Cytomegalovirus and human immunosenescence Pawelec, Graham; Derhovanessian, Evelyna; Larbi, Anis ...
Reviews in medical virology,
January 2009, Letnik:
19, Številka:
1
Journal Article
In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected ...intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 patients keyhole limpet hemocyanin (KLH) was added to the vaccine. Granulocyte macrophage colony-stimulating factor was applied as an adjuvant. Endpoints were toxicity and immune responses. No adverse events more than grade II have been observed. During treatment the frequency of Foxp3+/CD4+ regulatory T cells was significantly decreased upon mRNA vaccination in peripheral blood of the patients in the KLH arm, whereas myeloid suppressor cells (CD11b+HLA-DR lo monocytes) were reduced in the patients not receiving KLH. A reproducible increase of vaccine-directed T cells was observed in 2 of 4 immunologically evaluable patients. One of 7 patients with measurable disease showed a complete response. In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe. The significant influence of the treatment on the frequency of immunosuppressive cells, the increase of vaccine-directed T cells upon treatment in a subset of patients together with the demonstration of a complete clinical response encourage further clinical investigation of the protamine-mRNA vaccine.
Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this ...phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence. The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided. Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient.
T cell-mediated immunity in elderly people is compromised in ways reflected in the composition of the peripheral T cell pool. The advent of polychromatic flow cytometry has made analysis of cell ...subsets feasible in unprecedented detail.
Here we document shifts in subset distribution within naïve (N), central memory (CM) and effector memory (EM) cells defined by CD45RA and CCR7 expression in the elderly, additionally using the costimulatory receptors CD27 and CD28, as well as the coinhibitory receptors CD57 and KLRG-1, to further dissect these. Although differences between young and old were more marked in CD8 than in CD4 cells, a similar overall pattern prevailed in both. Thus, the use of all these markers together, and inclusion of assays of proliferation and cytokine secretion, may enable the construction of a differentiation scheme applicable to CD4 as well as CD8 cells, with the model (based on Romero et al.) suggesting the progression N-->CM-->EM1-->EM2-->pE1-->pE2-->EM4-->EM3-->E end-stage non-proliferative effector cells.
Overall, the results suggest that both differences in subset distribution and differences between subsets are responsible for age-related changes in CD8 cells but that differences within rather than between subsets are more prominent for CD4 cells.
To analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis.
We examined 84 patients with ...follow-up after analysis (cohort A), 18 long-term survivors with an extraordinarily favorable course of disease before analysis (> 24 months survival after first occurrence of distant metastases; cohort B), and 14 healthy controls. Circulating antigen-reactive T cells were characterized by intracellular cytokine staining after in vitro stimulation.
In cohort A patients, the presence of T cells responding to peptides from NY-ESO-1, Melan-A, or MAGE-3 and the M category according to the American Joint Committee on Cancer classification were significantly associated with survival. T cells responding to NY-ESO-1 and Melan-A (hazard ratios, 0.29 and 0.18, respectively) remained independent prognostic factors in Cox regression analysis and were superior to the M category in predicting outcome. Median survival of patients possessing T cells responding to NY-ESO-1, Melan-A, or both was 21 months, compared with 6 months for all others. NY-ESO-1-responsive T cells were detected in 70% of cohort A patients surviving > 18 months and in 50% of cohort B patients. Melan-A responses were found in 42% and 47% of patients in cohorts A and B, respectively. In contrast, the proportion was only 22% for NY-ESO-1 and 23% for Melan-A in those who died within 6 months.
The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.
Inflammation, ageing and chronic disease Pawelec, Graham; Goldeck, David; Derhovanessian, Evelyna
Current opinion in immunology,
08/2014, Letnik:
29
Journal Article
Recenzirano
Highlights • Elderly people commonly show signs of low level systemic inflammation. • Causes include presence of senescent cells, chronic infections and obesity. • Systemic inflammation has been ...linked to multiple chronic diseases of ageing. • Addressing dysregulated control of inflammation will attenuate chronic disease.
