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1. Nanotechnology-enabled immunoengineering approaches to advance therapeutic applications

   https://doi.org/10.1186/s40580-022-00310-0  

   Chuang, Skylar T.; Conklin, Brandon; Stein, Joshua B.; Pan, George; Lee, Ki-Bum (April 2022, Nano Convergence)

   Abstract Immunotherapy has reached clinical success in the last decade, with the emergence of new and effective treatments such as checkpoint blockade therapy and CAR T-cell therapy that have drastically improved patient outcomes. Still, these therapies can be improved to limit off-target effects, mitigate systemic toxicities, and increase overall efficacies. Nanoscale engineering offers strategies that enable researchers to attain these goals through the manipulation of immune cell functions, such as enhancing immunity against cancers and pathogens, controlling the site of immune response, and promoting tolerance via the delivery of small molecule drugs or biologics. By tuning the properties of the nanomaterials, such as size, shape, charge, and surface chemistry, different types of immune cells can be targeted and engineered, such as dendritic cells for immunization, or T cells for promoting adaptive immunity. Researchers have come to better understand the critical role the immune system plays in the progression of pathologies besides cancer, and developing nanoengineering approaches that seek to harness the potential of immune cell activities can lead to favorable outcomes for the treatment of injuries and diseases. 

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2. Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1

   https://doi.org/10.1016/j.chembiol.2024.02.014  

   Ludwig, Seth D; Meksiriporn, Bunyarit; Tan, Jiacheng; Kureshi, Rakeeb; Mishra, Akhilesh; Kaeo, Kyle J; Zhu, Angela; Stavrakis, Georgia; Lee, Stephen J; Schodt, David J; et al (May 2024, Cell Chemical Biology)

   NA (Ed.)

   Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engage- ment of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessi- tating novel approaches to enhance performance. Here, we report the development of antibody fusion pro- teins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The comple- mentary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell acti- vation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic anti- bodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes. 

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3. Efficacy and clinical monitoring strategies for immune checkpoint inhibitors and targeted cytokine immunotherapy for locally advanced and metastatic colorectal cancer

   https://doi.org/https://doi.org/10.1016/j.cytogfr.2019.10.002  

   Bess, S; Greening, G; Muldoon, T (October 2019, Cytokine growth factor reviews)

   Colorectal cancer (CRC) is the fourth most common cancer type and is the second leading cause of cancer deaths annually in the United States. Conventional treatment options include postoperative (adjuvant) and preoperative (neoadjuvant) chemotherapy and radiotherapy. Although these treatment modalities have shown to decrease tumor burden, a major limitation to chemothearpy/radiotherapy is the high recurrence rate in patients. Immune-modulation strategies have emerged as a promising new therapeutic avenue to reduce this recurrence rate while minimizing undesirable systemic side effects. This review will focus specifically on the mechanisms of monoclonal antibodies: immune checkpoint inhibitors and cytokines, as well as current drugs approved by the Food and Drug Administration (FDA) and new clinical/pre-clinical trials. Finally, this review will investigate emerging methods used to monitor tumor response post-treatment. 

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4. Microbiota-dependent activation of CD4 ⁺ T cells induces CTLA-4 blockade–associated colitis via Fcγ receptors

   https://doi.org/10.1126/science.adh8342  

   Lo, Bernard C; Kryczek, Ilona; Yu, Jiali; Vatan, Linda; Caruso, Roberta; Matsumoto, Masanori; Sato, Yosuke; Shaw, Michael H; Inohara, Naohiro; Xie, Yuying; et al (January 2024, Science)

   Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4⁺T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade. 

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5. Macrophage-targeted anti-CCL2 immunotherapy enhances tumor sensitivity to 5-fluorouracil in a Balb/c-CT26 murine colon carcinoma model measured using diffuse reflectance spectroscopy

   https://doi.org/10.1186/s12865-022-00493-5  

   Bess, Shelby N.; Greening, Gage J.; Rajaram, Narasimhan; Muldoon, Timothy J. (December 2022, BMC Immunology)

   Abstract Background Immunotherapy in colorectal cancer (CRC) regulates specific immune checkpoints and, when used in combination with chemotherapy, can improve patient prognosis. One specific immune checkpoint is the recruitment of circulating monocytes that differentiate into tumor-associated macrophages (TAMs) and promote tumor angiogenesis. Changes in vascularization can be non-invasively assessed via diffuse reflectance spectroscopy using hemoglobin concentrations and oxygenation in a localized tumor volume. In this study, we examine whether blockade of monocyte recruitment via CCL2 (macrophage chemoattractant protein-1) leads to enhanced sensitivity of 5-fluorouracil (5-FU) in a CT26-Balb/c mouse model of CRC. It was hypothesized that the blockade of TAMs will alter tumor perfusion, increasing chemotherapy response. A subcutaneous tumor model using Balb/c mice injected with CT26 colon carcinoma cells received either a saline or isotype control, anti-CCL2, 5-FU, or a combination of anti-CCL2 and 5-FU. Results Findings show that 12 days post-treatment, monocyte recruitment was significantly reduced by approximately 61% in the combination group. This shows that the addition of anti-CCL2 to 5-FU slowed the fold-change (change from the original measurement to the final measurement) in tumor volume from Day 0 to Day 12 (~ 5 fold). Modest improvements in oxygen saturation (~ 30%) were observed in the combination group. Conclusion The findings in this work suggest that the blockade of CCL2 is sufficient in the reduction of TAMs that are recruited into the tumor microenvironment and has the ability to modestly alter tumor perfusion during early-tumor response to treatment even though the overall benefit is relatively modest. 

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