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Recent developments in the fields of biomedical chemistry and immune bioengineering have enabled innovative therapeutic approaches that can enhance the efficacy, accuracy, and safety of cancer immunotherapy. Among the numerous strategies utilized in cancer immunotherapy, Toll-like receptor (TLR) agonist-based approaches have been studied for a long time since they trigger the innate immune system and generate antigen-specific T cell responses to fight against tumors. In addition to these immunostimulatory functions, TLR agonists also contribute to the reprogramming of immune suppressive tumor microenvironments. Although TLR agonists are now being intensively studied in clinical trials due to their substantial immunomodulatory properties, they still show a low therapeutic index. Nonspecific and random stimulation of various immune cells produces excess levels of proinflammatory cytokines, resulting in cytokine storms and chronic diseases. Therefore, the development of chemical strategies to enhance the therapeutic efficacy as well as the safety of TLR agonist-based immunotherapy is essential and in high demand.In this Account, we summarize and discuss recent developments in biomedical chemistry and bioengineering techniques for the immunomodulation of TLR agonists that have addressed the limitations in current cancer immunotherapy. Immunomodulation of TLR agonists can be classified into two different approaches: (1) molecular modulation via chemical structure modification and (2) macroscopic modulation via an engineered drug delivery system. In molecular modulation, based on prodrug and antedrug principles, activity is modulated (active or inactive) through immolative chemical linkers that can respond to extrinsic or intrinsic biological stimulation and the plasmatic environment, respectively. To increase the effectiveness of TLR agonists as immunostimulatory agents, researchers have conjugated TLR agonists with other immunotherapeutic moieties (antigen, antibody, other TLR agonist, etc.). For macroscopic modulation, bioengineering of delivery carriers differing in size or with albumin hitchhiking moieties has been utilized to increase the efficiency of the targeting of these carriers to secondary lymphoid organs (lymph nodes (LNs) and spleen). The conjugation of specific targeting ligands and incorporation of stimulus-triggering moieties can promote the delivery of TLR agonists into specific cells or intracellular compartments. Implantable porous scaffolds for specific immune cell recruitment and in situ depot-forming gel systems for controlled release of immunomodulatory drugs can increase the therapeutic efficacy of TLR agonists while reducing systemic toxicity. Taken together, these findings show that well-designed and precisely controlled chemical strategies for the immunomodulation of TLR agonists at both the molecular and macroscopic levels are expected to play key roles in improving the therapeutic efficacy of cancer immunotherapy while minimizing immune-related toxicity.

The deficiency of antigen‐specific T cells and the induction of various treatment‐induced immunosuppressions still limits the clinical benefit of cancer immunotherapy. Although the chemo‐immunotherapy adjuvanted with Toll‐like receptor 7/8 agonist (TLR 7/8a) induces immunogenic cell death (ICD) and in situ vaccination effect, indoleamine 2,3‐dioxygenase (IDO) is also significantly increased in the tumor microenvironment (TME) and tumor‐draining lymph node (TDLN), which offsets the activated antitumor immunity. To address the treatment‐induced immunosuppression, an assemblable immune modulating suspension (AIMS) containing ICD inducer (paclitaxel) and supra‐adjuvant (immune booster; R848 as a TLR 7/8a, immunosuppression reliever; epacadostat as an IDO inhibitor) is suggested and shows that it increases cytotoxic T lymphocytes and relieves the IDO‐related immunosuppression (TGF‐β, IL‐10, myeloid‐derived suppressor cells, and regulatory T cells) in both TME and TDLN, by the formation of in situ depot in tumor bed as well as by the efficient migration into TDLN. Local administration of AIMS increases T cell infiltration in both local and distant tumors and significantly inhibits the metastasis of tumors to the lung. Reverting treatment‐induced secondary immunosuppression and reshaping “cold tumor” into “hot tumor” by AIMS also increases the response rate of immune checkpoint blockade therapy, which promises a new nanotheranostic strategy in cancer immunotherapy., Assemblable immune modulating suspension (AIMS) is prepared by immunogenic cell death (ICD) inducer (paclitaxel) and supra‐adjuvant (Toll‐like receptor 7/8a as an immune booster and indoleamine 2,3‐dioxygenase (IDO) inhibitor as an immunosuppression reliever), enabling the relieving of chemo‐immunotherapy‐induced immunosuppression. Reverting treatment‐induced secondary immunosuppression and reshaping “cold tumor” into “hot tumor” by AIMS increases the response rate of immune checkpoint blockade therapy.

Cancer immunotherapy uses host’s inherent immune system to treat cancer and imparts a memory effect on the immune system that can inhibit cancer relapse. However, due to the complexity and diversity of the immune context of the tumour microenvironments (TMEs), tumour cells form their own immune mechanisms to interact with TMEs, and they usually escape from cancer immunotherapy using it. The TMEs that down-regulate the therapeutic effects contains (1) immune suppressive cells (myeloid-derived suppression cells (MDSCs), tumour-associated macrophages (TAMs), and regulatory T cells (Treg)), (2) cytokines and chemokines (inflammatory(anti-tumoural) cytokines; TNF-α, IL-12, IL-6, IFN-γ, anti-inflammatory (pro-tumoural) cytokines; IL-10, TGF-β, angiogenic cytokine; VEGF, cell-promoting cytokines/chemokines; CCL22 and GM-CSF), and (3) enzymes controlling TMEs-related cell metabolism (IDO, arginase, and NOS2). These immune-suppressive factors have remained as an essential target for elaborating the therapeutic responsive rates. In these days, nanotechnology-based approach was suggested as a novel strategy to revert pro-tumoral TMEs to antitumoral immune niches. In this chapter, we will review on the progress of engineered nanostructured materials that were developed to enhance the therapeutic efficacy of cancer immunotherapy by modulating such immune suppressive factors in TMEs.

