Dual-Function CpG-STAT3 Antisense Oligonucleotides for Immunotherapy of Metastatic Prostate Cancer
Abstract
Cancer immunotherapies have shown efficacy in treating several types of human malignancies, except for the advanced prostate tumors. While these new approaches prod the patient’s immune system to detect and attack cancer cells, prostate cancers proved resilient and capable of neutralizing immune responses. STAT3 protein, which is the master brake of the immune system, is one of the key prostate cancer resistance mechanisms. The majority of human prostate cancers depend on STAT3, but there are still no FDA-approved drugs to target it. To overcome this obstacle, we engineered a new synthetic drug (oligonucleotide) to block STAT3 with high efficiency and precision in selected immune cells and in the most resilient prostate cancer cells. Our strategy uses small DNA fragments (CpG molecules) to deliver a STAT3 inhibitor (antisense oligonucleotide or ASO) to target cells within minutes. In addition, the CpG-STAT3ASO has a two-step immunostimulatory effect: it releases the brake, STAT3, and then activates immune attack though CpG DNA. With support from the DoD-PCRP (Idea Award), we recently developed a new generation of chemically improved CpG-STAT3ASO that can now be injected intravenously to target prostate tumors in their various hideouts, especially in bones. We confirmed that our strategy induces potent immune responses against cancer cells, which completely eliminated prostate tumors in a majority of treated mice. Importantly, we observed that CpG-STAT3ASO also reactivates human immune cells taken out of the blood of metastatic prostate cancer patients. Since CpG-STAT3ASO fixes and activates immune cells, which are similar in all patients, our strategy works effectively against genetically different prostate tumors and even other types of cancers. Thus, we propose studies that will characterize the effects of CpG-STAT3ASO on the human immune system and human prostate tumors in mice. These studies will assess the antitumor efficacy and safety of our strategy in studies designed to mimic conditions in cancer patients as closely as technically possible. Two major aims of this study are: 1. Select the most active of human-specific CpG-STAT3ASO and characterize the pharmacologic properties of this drug when injected intravenously into mice. Because the activities of immune systems in mice and in men differ, we will create mice with human immune systems and human tumors for these studies. We will determine the optimal drug regimen to reach maximum immune cell activation and cancer cell killing, which will later be used to design clinical prostate cancer immunotherapy. 2. Evaluate the antitumor effects and safety of intravenously injected CpG-STAT3ASO in humanized mice. First, we will study the antitumor effects of CpG-STAT3ASO against two aggressive human prostate cancers in humanized mice. Next, we will find the maximum safe dose and potential toxicity of CpG-STAT3ASO in mice. Based on these results, we will start complete toxicology and safety studies in mice and in non-rodent animals, as required by the FDA. Results from these studies will be reviewed by the FDA and should inform the design of future clinical trials for prostate cancer immunotherapy. Emerging cancer immunotherapies using vaccinations, oligonucleotides, or antibodies to stimulate immunity were not effective against late-stage prostate cancers. However, similar oligonucleotide drugs were safe and well-tolerated by patients. The CpG-STAT3ASO can overcome these obstacles by releasing the brakes in immune cells and jump-starting their antitumor activity. The two-pronged attack on tumor and tumor-supporting immune cells can not only eliminate tumors in multiple locations, but also protect patients from cancer remissions in the long term. We expect that the successful completion of these studies, which align with the FY18 PCRP Focus Area on developing treatments that improve outcomes for men with lethal prostate cancers, will generate novel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910852
Entities
People
- Marcin Kortylewski
Organizations
- Beckman Research Institute of City of Hope
- United States Army