army