scholarly journals Novel Immune Stimulant Amplifies Direct Tumoricidal Effect of Cancer Ablation Therapies and Their Systemic Antitumor Immune Efficacy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 492
Author(s):  
Mladen Korbelik ◽  
Tomas Hode ◽  
Samuel S. K. Lam ◽  
Wei R. Chen
Keyword(s):  
Cell Membrane ◽  
Immune Responses ◽  
Tumor Antigens ◽  
T Cell Response ◽  
Membrane Repair ◽  
Local Ablation ◽  
Antigen Presenting ◽  
Immune Efficacy ◽  
Cancer Ablation ◽  
Potential Antitumor

Ablation therapies have emerged as an effective tool for destroying cancerous tissue, but for advanced and disseminated tumors their application remains mainly a palliative measure. However, it is becoming increasingly clear that this limitation can be redressed by the use of intratumoral immune stimulating agents for amplifying potential antitumor immune responses that are induced by ablation therapies. A novel immune stimulating drug IP-001, a specific variant of the N-dihydrogalactochitosan (GC) family of molecules, has shown to be effective against metastatic tumors, when combined with different forms tumor ablation. It acts as a multi-function immune stimulant both by directly inhibiting cell membrane repair and recycling of ablation-damaged tumor cells, and indirectly by sequestering ablation-released tumor antigens, as well as recruiting and stimulating antigen presenting cells to induce a potent Th1 type T cell response against the cancer. In this review, we briefly discuss the current applications of local ablation for cancer treatment and the effects of GC in combination with other ablation therapies, a therapeutic approach that is pioneering the field of Interventional Immuno-Oncology (IIO).

scholarly journals Hybrid membrane-coated nanosuspensions for multi-modal anti-glioma therapy via drug and antigen delivery

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wenyan Hao ◽  
Yuexin Cui ◽  
Yueyue Fan ◽  
Mengyu Chen ◽  
Guobao Yang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Cell Membrane ◽  
Tumor Antigens ◽  
Hybrid Membrane ◽  
Antigen Delivery ◽  
Nano Drug Delivery ◽  
Membrane Antigens ◽  
Membrane Bound ◽  
Cell Membrane Antigens ◽  
Antigen Presenting

Abstract Background Glioma is one of the deadliest human cancers. Although many therapeutic strategies for glioma have been explored, these strategies are seldom used in the clinic. The challenges facing the treatment of glioma not only involve the development of chemotherapeutic drugs and immunotherapeutic agents, but also the lack of a powerful platform that could deliver these two moieties to the targeted sites. Herein, we developed chemoimmunotherapy delivery vehicles based on C6 cell membranes and DC membranes to create hybrid membrane-coated DTX nanosuspensions (DNS-[C6&DC]m). Results Results demonstrated successful hybrid membrane fusion and nanosuspension functionalization, and DNS-[C6&DC]m could be used for different modes of anti-glioma therapy. For drug delivery, membrane coating could be applied to target the source cancer cells via a homotypic-targeting mechanism of the C6 cell membrane. For cancer immunotherapy, biomimetic nanosuspension enabled an immune response based on the professional antigen-presenting characteristic of the dendritic cell membrane (DCm), which carry the full array of cancer cell membrane antigens and facilitate the uptake of membrane-bound tumor antigens for efficient presentation and downstream immune n. Conclusion DNS-[C6&DC]m is a multifunctional biomimetic nano-drug delivery system with the potential to treat gliomas through tumor-targeted drug delivery combined with immunotherapy, thereby presenting a promising approach that may be utilized for multiple modes of cancer therapy. Graphical Abstract

Antibody Response after Vaccination with Antigen-Pulsed Dendritic Cells

2004 ◽  
Vol 19 (3) ◽  
pp. 213-220
Author(s):  
F. Battaini ◽  
D. Besusso ◽  
L. Sfondrini ◽  
A. Rossini ◽  
D. Morelli ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Immune Responses ◽  
Antibody Response ◽  
Cancer Patients ◽  
Antibody Production ◽  
Tumor Antigens ◽  
Antigen Uptake ◽  
Antigen Presenting

Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system capable of initiating immune responses to antigens. It is also well documented that cancer patients often experience anergy against tumor antigens. In this study we selected the best protocol for inducing the production of antibodies against the HER2 oncoprotein using DCs to overcome anergy. Murine DCs were pulsed in vitro, using different protocols, with recombinant HER2 fused to a human Fc (in order to improve DC antigen uptake) and were used to vaccinate mice. The obtained results indicate that antigen-pulsed DCs can induce an antibody response and that adding CpG after antigen pulsing greatly increases anti-HER2 antibody production.