Role of CMV in immune senescence Pawelec, Graham; Derhovanessian, Evelyna
Virus research,
05/2011, Letnik:
157, Številka:
2
Journal Article
Recenzirano
“Immune senescence” is a descriptive term for the deleterious age-associated changes to immunity observed in all mammals studied so far. While all components of innate and adaptive immunity are ...changed with age, the clinical impact of these changes is not clear, and mechanisms of and markers for immunosenescence are controversial. In humans, several cross-sectional studies have demonstrated that the major accepted age-associated changes to parameters used to assess adaptive immune status are markedly influenced by infection with cytomegalovirus (CMV). In the very limited longitudinal studies thus far carried out, a cluster of immune parameters associating with 2-, 4- and 6-year survival of the very elderly has been identified and termed the “immune risk profile” (IRP). This cluster includes seropositivity for CMV and is characterised by accumulations of clonal expansions of late-differentiated CD8+ T cells, many of which are specific for CMV antigens. Here we review the impact of CMV on “immune senescence” in humans.
Tumours are commonly hypoxic and this can be associated with aggressive tumour type, metastasis and resistance to therapy. Heat shock proteins (hsps) are induced in response to hypoxia, provide ...cancer cells with protection against tumour-associated stressors and chaperone oncoproteins that drive tumour proliferation. This study examined the effect of different oxygen concentrations on the expression of hsps in melanoma cell lines.
Melanoma cell lines were cultured in 2% and 20% O(2). Expression of Hsp90, Hsp70, Hsp60, Hsp40 and Hsp32 proteins were determined by flow cytometry.
Growth rates and viability were reduced in the majority of cell lines by culture in 2% O(2). Hsp expression was different in 2% compared to 20% O(2) and changes in Hsp90 expression correlated with cell line generation time (P<0.005) and viability (P<0.01). Greater total hsp expression correlated with improved viability in 2% but not 20% O(2) (P<0.05). Relative expression of the different hsps was consistent across cell lines and each correlated with the others (P = 0.0001) but not with Hsp32. Hsp expression was inversely correlated with cell line adhesion to laminin as well as collagen type IV and Breslow depth of the original primary tumour tissue (P<0.05), but not with Clark level or patient survival. All five hsps were identified on the cell surface.
Culture in 2% O(2) variably altered hsp expression in a panel of melanoma cell lines. Hsp expression was associated with certain cell line characteristics and clinical parameters of the originating tumour.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BNT162b2, an mRNA vaccine against COVID-19, is being utilised worldwide, but immunogenicity and safety data in Chinese individuals are limited.
This phase 2, randomised, double-blind, ...placebo-controlled trial included healthy or medically stable individuals aged 18–85 years enrolled at two clinical sites in China. Participants were stratified by age (≤55 or >55 years) and randomly assigned (3:1) by an independent randomisation professional to receive two doses of intramuscular BNT162b2 30 μg or placebo, administered 21 days apart. Study participants, study personnel, investigators, statisticians, and the sponsor's study management team were blinded to treatment assignment. Primary immunogenicity endpoints were the geometric mean titers (GMTs) of neutralising antibodies to live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seroconversion rates (SCR) 1 month after the second dose. Safety assessments included reactogenicity within 14 days of vaccination, adverse events (AEs), and clinical laboratory parameters. Randomised participants who received at least one dose were included in the efficacy and safety analyses on a complete case basis (incomplete/missing data not imputed). Results up to 6 months after the second dose are reported.