The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Here, we develop a syringeable immunomodulatory multidomain nanogel (iGel) that overcomes the limitation by reprogramming of the pro-tumoral TME to antitumoral immune niches. Local and extended release of immunomodulatory drugs from iGel deplete immunosuppressive cells, while inducing immunogenic cell death and increased immunogenicity. When iGel is applied as a local postsurgical treatment, both systemic antitumor immunity and a memory T cell response are generated, and the recurrence and metastasis of tumors to lungs and other organs are significantly inhibited. Reshaping of the TME using iGel also reverts non-responding groups to checkpoint blockade therapies into responding groups. The iGel is expected as an immunotherapeutic platform that can reshape immunosuppressive TMEs and synergize cancer immunotherapy with checkpoint therapies, with minimized systemic toxicity., The limited efficacy of current immunotherapy suggests low antigen-specific T cells and immunosuppressive factors in tumor microenvironment (TME). Here, the authors develop a syringeable immunomodulatory multi-domain nanogel that can reprogram the TME and induce enhanced cancer immunotherapy.

The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Toll-like receptor (TLR) 7/8 agonist-based adjuvants have been widely used to activate antigen-presenting cells (APCs) and induce antigen-specific therapeutic T cells. However, the incorporation of TLR 7/8 agonists also induces immunosuppressive factors, such as Indoleamine 2,3-dioxygenase (IDO) in APCs and tumor cells, which results in the formation of immunosuppressive TME. In this research, we report the assemblable immune-modulating suspension (AIMS) consisting of TLR 7/8 agonist and IDO inhibitor, which was designed to down-regulate the immune-suppressive factors (TGF-β, IL-10, myeloid-derived suppressor cells, regulatory T cells) and to increase the infiltration of cytotoxic T lymphocytes. The best combination of immune-modulating agents in AIMS, we called supra-adjuvant, was selected by screening possible combinations of commercialized TLR 7/8 agonists and IDO inhibitors based on the ratio of pro- and anti-inflammatory cytokines. Paclitaxel was also introduced into AIMS to induce immunogenic cell death (ICD) and in situ vaccination efficacy with TLR 7/8 agonist at the tumor bed. Local administration of AIMS increased infiltrated T cells in both local and distant tumors, and inhibited the metastasis of tumors to lung significantly. AIMS also reshaped the TME from ‘cold tumor' to ‘hot tumor' successfully, and increased the responsive rate of immune checkpoint blockade therapy (ICBT) significantly. Taken together, the AIMS composed of supra-adjuvant and ICD-inducer is expected to be used as a platform for the re-programming of immunosuppressive TME and the induction of synergistic cancer immunotherapy with ICBT. Citation Format: Seung Mo Jin, Sang Nam Lee, Yong Taik Lim. Reprogramming of immunosuppressive tumor microenvironments by multifunctional nanoemulsion and enhance immune checkpoint blockade therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1598.

We present an FPGA based passive auto focus system which uses an adaptive thresholding to obtain well-focused images. Because the adaptive thresholding algorithm can evaluate the difference between each pixel and its neighborhoods, it can be applied to decide the specific area of an image contains high-frequency components or not. If the system decides a captured image has low-frequency components, the auto focus lens driver drives the lens until it obtains well-focused image. The algorithm we use is reasonably straightforward and does not require high computational power for real-time operation. The proposed system was implemented using FPGA and was successfully evaluated with a standard RS-170 video camera capturing 640 times 480 gray-level images at 30 frames per second with a 12.5-75mmF1.8TV lens

Object tracking is a challenging problem in a number of computer vision applications. A number of approaches have been proposed and implemented to track moving objects in image sequences. The particle filter, which recursively constructs the posterior probability distributions of the state space, is the most popular approach. In the particle filter, many kinds of features are used for tracking a moving object in cluttered environments. The specific feature for tracking is selected according to the type of moving object and condition of the tracking environment. Improved tracking performance is obtained by using multiple features concurrently. This paper proposes the particle filter algorithm, using multiple features, such as IFD (Inter-Fame Difference) and gray level, to track a moving object. The IFD is used to detect an object and the gray level is used to distinguish the target object from other objects. This paper designs the circuit of the proposed algorithm using VHDL (VHSIC Hardware Description Language) in an FPGA (Field Programmable Gate Array) for tracking without considerable computational cost, since the particle filter requests many computing powers to track objects in real-time. All functions of the proposed tracking system are implemented in an FPGA. A tracking system with this FPGA is implemented and the corresponding performance is measured.