KT-1 Paired with Multivalent Polymer-Anti-PD-L1 Peptide Hybrid: A Synergistic Chemoimmunotherapy for Treatment of Triple-Negative and Metastatic Breast Cancer
Abstract
Tumor cells often overexpress immune checkpoint proteins to avoid being attacked by the immune system. For instance, interaction of programmed death-ligand 1 (PD-L1) overexpressed on cancer cells with its receptor, programmed cell death protein 1 (PD-1) on immune T cells promotes immune evasion and results in cancer immune resistance. Immunotherapy that blocks interaction of PD-1 with PD-L1 (immune checkpoint blockade; ICB) has shown marked clinical success, as exemplified by clinically approved anti-PD-1 and anti-PD-L1 antibodies. However, clinical trials using ICB in breast cancer have shown relatively low overall response rates. The therapeutic efficacy largely relies on recruiting pre-existing antitumor T cells to kill cancer cells. However, breast cancer patients possess immunologically “cold” tumors, which have a low number of tumor antigen-specific T cells present in the tumor tissue. This results in poor treatment outcome. Herein, we propose to use a combination of KT-1 with MPPA, a unique peptide-based checkpoint inhibitor. KT-1, a polymer-epirubicin conjugate, is able to “heat up” the tumor immune environment and sensitize cancer cells to immune checkpoint inhibitors. The most important advantage of KT-1 is its matchless mechanism of action – dual attack on cancer including immunostimulation of the organism and induction of immunogenic cell death of cancer tissue. The peptide-based checkpoint inhibitor (MPPA) not only initiates an efficient immune checkpoint blockade, but also inhibits PD-L1 recycling to the cell surface by directing the PD-L1 – peptide complex to the lysosomes where it degrades. KT-1 will specifically deliver epirubicin (EPI) to solid tumor site. After EPI release in cancer cells, it will induce a special form of tumor-cell killing, known as immunogenic cell death (ICD), which sends “find me” and “eat me” signals to boost T cell responses. As a result, the therapeutic efficacy of consecutive treatment with MPPA will be potentiated. Thus, a long-lasting eradication of breast tumors might be achieved because of the dual functions of our system: (1) KT-1 mediated immunogenic killing of rapid dividing cancer cells and (2) immunomodulation effect that primes the anti-cancer immunity and enhances immunotherapy with MPPA to eliminate residual cancer cells and prevent tumor relapse. By turning the tumor immune environment from “cold” to “hot,” this approach has the potential to help otherwise non-responding patients benefit from immune checkpoint inhibitor therapy. It will especially benefit patients diagnosed with triple-negative or metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010573
Entities
People
- Jiyuan Yang
Organizations
- United States Army
- University of Utah