Safety and preliminary immunogenicity of JNJ-64041809, a live attenuated, double-deleted Listeria monocytogenes-based immunotherapy, in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16509-e16509
Author(s):  
Charles G. Drake ◽  
Russell Kent Pachynski ◽  
Sumit Kumar Subudhi ◽  
Douglas G. McNeel ◽  
Emmanuel S. Antonarakis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Antigens ◽  
Phase 1 ◽  
Blood Cultures ◽  
T Cell Response ◽  
Clinical Activity ◽  
Grade 3

e16509 Background: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live attenuated, double-deleted Listeria monocytogenes (LADD- Lm)-based immunotherapy targeting relevant prostate cancer antigens, was evaluated in a phase 1, multicenter, open-label study in patients (pts) with mCRPC. Methods: Men aged ≥18 years with progressive mCRPC who had received ≥2 prior approved therapies were included. The recommended phase 2 dose (RP2D) and the safety and immunogenicity of JNJ-809 were evaluated. Dose-limiting toxicities (DLTs), adverse events (AEs), T cell response, tumor response, and JNJ-809 bacterial shedding profile were assessed at 2 dose levels, 1 x 108 and 1 x 109 colony forming units (CFU). Results: 26 pts (median age 66.5 years, White 96%) were enrolled (1 x 108 CFU, n = 6; 1 x 109 CFU, n = 20). Median duration of treatment was 2.5 months (range 0-9.7). No DLTs occurred and 1 x 109 CFU was selected as the RP2D. Most common AEs were chills (n = 24, 92%), pyrexia (n = 21, 81%), and fatigue (n = 16, 62%). Grade ≥3 AEs were reported in 18 (69%) pts and serious AEs in 7 (27%) pts including 1 pt with investigator-assessed treatment-related grade 3 intestinal obstruction. At 1 x 108 CFU, all pts had negative blood cultures. At 1 x 109 CFU, 6 pts had LADD- Lm-positive blood cultures on day 1; blood cultures on all subsequent days were negative. JNJ-809 transiently induced peripheral cytokines including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of 7 evaluable pts (1 x 109 CFU), post-treatment T cell responses were demonstrated in 6 pts to the Listeria antigen LLO and in 5 pts to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease (SD) in 13/25 evaluable pts with SD ≥16 weeks in 4 pts. The study was terminated early as the data collected from 26 pts were considered sufficient to evaluate safety and immune responses. Conclusions: JNJ-809 has a manageable safety profile consistent with that of other LADD- Lm-based therapies. Observed activation of immune responses with monotherapy did not translate into clinical activity, and further development of JNJ-809 will likely require a combination approach. Clinical trial information: NCT02625857.

scholarly journals The inability to process a self-peptide allows autoreactive T cells to escape tolerance.

1993 ◽  
Vol 177 (2) ◽  
pp. 567-571 ◽  
Author(s):  
M J Mamula
Keyword(s):  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Cell Response ◽  
T Cell Response ◽  
The Self ◽  
Autoreactive T Cells ◽  
Cyt C ◽  
Antigen Presenting ◽  
Self Peptides

It is now clear that antigen presenting cells (APCs) do not present all the possible peptides of self-proteins to the immune system. When then, is the fate of T cells specific for those self-peptides that escape processing? In this study, the COOH-terminal peptide (residues 81-104) of self cytochrome c (cyt c) elicited strong autoimmune T cells, as well as autoantibodies specific for this immunogen. These T cells did not respond to stimulation with the whole self cyt c molecule, demonstrating that APCs cannot process and present the self 81-104 peptide. Whereas mice were unresponsive to immunization with the whole mouse cyt c molecule, the mouse 81-104 fragment together with the whole self-molecule induced and amplified the autoimmune T cell response to sites within the 1-80 peptide. T cells that never contact the relevant self-peptide are functionally ignorant. They do not become tolerized or deleted, nor do they normally participate in immune responses to the native whole self-protein, since APCs cannot present the 81-104 peptide.

scholarly journals Acute myeloid leukemia cell membrane-coated nanoparticles for cancer vaccination immunotherapy

Leukemia ◽  
2021 ◽  
Author(s):  
Daniel T. Johnson ◽  
Jiarong Zhou ◽  
Ashley V. Kroll ◽  
Ronnie H. Fang ◽  
Ming Yan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Membrane ◽  
Immune Responses ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Antigen Presenting Cells ◽  
Vaccine Platform ◽  
Antigen Presenting ◽  
Acute Myeloid

AbstractCancer vaccines are promising treatments to prevent relapse after chemotherapy in acute myeloid leukemia (AML) patients, particularly for those who cannot tolerate intensive consolidation therapies. Here, we report the development of an AML cell membrane-coated nanoparticle (AMCNP) vaccine platform, in which immune-stimulatory adjuvant-loaded nanoparticles are coated with leukemic cell membrane material. This AMCNP vaccination strategy stimulates leukemia-specific immune responses by co-delivering membrane-associated antigens along with adjuvants to antigen-presenting cells. To demonstrate that this AMCNP vaccine enhances leukemia-specific antigen presentation and T cell responses, we modified a murine AML cell line to express membrane-bound chicken ovalbumin as a model antigen. AMCNPs were efficiently acquired by antigen-presenting cells in vitro and in vivo and stimulated antigen cross-presentation. Vaccination with AMCNPs significantly enhanced antigen-specific T cell expansion and effector function compared with control vaccines. Prophylactic vaccination with AMCNPs enhanced cellular immunity and protected against AML challenge. Moreover, in an AML post-remission vaccination model, AMCNP vaccination significantly enhanced survival in comparison to vaccination with whole leukemia cell lysates. Collectively, AMCNPs retained AML-specific antigens, elicited enhanced antigen-specific immune responses, and provided therapeutic benefit against AML challenge.

