Generating Systemic Antitumor Immunity in Renal Cell Carcinoma by Intratumoral Injection of Multiplexed Anti-PD-1 Antibody and Adenosine Deaminase
Abstract
Kidney cancer can be treated by a new class of drugs called immune checkpoint inhibitors, one type of which are called anti-PD1 antibodies. Although many patients with renal cell carcinoma (RCC) have benefited from anti-PD1 antibodies, the majority of the individuals treated with checkpoint inhibitors do not. One reason for the lack of response to anti-PD1 and other inhibitors is the accumulation of adenosine (ADO) in RCC tumors. Released by cells in tumors, ADO impairs the ability of cancer-destroying immune cells to be amplified by anti-PD1 antibodies. Therefore, it is possible that depleting ADO in RCC tumors can increase the sensitivity of the cancer towards anti-PD1 antibodies. The purpose of this research project is to test whether injecting adenosine deaminase (ADA), the enzyme by which ADO is metabolized, can enhance the therapeutic efficacy of an anti-PD1 antibody in a mouse model of RCC. Direct injection of the two into tumors represents a form of vaccination, generating immunity locally and throughout the body. The key is to keep both ADA and anti-PD1 antibody in the same place at the same time in order to generate synergism. We have developed an injectable gel called "pG_EAK", designed to concentrate both anti-PD1 antibody and ADA in tumors. The gel can render concentrations of the agents that cannot be achieved by injecting simple solutions of the two proteins. This technology is referred to as “multiplexing” (mux), and the formulation of the gel containing the two agents is termed mux-alpha-PD1ADA. The goal is to understand the mechanisms and efficacy of mux-alpha-PD1ADA in mice carrying kidney cancer. The hypothesis is that simultaneous and proximal delivery of anti-PD1 and ADA (mux-alpha-PD1ADA) into kidney tumors will induce a body-wide immune response that can reduce the spreading and relapse of the cancer. The hypothesis will be tested in mice inoculated with the classical mouse model of RCC called RENCA. Two tasks will be carried out, the first testing the specific nature of the immune responses generated by mux-alpha-PD1ADA and the second documenting the efficacy of the formulation in inhibiting tumor growth and metastasis, and protection from a second cancer challenge. The research is novel because the intervention is aimed at neutralizing a metabolite that has not been targeted in kidney cancer. It is distinct from other approaches because it restricts the neutralization inside the tumors in raising the sensitivity of the cancer towards checkpoint inhibitors. The short-term impact is that the experiments will provide evidence for advancing the idea to clinical trials. It may lead to improved formulations of mux-alpha-PD1ADA that are effective in humans. In the long run, the study has the potential to improve the quality of life in patients with refractory RCC by using ADA as an adjuvant. The research will benefit the American public because new treatments are needed for kidney cancer. More than 14,000 Americans die every year from kidney and renal pelvic cancer. New cases have risen, from 10.4 (per 100,000 persons) in 1992 to 15.3 in 2015. The investigation can benefit current Service members of the Armed Forces who are at high risk of developing kidney cancer. The localized approach provides a treatment alternative for elderly Veterans because it is expected to have fewer side effects. Veterans who have exposed to battlefield solvent and chemical agents linked to kidney cancer could also benefit from the results of the research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810644
Entities
People
- Wilson S. Meng
Organizations
- Duquesne University
- United States Army