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Frontiers in Immunology 2023Tissue biomarkers that aid in identifying cutaneous melanoma (CM) patients who will benefit from adjuvant immunotherapy are of crucial interest. Metastatic...
HEV-associated dendritic cells are observed in metastatic tumor-draining lymph nodes of cutaneous melanoma patients with longer distant metastasis-free survival after adjuvant immunotherapy.
INTRODUCTION
Tissue biomarkers that aid in identifying cutaneous melanoma (CM) patients who will benefit from adjuvant immunotherapy are of crucial interest. Metastatic tumor-draining lymph nodes (mTDLN) are the first encounter site between the metastatic CM cells and an organized immune structure. Therefore, their study may reveal mechanisms that could influence patients´ outcomes.
METHODS
Twenty-nine stage-III CM patients enrolled in clinical trials to study the vaccine VACCIMEL were included in this retrospective study. After radical mTDLN dissection, patients were treated with VACCIMEL (n=22) or IFNα-2b (n=6), unless rapid progression (n=1). Distant Metastasis-Free Survival (DMFS) was selected as an end-point. Two cohorts of patients were selected: one with a good outcome (GO) (n=17; median DMFS 130.0 months), and another with a bad outcome (BO) (n=12; median DMFS 8.5 months). We analyzed by immunohistochemistry and immunofluorescence the expression of relevant biomarkers to tumor-cell biology and immune cells and structures in mTDLN, both in the tumor and peritumoral areas.
RESULTS
In BO patients, highly replicating Ki-67 tumor cells, low tumor HLA-I expression and abundant FoxP3 lymphocytes were found ( and ). In GO patients, the most favorable biomarkers for prolonged DMFS were the abundance of peri- and intra-tumoral CD11c cells ( and ), peri-tumoral DC-LAMP dendritic cells (DCs) (), and PNAd High Endothelial Venules (HEVs) (). Most strikingly, we describe in GO patients a peculiar, heterogeneous structure that we named FAPS (Favoring Antigen-Presenting Structure), a triad composed of DC, HEV and CD62L naïve lymphocytes, whose postulated role would be to favor tumor antigen (Ag) priming of incoming naïve lymphocytes. We also found in GO patients a preferential tumor infiltration of CD8 and CD20 lymphocytes ( and ), as well as peritumoral CD20 aggregates, with no CD21 follicular dendritic cells detected (). Heterogeneous infiltration with CD64CD68CD163, CD64CD68CD163 and CD64CD68CD163 macrophages were observed in both cohorts.
DISCUSSION
The analysis of mTDLN in GO and BO patients revealed marked differences. This work highlights the importance of analyzing resected mTDLN from CM patients and suggests a correlation between tumor and immune characteristics that may be associated with a spontaneous or vaccine-induced long DMFS. These results should be confirmed in prospective studies.
Topics: Humans; Melanoma; Skin Neoplasms; Venules; Prospective Studies; Retrospective Studies; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Lymph Nodes; Immunotherapy; Dendritic Cells; Melanoma, Cutaneous Malignant
PubMed: 37691949
DOI: 10.3389/fimmu.2023.1231734 -
Frontiers in Immunology 2022VSA-1 is a semisynthetic saponin adjuvant prepared from naturally occurring saponin and capable of stimulating antigen-specific humoral and cellular immune responses....
VSA-1 is a semisynthetic saponin adjuvant prepared from naturally occurring saponin and capable of stimulating antigen-specific humoral and cellular immune responses. Its immunostimulating activity in enhancing the immune responses induced by the clinical glycoconjugate pneumococcal vaccine PCV13 is compared with QS-21 in female BALB/c mice. Both VSA-1 and QS-21 boosted IgG and opsonic antibodies titers against seven selected serotypes, including serotypes 3, 14, and 19A that are involved in most PCV13 breakthroughs. Since VSA-1 is much more accessible and of lower toxicity than QS-21, it can be a practical saponin immunostimulant to be included in a new glycoconjugate pneumococcal vaccine formulation.
Topics: Animals; Mice; Female; Pneumococcal Vaccines; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Immunoglobulin G; Saponins
PubMed: 36578488
DOI: 10.3389/fimmu.2022.1079047 -
Upsala Journal of Medical Sciences 2024Staging and treatment of rectal cancer have evolved over several decades with considerably fewer locoregional recurrences but no marked improved survival since systemic... (Review)
Review
BACKGROUND
Staging and treatment of rectal cancer have evolved over several decades with considerably fewer locoregional recurrences but no marked improved survival since systemic recurrence risks remain virtually unchanged. This development will briefly be summarised followed by a thorough discussion of two recent developments.
METHODS
A systematic approach towards the literature is aimed at focusing on organ preservation and the delivery of all non-surgical treatments prior to surgery or total neoadjuvant treatment (TNT).