Transduction of CLL cells by CD40 ligand enhances an antigen-specific immune recognition by autologous T cells

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3223-3226 ◽  
Author(s):  
Christine Mayr ◽  
David M. Kofler ◽  
Hildegard Büning ◽  
Dagmar Bund ◽  
Michael Hallek ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Antigens ◽  
Therapeutic Potential ◽  
Cd40 Ligand ◽  
T Cell Response ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Immune Recognition ◽  
Antigen Presenting

AbstractSeveral features of chronic lymphocytic leukemia (CLL) suggest that immune-based strategies may have therapeutic potential. A promising approach is provided by the transduction of CLL cells with CD40 ligand (CD40L) by viral vectors to enhance their immunogenicity. We compared the antigen-presenting capacity of CD40L-transduced CLL cells with mock-transduced or CD40L-stimulated CLL cells (CD40-CLL). A significantly higher number of T cells could be expanded using CD40L-transduced CLL cells as antigen-presenting cells (APCs) compared with the control group (P = .008). Using 5 different CLL-associated tumor antigens, including fibromodulin, MDM2 (murine double minute 2), survivin, p53, and KW-13, we show in interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assays after 35 days of in vitro culture that the number of antigen-specific autologous T cells was also significantly higher when CD40L-transduced CLL cells were used as APCs (P < .001). Thus, CD40L-transduced CLL cells are able to induce an antigen-specific T-cell response and might be superior to CD40-CLL cells for immune-based therapeutic strategies in CLL.

The effect of polysaccharide-based hydrogels on the response of antigen presenting cell lines to immunomodulators

2021 ◽  
Author(s):  
Jin Teng, Melody Chung ◽  
Chi Ming Laurence Lau ◽  
Ying Chau
Keyword(s):  
Immune Responses ◽  
Cell Lines ◽  
Foreign Material ◽  
Antigen Presenting Cell ◽  
Antigen Presenting

Hydrogel presents as foreign material to the host and participates in immune responses which would skew the biofunctions of immunologic loads (antigen and adjuvants) for in-situ DC priming. This study...

Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2570-2577 ◽  
Author(s):  
John Stagg ◽  
Sandra Pommey ◽  
Nicoletta Eliopoulos ◽  
Jacques Galipeau
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Stromal Cells ◽  
Matrix Protein ◽  
Marrow Stromal Cells ◽  
Human Mscs ◽  
Dependent Manner ◽  
Antigen Presenting ◽  
Significant Production

AbstractSeveral studies have demonstrated that marrow stromal cells (MSCs) can suppress allogeneic T-cell responses. However, the effect of MSCs on syngeneic immune responses has been largely overlooked. We describe here that primary MSCs derived from C57BL/6 mice behave as conditional antigen-presenting cells (APCs) and can induce antigen-specific protective immunity. Interferon gamma (IFNγ)-treated C57BL/6 MSCs, but not unstimulated MSCs, cocultured with ovalbumin-specific major histocompatibility (MHC) class II-restricted hybridomas in the presence of soluble ovalbumin-induced significant production of interleukin-2 (IL-2) in an antigen dose-dependent manner (P < .005). IFNγ-treated MSCs could further activate in vitro ovalbumin-specific primary transgenic CD4+ T cells. C57BL/6 MSCs, however, were unable to induce antigen cross-presentation via the MHC class I pathway. When syngeneic mice were immunized intraperitoneally with ovalbumin-pulsed IFNγ-treated MSCs, they developed antigen-specific cytotoxic CD8+ T cells and became fully protected (10 of 10 mice) against ovalbumin-expressing E.G7 tumors. Human MSCs were also studied for antigen-presenting functions. IFNγ-treated DR1-positive human MSCs, but not unstimulated human MSCs, induced significant production of IL-2 when cocultured with DR1-restricted influenza-specific humanized T-cell hybridomas in the presence of purified influenza matrix protein 1. Taken together, our data strongly suggest that MSCs behave as conditional APCs in syngeneic immune responses. (Blood. 2006;107:2570-2577)

scholarly journals Immune Restoration Diseases Reflect Diverse Immunopathological Mechanisms

2009 ◽  
Vol 22 (4) ◽  
pp. 651-663 ◽  
Author(s):  
Patricia Price ◽  
David M. Murdoch ◽  
Upasna Agarwal ◽  
Sharon R. Lewin ◽  
Julian H. Elliott ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
De Novo ◽  
Granulomatous Inflammation ◽  
T Cell Response ◽  
Immune Restoration ◽  
Immunological Parameters ◽  
Varicella Zoster

SUMMARY Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

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