scholarly journals Cytosolic delivery of the immunological adjuvant Poly I:C and cytotoxic drug crystals via a carrier-free strategy significantly amplifies immune response

2021 ◽  
Author(s):  
Xiaoqing Du ◽  
Yuqi Hou ◽  
Jia Huang ◽  
Yan Pang ◽  
Chenlu Ruan ◽  
...  
Keyword(s):  
Immune Response ◽  
Cytotoxic Drug ◽  
Poly I:C ◽  
Cytosolic Delivery ◽  
Carrier Free

IMMU-44. AN IMMUNOTHERAPEUTIC VACCINE COMPOSED OF IRRADIATED WHOLE TUMOR CELLS PULSED WITH MANNAN-BAM, TLR LIGANDS AND ANTI-CD40 ANTIBODY INDUCES POTENT IMMUNE RESPONSE IN PRECLINICAL GBM ANIMAL MODEL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi102-vi102
Author(s):  
Herui Wang ◽  
Rogelio Medina ◽  
Juan Ye ◽  
Pashayar Lookian ◽  
Ondrej Uher ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Cells ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Therapeutic Efficacy ◽  
Poly I:C ◽  
Control Group ◽  
Complete Regression ◽  
Adaptive Immune

Abstract Despite numerous therapeutic advances, the treatment of glioblastoma multiforme (GBM) remains a challenge, with current 5-year survival rates estimated at 4%. Multiple characteristic elements of GBM contribute to its treatment-resistance, including its low immunogenicity and its highly immunosuppressive microenvironment that can effectively disarm adaptive immune responses. Hence, therapeutic strategies that aim to boost T-lymphocyte mediated responses against GBM are of great therapeutic value. Herein, we present a therapeutic vaccination strategy that promotes the phagocytosis of tumor cells, enhances tumor antigen presentation, and induces a tumor-specific adaptive immune response. This strategy consists of vaccinations with irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists (Mannan-BAM), TLR ligands [LTA, Poly (I:C), and R-848], and anti-CD40 antibody (collectively abbreviated as rWTC-MBTA). We evaluated the therapeutic efficacy of rWTC-MBTA strategy in a mouse syngeneic GL261 orthotopic GBM tumor model. rWTC-MBTA or vehicle control were administered subcutaneously over the right foreleg three days after intracranial injection of GL261 cells. Complete regression (CR) of intracranial tumors was achieved in 70% (7/10) of rWTC-MBTA treated animals while none survived in the control group. Immunophenotyping analyses of peripheral lymph nodes and brain tumors of rWTC-MBTA treated mice demonstrated: (1) increased mature dendritic cells and MHC II+ monocytes; (2) increased effector (CD62L-CD44+) CD4-T and CD8-T cells; (3) increased cytotoxic IFNγ-, TNFα-, and granzyme B-secreting CD4-T and CD8-T cells. Of note, the therapeutic efficacy of rWTC-MBTA disappeared in CD4-T and/or CD8-T lymphocyte depleted mice. Three mice that achieved CR were rechallenged with 50k GL261 cells intracranially 14 months after the last rWTC-MBTA treatment and all rechallenged animals resisted GL261 tumor development, confirming the establishment of long-term immunological memory against GL261 tumor cells. Collectively, our study demonstrated that rWTC-MBTA strategy can effectively activate antigen presenting cells and induce more favorable T-cell signatures in the GBM tumors.

scholarly journals An In Vitro Assessment of Immunostimulatory Responses to Ten Model Innate Immune Response Modulating Impurities (IIRMIs) and Peptide Drug Product, Teriparatide

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7461
Author(s):  
Claire K. Holley ◽  
Edward Cedrone ◽  
Duncan Donohue ◽  
Barry W. Neun ◽  
Daniela Verthelyi ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Cytokine Secretion ◽  
Poly I:C ◽  
In Vitro Assays ◽  
Innate Immune Responses ◽  
Vitro Assay

Understanding, predicting, and minimizing the immunogenicity of peptide-based therapeutics are of paramount importance for ensuring the safety and efficacy of these products. The so-called anti-drug antibodies (ADA) may have various clinical consequences, including but not limited to the alteration in the product’s distribution, biological activity, and clearance profiles. The immunogenicity of biotherapeutics can be influenced by immunostimulation triggered by the presence of innate immune response modulating impurities (IIRMIs) inadvertently introduced during the manufacturing process. Herein, we evaluate the applicability of several in vitro assays (i.e., complement activation, leukocyte proliferation, and cytokine secretion) for the screening of innate immune responses induced by ten common IIRMIs (Bacillus subtilis flagellin, FSL-1, zymosan, ODN2006, poly(I:C) HMW, poly(I:C) LMW, CLO75, MDP, ODN2216, and Escherichia coli O111:B4 LPS), and a model biotherapeutic Forteo™ (teriparatide). Our study identifies cytokine secretion from healthy human donor peripheral blood mononuclear cells (PBMC) as a sensitive method for the in vitro monitoring of innate immune responses to individual IIRMIs and teriparatide (TP). We identify signature cytokines, evaluate both broad and narrow multiplex cytokine panels, and discuss how the assay logistics influence the performance of this in vitro assay.