RESULTS
Organ preservation, that is to defer surgery if the tumour happens to disappear completely after any pre-treatment given to locally advanced tumours to decrease recurrence risks has increased in popularity and is, if not universally, widely accepted. To give neo-adjuvant treatment to intentionally obtain a clinically complete remission to avoid surgery is practised in some environments but is mostly still experimental. TNT, that is to provide both radiotherapy and chemotherapy aimed at killing microscopic disease in the pelvis or elsewhere has been subject to several trials. Collectively, they show that the chance of achieving a complete response, pathologically or clinically, has approximately doubled, increasing the chance for organ preservation, and the risk of distant metastasis has decreased at least in some trials. The best schedule remains to be established.
CONCLUSIONS
To obtain substantial progress and also improve survival, the systemic treatments need to be improved even if preoperative delivery is more effective and better tolerated than postoperative. The locoregional treatment may be further optimised through better risk prediction.
Topics: Humans; Rectal Neoplasms; Pelvis; Adjuvants, Pharmaceutic; Pathologic Complete Response
PubMed: 38449909
DOI: 10.48101/ujms.v129.10537 -
PeerJ 2023Emulsions have been widely used as immunological adjuvants. But the use of materials derived from plants such as cottonseed oil, alpha-tocopherol, or minerals such as...
BACKGROUND
Emulsions have been widely used as immunological adjuvants. But the use of materials derived from plants such as cottonseed oil, alpha-tocopherol, or minerals such as zinc, as well as their use at the nanometric scale has been little explored. In this study, we develop a new miniemulsion and evaluated its antioxidant and phagocytic capacity, as well as parameters related to immune response stimulation by cytokine expression and antibodies production in a mice model.
METHODS
Formulated CN (cottonseed oil miniemulsion) and CNZ (cottonseed oil miniemulsion whit zinc oxide nanoparticles) miniemulsions were characterized by scanning electronic microscopy SEM, DLS and FT-IR. In murine macrophages, splenocytes and thymocytes primary cultures safety and cytotoxicity were determined by MTT. In macrophages the antioxidant and phagocytic capacity was evaluated. In BALB/c mice, the stimulation of the immune system was determined by the expression of cytokines and the production of antibodies.
RESULTS
The CN and CNZ presented stability for 90 days. Immediately after preparation, the CN presented a higher particle size (543.1 nm) than CNZ (320 nm). FT-IR demonstrated the correct nanoparticle synthesis by the absence of sulfate groups. CN and CNZ (1.25 to 10 µL/mL) had no toxic effect on macrophages ( = 0.108), splenocytes ( = 0.413), and thymocytes ( = 0.923). All CN and CNZ doses tested induced nitric oxide and antioxidants production in dose dependent manner when compared with control. CN-ovalbumin and CNZ-ovalbumin treatments in femoral subcutaneous tissue area showed inflammation with higher leukocyte infiltration compared with FCA. The intraperitoneal administration with CN, CNZ, and FCA showed a higher total intraperitoneal cells recruitment (CD14) after 24 h of inoculation than control ( = 0.0001). CN and CNZ increased the phagocyte capacity with respect to untreated macrophages in the -phagocytosis assay. The evaluation of residual CFU indicated that only CN significantly decreased ( = 0.004) this value at 3 h. By other side, only CN increased ( = 0.002) the nitric oxide production. CNZ stimulated a major INFγ secretion compared with FCA at day 7. A major IL-2 secretion was observed at days 7 and 14, stimulated with CN and CNZ. Both miniemulsions did not affect the antibody isotypes production (IgG1, IgG2a, IgG3, IgA and IgM) at days 7, 14, 28, and 42. CN induced a significant IgG production against OVA, but lesser than FCA.
CONCLUSIONS
The two new miniemulsions with adjuvant and antioxidant capacity, were capable of generating leukocyte infiltration and increased cytokines and antibodies production.