Overall, 959 participants (all of Han ethnicity) who were recruited between December 5th, 2020 and January 9th, 2021 received at least one injection (BNT162b2, n=720; placebo, n=239). At 1 month after the second dose, the 50% neutralising antibody GMT was 294.4 (95% CI; 281.1–308.4) in the BNT162b2 group and 5.0 (95% CI; 5.0–5.0) in the placebo group. SCRs were 99.7% (95% CI; 99.0%–100.0%) and 0% (95% CI; 0.0%–1.5%), respectively (p<0.0001 vs placebo). Although the GMT of neutralising antibodies in the BNT162b2 group was greatly reduced at 6 months after the second dose, the SCR still remained at 58.8%. BNT162b2-elicited sera neutralised SARS-CoV-2 variants of concern. T-cell responses were detected in 58/73 (79.5%) BNT162b2 recipients. Reactogenicity was mild or moderate in severity and resolved within a few days after onset. Unsolicited AEs were uncommon at 1 month following vaccine administration, and there were no vaccine-related serious AEs at 1 month or 6 months after the second dose.
BNT162b2 vaccination induced a robust immune response with acceptable tolerability in Han Chinese adults. However, follow-up duration was relatively short and COVID-19 rates were not assessed. Safety data collection is continuing until 12 months after the second dose.
BioNTech – sponsored the trial. Shanghai Fosun Pharmaceutical Development Inc. (Fosun Pharma) – conducted the trial, funded medical writing.
NCT04649021. Trial status: Completed.
BackgroundmRNA-based-drugs can be applied for cancer immunotherapy.1 SAR441000 is a novel saline-formulated mixture of four mRNAs encoding interleukin-12 single chain, interferon alpha-2b, ...granulocyte-macrophage colony-stimulating factor, and interleukin-15 sushi that we have identified as mediators of tumor regression across different murine tumor models. Local intratumoral administration of SAR441000 in immunocompetent mice, mediates successful antitumor immunity leading to tumor eradication. Effective antitumor activity of these cytokines involved multiple immune cell populations and was accompanied by intratumoral interferon gamma induction, systemic antigen-specific T-cell expansion, increased granzyme B+ T-cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of non-injected distant tumors. Combining the mRNAs with checkpoint inhibitors enhanced antitumor responses in both injected and non-injected tumors, improving survival and tumor regression in mice. Based on these preclinical observations a clinical study was initiated.MethodsIn a phase 1 dose escalation study, patients with advanced solid tumors were treated with weekly intratumoral administration of SAR441000 monotherapy and in combination with fixed dose of cemiplimab 350 mg. Plasma samples for cytokine analysis and tumor biopsies were collected at baseline and throughout the study to characterize the PK/PD profile of SAR441000, immune cell tumor infiltration by immunohistochemistry and the presence of corresponding tumor proinflammatory signatures by RNA sequencing.ResultsAs of July 2020, 17 patients received SAR441000 monotherapy (melanoma 7, breast 4, sarcoma 2, Cutaneous Squamous Cell 2, Basal Cell 1, and Merkel Cell 1) at dose levels 1 through 7. Six patients received SAR441000 in combination therapy (melanoma 3, breast 3) at dose levels 4 and 5. No patient experienced a Dose Limiting Toxicity. No grade 3, 4 or 5 adverse events related to study treatment were reported. Adverse events related to study treatment in two or more subjects in both treatment groups combined were nonserious grade 1 or 2 fatigue (43%;10/23), vomiting (17%; 4/23), nausea (13%;3/23); local injection site reaction (11.7%, 2/23); and chills, diarrhea, and rash were reported as 9% (2/23), respectively (table 1 and 2). In some patients, increases in plasma IP10 and IFN gamma and CD8+ T cell infiltration in tumor biopsies were observed.Abstract 391 Table 1Frequency of patients with a TEAE related to SAR44100* by dose group and gradeAbstract 391 Table 2Frequency of patients with a TEAE related to study treatment (SAR441000+cemiplimab) * by dose group and gradeConclusionsSAR441000 administered as monotherapy and in combination with cemiplimab was generally well tolerated. An immunomodulatory effect is suggested by downstream effector cytokines and T cell infiltration. These data support further clinical evaluation of SAR441000.Ethics ApprovalThe study was approved by each participating Institution’s Ethics or Institutional Review Board(s).ReferenceSahin U, Karikó K, Türeci Ö. mRNA-based therapeutics-developing a new class of drugs. Nat. Rev. Drug Discov 2014;13:759–780.
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