Effect of bacterial LPS, poly I:C and temperature on the immune response of coelomocytes in short term cultures of red sea urchin (Loxechinus albus)

2020 ◽  
Vol 107 ◽  
pp. 187-193
Author(s):  
Phillip Dettleff ◽  
Maximiliano Villagra ◽  
Joaquín González ◽  
Marcia Fuentes ◽  
Juan Manuel Estrada ◽  
...  
Keyword(s):  
Immune Response ◽  
Sea Urchin ◽  
Red Sea ◽  
Poly I:C ◽  
Short Term ◽  
Red Sea Urchin ◽  
Loxechinus Albus

scholarly journals Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade

2017 ◽  
Vol 7 (3) ◽  
pp. e1407899 ◽  
Author(s):  
Jorrit De Waele ◽  
Elly Marcq ◽  
Jonas RM Van Audenaerde ◽  
Jinthe Van Loenhout ◽  
Christophe Deben ◽  
...  
Keyword(s):  
Immune Response ◽  
Poly I:C ◽  
Glioblastoma Cells ◽  
Human Glioblastoma ◽  
Human Glioblastoma Cells

scholarly journals The extradomain A of fibronectin (EDA) combined with poly(I:C) enhances the immune response to HIV-1 p24 protein and the protection against recombinant Listeria monocytogenes-Gag infection in the mouse model

Vaccine ◽  
2012 ◽  
Vol 30 (15) ◽  
pp. 2564-2569 ◽  
Author(s):  
Beatriz San Román ◽  
Ximena De Andrés ◽  
Pilar-María Muñoz ◽  
Patricia Obregón ◽  
Aaron-C. Asensio ◽  
...  
Keyword(s):  
Immune Response ◽  
Listeria Monocytogenes ◽  
Mouse Model ◽  
Poly I:C ◽  
P24 Protein ◽  
Hiv 1

scholarly journals The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation

2021 ◽  
Vol 17 (2) ◽  
pp. e1009300
Author(s):  
Yan Zeng ◽  
Shuai Xu ◽  
Yanli Wei ◽  
Xuegang Zhang ◽  
Qian Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza A Virus ◽  
Innate Immune Response ◽  
Influenza A ◽  
Innate Immune ◽  
Negative Regulator ◽  
Poly I:C ◽  
H7n9 Virus ◽  
Autophagic Degradation ◽  
Negative Regulatory Mechanism

Influenza A virus (IAV) has evolved various strategies to counteract the innate immune response using different viral proteins. However, the mechanism is not fully elucidated. In this study, we identified the PB1 protein of H7N9 virus as a new negative regulator of virus- or poly(I:C)-stimulated IFN induction and specifically interacted with and destabilized MAVS. A subsequent study revealed that PB1 promoted E3 ligase RNF5 to catalyze K27-linked polyubiquitination of MAVS at Lys362 and Lys461. Moreover, we found that PB1 preferentially associated with a selective autophagic receptor neighbor of BRCA1 (NBR1) that recognizes ubiquitinated MAVS and delivers it to autophagosomes for degradation. The degradation cascade mediated by PB1 facilitates H7N9 virus infection by blocking the RIG-I-MAVS-mediated innate signaling pathway. Taken together, these data uncover a negative regulatory mechanism involving the PB1-RNF5-MAVS-NBR1 axis and provide insights into an evasion strategy employed by influenza virus that involves selective autophagy and innate signaling pathways.

scholarly journals Self-Assembled, Adjuvant/Antigen-Based Nanovaccine Mediates Anti-Tumor Immune Response Against Melanoma Tumor

2018 ◽  
Author(s):  
Santhosh Kalash Rajendrakumar ◽  
Adityanarayan Mohapatra ◽  
Bijay Singh ◽  
Chong-Su Cho ◽  
In-Kyu Park
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
Delivery System ◽  
Treatment Strategies ◽  
Xenograft Model ◽  
Poly I:C ◽  
Tumor Xenograft ◽  
Preclinical Research ◽  
Melanoma Tumor ◽  
B16f10 Cells

Malignant melanoma is a highly aggressive type of cancer that requires radical treatment strategies to inhibit the cancer cell progression and metastasis. In recent years, preclinical research and clinical trials on melanoma treatment are considerably focused on the adjuvant-based immunotherapy for enhancing the immune response of innate immune cells against cancer cells. However, the clinical outcome of these adjuvant-based treatments are inadequate due to improper delivery system for these immune activators to reach the target site. Hence, we developed a vaccine formulation containing tumor lysate protein (TL) and poly I:C (PIC) complexed with positively charged poly (sorbitol-co- polyethylenimine (PEI)(PSPEI). The resulting ionic PSPEI-polyplexed antigen/adjuvant (PAA) (PSPEI-PAA) nanocomplexes were stable at the physiological condition, non-toxic and  enhanced intracellular uptake in immature dendritic cells. In murine B16F10 tumor xenograft model, PSPEI-PAA nanocomplexes significantly suppressed tumor growth and did not exhibit any noticeable sign of toxicity. Additionally, the cytotoxic T lymphocytes (CTLs) assay involving co-culturing of splenocytes isolated from the PSPEI-PAA-treated mice with that of B16F10 cells significantly revealed enhanced cancer killing by the TL-reactivated CTLs compared to untreated control mice bearing tumor. Therefore, we strongly believe that PSPEI-PAA nanocomplexes could be an efficient antigen/adjuvant delivery system and also enhance the antitumor immune response against melanoma tumor in the future clinical trials.

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