Topics: Animals; Mice; Zinc Oxide; alpha-Tocopherol; Cottonseed Oil; Ovalbumin; Antioxidants; Nitric Oxide; Spectroscopy, Fourier Transform Infrared; Adjuvants, Immunologic; Cytokines; Immunoglobulin G; Adjuvants, Pharmaceutic
PubMed: 36968001
DOI: 10.7717/peerj.14981 -
The Indian Journal of Medical Research Nov 2013The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism... (Review)
Review
The pure recombinant and synthetic antigens used in modern day vaccines are generally less immunogenic than older style live/attenuated and killed whole organism vaccines. One can improve the quality of vaccine production by incorporating immunomodulators or adjuvants with modified delivery vehicles viz. liposomes, immune stimulating complexes (ISCOMs), micro/nanospheres apart from alum, being used as gold standard. Adjuvants are used to augment the effect of a vaccine by stimulating the immune system to respond to the vaccine, more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionary conserved molecules which include lipopolysaccharides (LPS), components of bacterial cell wall, endocytosed nucleic acids such as dsRNA, ssDNA and unmethylated CpG dinucleotide containing DNA. This review provides information on various vaccine adjuvants and delivery vehicles being developed to date. From literature, it seems that the humoral immune responses have been observed for most adjuvants and delivery platforms while viral-vector, ISCOMs and Montanides have shown cytotoxic T-cell response in the clinical trials. MF59 and MPL® have elicited Th1 responses, and virus-like particles (VLPs), non-degradable nanoparticle and liposomes have also generated cellular immunity. Such vaccine components have also been evaluated for alternative routes of administration with clinical success reported for intranasal delivery of viral-vectors and proteosomes and oral delivery of VLP vaccines.
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Clinical Trials as Topic; Drug Delivery Systems; Drug Discovery; Humans; Immunity, Humoral; Lipopolysaccharides; Liposomes; T-Lymphocytes, Cytotoxic; Vaccines
PubMed: 24434331
DOI: No ID Found -
Oncoimmunology 2022Type 1 conventional dendritic cells (cDC1) efficiently cross-present antigens that prime cytotoxic CD8 T cells. cDC1 therefore constitute conceivable targets in cancer...
Type 1 conventional dendritic cells (cDC1) efficiently cross-present antigens that prime cytotoxic CD8 T cells. cDC1 therefore constitute conceivable targets in cancer vaccine development. We generated recombinant fusion cancer vaccines that aimed to concomitantly deliver tumor antigen and adjuvant to CD103 migratory cDC1, following intranasal administration. The fusion vaccine constructs comprised a cDC1-targeting anti-CD103 single chain antibody (aCD103) and a cholera toxin A1 (CTA1) subunit adjuvant, fused with MHC class I and II- or class II-restricted tumor cell antigens to generate a CTA1-I/II-aCD103 vaccine and a CTA1-II-aCD103 vaccine. The immunostimulatory and anti-tumor efficacy of these vaccines was evaluated in murine B16F1-ovalbumin (OVA) melanoma models in C57BL/6 J mice. The CTA1-I/II-aCD103 vaccine was most efficacious and triggered robust tumor antigen-specific CD8 T cell responses along with a Th17-polarized CD4 T cell response. This vaccine construct reduced the local growth of implanted B16F1-OVA melanomas and efficiently prevented hematogenous lung metastasis after prophylactic and therapeutic vaccination. Anti-tumor effects of the CTA1-I/II-aCD103 vaccine were antigen-specific and long-lasting. These results imply that adjuvant-containing recombinant fusion vaccines that target and activate cDC1 trigger effective anti-tumor immunity to control tumor growth and metastasis.
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Animals; Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cholera Toxin; Melanoma; Mice; Mice, Inbred C57BL; Ovalbumin; Recombinant Fusion Proteins; Vaccines, Synthetic
PubMed: 36046810
DOI: 10.1080/2162402X.2022.2115618 -
Journal of Pain and Symptom Management Nov 1994Baclofen is a gamma-aminobutyric acid (GABA) agonist approved for the treatment of spasticity and commonly used in the management of many types of neuropathic pain.... (Review)
Review
Baclofen is a gamma-aminobutyric acid (GABA) agonist approved for the treatment of spasticity and commonly used in the management of many types of neuropathic pain. Controlled studies have demonstrated the efficacy of this drug in trigeminal neuralgia. Although its precise mechanism of analgesic action is unknown, it is likely that a drug-induced increase in inhibitory activity is sufficient to interrupt the cascade of neural events that culminates in aberrant activity of wide dynamic range neurons, or more rostral neurons in nociceptive pathways, that is the substrate for some types of neuropathic pain. The optimal use of baclofen as an adjuvant analgesic requires an understanding of its pharmacology, side effect spectrum, and dosing guidelines that have proven useful in clinical practice. Failure of baclofen therapy following a prolonged trial requires dose tapering prior to discontinuation due to the potential for a withdrawal syndrome.
Topics: Adjuvants, Pharmaceutic; Analgesics; Baclofen; Clinical Trials as Topic; Drug Administration Schedule; Humans; Trigeminal Neuralgia
PubMed: 7852758
DOI: 10.1016/0885-3924(94)90111-2 -
Frontiers in Immunology 2022With the clinical approval of T-cell-dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy....
