Engineering platforms for localized long-acting immune modulation.

Systemic immunotherapeutics have been a clinical staple in the treatment of cancer, infectious diseases, organ and cell transplantation, autoimmunity, and allergies. Although their utility remains unquestioned, systemic administration of these drugs is associated with limited efficacy, significant adverse off-target effects, transient activity, and the requirement for frequent repeated dosing. To this end, recent technological advancements have provided novel means for sustained drug delivery to specific tissues and targeted localized approaches for immunotherapeutics.

Intratumoral nanofluidic system enhanced tumor biodistribution of PD-L1 antibody in triple-negative breast cancer.

Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment-refractory triple-negative breast cancer (TNBC), where those with Programmed death-ligand 1 (PD-L1) positive early-stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off-tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach.

Sustained Intratumoral Administration of Agonist CD40 Antibody Overcomes Immunosuppressive Tumor Microenvironment in Pancreatic Cancer.

Agonist CD40 monoclonal antibodies (mAb) is a promising immunotherapeutic agent for cold-to-hot tumor immune microenvironment (TIME) conversion. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer known as an immune desert, and therefore urgently needs more effective treatment. Conventional systemic treatment fails to effectively penetrate the characteristic dense tumor stroma.

Engineered implantable vaccine platform for continuous antigen-specific immunomodulation.

Cancer vaccines harness the host immune system to generate antigen-specific antitumor immunity for long-term tumor elimination with durable immunomodulation. Commonly investigated strategies reintroduce ex vivo autologous dendritic cells (DCs) but have limited clinical adoption due to difficulty in manufacturing, delivery and low clinical efficacy. To combat this, we designed the "NanoLymph", an implantable subcutaneous device for antigen-specific antitumor immunomodulation.

Emerging biomaterial-based strategies for personalized therapeutic in situ cancer vaccines.

Landmark successes in oncoimmunology have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor reduction in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunologically cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells.

Long-acting tunable release of amlodipine loaded PEG-PCL micelles for tailored treatment of chronic hypertension.

Hypertension is a chronic condition that requires lifelong therapeutic management. Strict adherence to drug administration timing improves efficacy, while poor adherence leads to safety concerns. In light of these challenges, we present a nanofluidic technology that enables long-acting drug delivery with tunable timing of drug administration using buried gate electrodes in nanochannels.

Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1.

Purpose: Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity.

NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing.

Natural killer (NK) cell activation triggers sequential cellular events leading to destruction of diseased cells. We previously identified lytic granule convergence, a dynein- and integrin signal-dependent movement of lysosome-related organelles to the microtubule-organizing center, as an early step in the cell biological process underlying NK cell cytotoxicity. Why lytic granules converge during NK cell cytotoxicity, however, remains unclear.

Quantification of natural killer cell polarization and visualization of synaptic granule externalization by imaging flow cytometry.

Defining immunological mechanisms underlying NK cell biology is crucial for the treatment and prevention of immune deficiency and malignancy. The limited availability of human biological specimens presents a challenge to the study of human immunobiology. The use of high throughput, multi-parametric assays will not only aid in the definition and diagnosis of complex human immune disorders affecting NK cell function but also advance NK cell biology through population-based assessment of molecular signaling.