Research

Current CAR-T therapies, which involve extracting, modifying, and reinfusing patient cells, face significant challenges including high costs, lengthy procedures, infection risks, and practical limitations. To address these issues, our research aims to overcome the constraints of existing cell therapies by developing a novel in vivo approach that directly enhances immune cells within the body, enabling faster and more practical use of cell therapies.

We propose the development of injectable therapies that can directly modify immune cells in vivo, focusing on antigen-presenting cells (APCs) to sustain T cell activation and promote effective anti-cancer immune responses. Specifically, we are enhancing dendritic cells (DCs) and macrophages to improve their functionality within the tumor microenvironment. Additionally, we explore the potential of macrophages engineered with chimeric antigen receptors (CARs) for their direct tumor-killing abilities.

By advancing these in vivo cell modification strategies, our research seeks to create more efficient and accessible cell therapies that can provide significant benefits in cancer treatment, reducing the need for complex ex vivo procedures and improving overall therapeutic outcomes.

This research is focused on creating innovative immune cell delivery systems aimed at enhancing cancer therapy. Our goal is to develop new strategies for effectively targeting and modifying immune cells within the body to improve therapeutic outcomes.

We are designing and optimizing novel drug delivery systems that specifically target antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. By utilizing advanced technologies, including chimeric antigen receptor (CAR) constructs and nanoparticle-based delivery vehicles, we aim to enhance the functionality of these immune cells in vivo.

Our approach involves creating a library of modified delivery systems, each tailored to target different immune cell types. These systems are engineered to deliver therapeutic agents, such as tumor antigens mRNA, directly to the target cells. This strategy is designed to boost T cell activation and promote effective anti-cancer immune responses.

In addition, our research explores the potential of integrating immune-modulating components into these delivery systems to address challenges in current cancer treatments. By developing these novel immune cell delivery systems, we seek to advance the effectiveness of cancer immunotherapy and improve patient outcomes through more targeted and efficient treatment approaches

Despite advances in combining cancer immunotherapy with chemotherapy for treating triple-negative breast cancer (TNBC), challenges such as target depletion, tumor heterogeneity, and metastasis remain. Traditional chemotherapy lacks precise targeting, and targeted therapies often fall short in addressing the diverse nature of tumors. To overcome these limitations, we introduce RGDEVD-DOX, a novel tumor-specific immunogenic agent known as TPD1, designed to target integrin αvβ3 and be continuously activated by apoptosis.

TPD1 facilitates a caspase-3-mediated in situ amplification, leading to tumor-specific accumulation of doxorubicin. This localized concentration of doxorubicin triggers immunogenic cell death, enhancing immune cell recruitment to the tumor site. Importantly, TPD1's tumor-targeting ability helps mitigate the systemic immunotoxicity typically associated with doxorubicin, thus remodeling the tumor microenvironment into a 'hot' tumor that is more responsive to immune checkpoint inhibitors.

Our study demonstrates the anti-metastatic and anti-cancer efficacy of this approach using various xenograft and metastatic models. The findings highlight the potential of caspase-3 cleavable peptide-drug conjugates for effective integration with anti-cancer immunotherapies, offering a promising strategy for remodeling the immune microenvironment and improving treatment outcomes in cancer therapy.

KRAS-mutant cancers pose significant therapeutic challenges due to their complex protein targeting requirements. The macropinocytic phenotype in these cancers presents a novel therapeutic target. Our study introduces MPD1, a macropinocytosis-targeting peptide-drug conjugate (PDC) designed to treat KRAS-mutant cancers. MPD1 is engineered to initiate a positive feedback loop through its caspase-3 cleavable feature. However, this loop is impeded by DNA-PK mediated DNA damage repair in cancer cells.

To overcome this barrier, we employ AZD7648, a DNA-PK inhibitor. The combination of MPD1 and AZD7648 achieves a 100% complete response rate in KRAS-mutant xenograft models. Our research highlights the synergistic mechanism of this combination, revealing that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. We observe a significant correlation between increased macropinocytosis and PI3K signaling, driven by AMPK pathways. Additionally, AZD7648 amplifies the positive feedback loop of MPD1, leading to increased apoptosis and enhanced payload accumulation within tumors.

AZD7648's broad applicability in augmenting nanoparticle-based drug delivery and mitigating DNA repair resistance further supports the efficacy of combining MPD1 with AZD7648. This combination presents a promising strategy for treating KRAS-mutant cancers, highlighting the potential of integrating nanoparticle delivery systems and peptide-drug conjugates in cancer therapy.