With the clinical approval of T-cell-dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy. Cancer vaccines require the addition of immunostimulatory adjuvants to increase vaccine immunogenicity, and increasingly multiple adjuvants are used in combination to bolster further and shape cellular immunity to tumor antigens. However, rigorous quantification of adjuvants' synergistic interactions is challenging due to partial redundancy in costimulatory molecules and cytokine production, leading to the common assumption that combining both adjuvants at the maximum tolerated dose results in optimal efficacy. Herein, we examine this maximum dose assumption and find combinations of these doses are suboptimal. Instead, we optimized dendritic cell activation by extending the Multidimensional Synergy of Combinations (MuSyC) framework that measures the synergy of efficacy and potency between two vaccine adjuvants. Initially, we performed a preliminary screening of clinically translatable adjuvant receptor targets (TLR, STING, NLL, and RIG-I). We determined that STING agonist (CDN) plus TLR4 agonist (MPL-A) or TLR7/8 agonist (R848) as the best pairwise combinations for dendritic cell activation. In addition, we found that the combination of R848 and CDN is synergistically efficacious and potent in activating both murine and human antigen-presenting cells (APCs) . These two selected adjuvants were then used to estimate a MuSyC-dose optimized for T-cell priming using ovalbumin-based peptide vaccines. Finally, using B16 melanoma and MOC1 head and neck cancer models, MuSyC-dose-based adjuvating of cancer vaccines improved the antitumor response, increased tumor-infiltrating lymphocytes, and induced novel myeloid tumor infiltration changes. Further, the MuSyC-dose-based adjuvants approach did not cause additional weight changes or increased plasma cytokine levels compared to CDN alone. Collectively, our findings offer a proof of principle that our MuSyC-extended approach can be used to optimize cancer vaccine formulations for immunotherapy.
Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Animals; Cancer Vaccines; Cytokines; Humans; Immunotherapy; Mice; Mice, Inbred C57BL; Neoplasms; Vaccine Efficacy
PubMed: 36059502
DOI: 10.3389/fimmu.2022.936129 -
Frontiers in Immunology 2023Direct administration of vaccines to mucosal surfaces, such as oral or nasal vaccination, represents an attractive alternative, or complement, to current parenteral...
Direct administration of vaccines to mucosal surfaces, such as oral or nasal vaccination, represents an attractive alternative, or complement, to current parenteral vaccination because it has a potential to induce antigen-specific immunity both at mucosal and systemic tissues. Although bacterium-like particles (BLPs), peptidoglycan structures derived from lactic acid bacteria, have been investigated as a novel adjuvant for oral or nasal vaccines, it remains unclear whether the administration routes differ the adjuvant effect of BLPs. Here, we showed that the adjuvant effect of BLPs from NZ9000 is greater with the nasal administration than with the oral administration. We conjugated BLPs with Tir, a virulence factor of , as a model adjuvant-antigen complex, and found that nasal, but not oral, immunization of mice with BLP-Tir induced robust antigen-specific IgA responses at the respiratory and intestinal mucosa, IgG2b-skewed systemic responses, and Th17 cellular responses. As one of the underlying mechanisms, we demonstrated that the nasal administration has a greater delivery efficiency (~1,000-fold) of the BLPs-conjugated antigens to mucosal-associated lymphoid tissues than the oral administration. Furthermore, the nasal, but not oral, administration of BLP-Tir elicited robust innate immune responses that were characterized by the expression of various pro-inflammatory cytokines and chemokines in the mucosal-associated lymphoid tissues. Considering these findings together, we anticipate that BLPs can be an attractive novel adjuvant for nasal vaccines targeting not only respiratory but also gastrointestinal infectious diseases.
Topics: Animals; Mice; Adjuvants, Immunologic; Immunization; Immunity, Mucosal; Vaccines; Antigens, Bacterial; Adjuvants, Pharmaceutic; Intestinal Mucosa
PubMed: 36742329
DOI: 10.3389/fimmu.2023.1082273 -
Oncology (Williston Park, N.Y.) Feb 1997Breast cancer treatment has evolved greatly within the last 25 years. Tamoxifen was first introduced for the treatment of metastatic breast cancer in the 1970s and later... (Review)
Review
Breast cancer treatment has evolved greatly within the last 25 years. Tamoxifen was first introduced for the treatment of metastatic breast cancer in the 1970s and later became accepted as standard adjuvant therapy. The emergence of tamoxifen as first-line hormonal therapy for metastatic disease and in the adjuvant setting occurred due to its efficacy in achieving prolonged overall survival as well as improved disease-free survival, the latter of which improves the psychological and physical quality of life of the patient. Tamoxifen is currently being studied for the prevention of breast cancer. Completion of this important trial is eagerly awaited.
Topics: Adjuvants, Pharmaceutic; Antineoplastic Agents, Hormonal; Breast Neoplasms; Consensus Development Conferences, NIH as Topic; Female; Humans; Medical Oncology; Patient Education as Topic; Tamoxifen; United States
PubMed: 9065928
DOI: No ID Found