PSMA-Targeted In Situ Immunization for the Treatment of Metastatic Castration-Resistant Prostate Cancer
Abstract
Rationale: Metastatic castrate-resistant prostate cancer (mCRPC) is incurable and the most lethal form of prostate cancer. Of the estimated 3 million prostate cancer patients in the U.S. (2020), ~50K deaths are attributed to mCRPC annually. The 5-year survival rate for patients with mCRPC is ~15%. Two main features contribute to the resilience of mCRPC to treatment: 1. A highly immunosuppressive tumor microenvironment, meaning that the body’s immune system is ineffective in suppressing tumor growth. Immunotherapies that show significant patient benefit in other cancer types, have no effect towards mCRPC. Currently, no approved therapy can effectively convert an immunosuppressive tumor microenvironment into an immune responsive state in mCRPC. 2. The second major challenge in treating mCRPC is tumor heterogeneity. The majority of mCRPC patients possess subpopulations of cancer cells with distinct morphological and genetic profiles that exhibiting different behaviors and response rates to therapies. Tumor heterogeneity explains why chemotherapies against mCRPC have limited benefit. Most cancer drugs are designed to kill cells by disrupting specific receptors, enzymes or cellular division. Therefore, even small subpopulations of cells in a tumor that are not susceptible to a drugs mechanism of action, will evade cell death and continue growing after treatment. In summary, a highly immunosuppressive tumor microenvironment and substantial tumor heterogeneity makes treatment of mCRPC a significant clinical challenge. Thus, the development of new drug paradigms that induce an immune response to prevent tumor growth and effectively kill all subpopulations of cancer cells in heterogeneous tumors would be highly significant and have a tremendous impact in treating mCRPC. Objective: We have developed a new drug paradigm, RadioIMmunoStimulant (RIMS), to addresses the clinical challenges in treating mCRPC, namely an immunosuppressive tumor microenvironment and tumor heterogeneity. RIMS accomplishes this by utilizing a therapeutic radiometal (M) that can kill a variety of cancer cell types and combines it with an immunostimulant payload that generates a long term adaptive immune response. Mechanistically, the cancer cell killing generated by the radiometal and the immune cell recruitment to the tumor elicited by the immunostimulant will synergize to generate a tumor vaccine in the body against heterogeneous tumors in mCRPC. This proposal builds on promising preliminary data to generate and test more efficacious RIMS compounds against a high bar preclinical animal model of prostate cancer. The goal is complete regression of heterogeneous prostate cancer tumors as this is the most challenging clinical scenario. This result would signify a significant impact in the field and would warrant pursuing further development of RIMS for clinical trials against mCRPC. Aim 1. We have already evaluated a proof-of-concept molecule, M-RIMS-1, against a clinically relevant mouse prostate cancer model and compared it to the recently approved radioligand therapy for mCRPC, 177Lu-PSMA- 617. M-RIMS-1 treated animals had a 2x increase in median overall survival compared to 177Lu-PSMA-617 treated animals at the same dose. In this aim, we will build on this preliminary data to generate more efficacious second-generation compounds, M-RIMS-X. We will accomplish this by incorporating different therapeutic radiometals such as Y-90 and Pb-212(Bi-212) to probe the effect of utilizing different clinically relevant radionuclides. Additionally, we will incorporate a more potent immunostimulant into the RIMS platform to generate a more robust immune response against the tumor. In total 5-second generation, M-RIMS-X compounds will be made and evaluated for drug-like properties. Aim 2: We will test the three best performing M-RIMS-X compounds from Aim 1, in a mouse prostate cancer model, RM1-PGLS. This preclinical animal mode
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210669
Entities
People
- Labros Meimetis
Organizations
- Stony Brook University
- United States Army