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1.
Cancer Cell ; 38(2): 161-163, 2020 08 10.
Article in English | MEDLINE | ID: covidwho-2130226

ABSTRACT

Two recent Lancet and Lancet Oncology papers report that cancer patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have higher mortality rates. Common independent factors associated with increased risk of death were older age, history of smoking status, number of comorbidities, more advanced performance status, and active cancer.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/mortality , Infection Control/standards , Infectious Disease Transmission, Professional-to-Patient/prevention & control , Neoplasms/mortality , Pneumonia, Viral/mortality , Age Factors , Aged , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Humans , Neoplasms/immunology , Neoplasms/therapy , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Risk Assessment , Risk Factors , SARS-CoV-2
2.
Front Immunol ; 13: 833310, 2022.
Article in English | MEDLINE | ID: covidwho-1902989

ABSTRACT

Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world's most serious public health challenges. A "storm" of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol misuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol misuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.


Subject(s)
Alcoholism/immunology , COVID-19/immunology , HIV Infections/immunology , HIV-1/physiology , Neoplasms/immunology , SARS-CoV-2/physiology , Biomarkers/blood , Humans , Immune Checkpoint Proteins/blood , Severity of Illness Index
3.
Eur J Cancer ; 162: 182-193, 2022 02.
Article in English | MEDLINE | ID: covidwho-1838736

ABSTRACT

Taking into account higher risk of severe coronavirus disease 2019 or death among patients with cancer, as well as impaired immunogenicity after anti-SARS-CoV-2 vaccines, in addition to waning immunity, booster dosing appears mandatory in this patient population. This review sought to provide reasonable evidence so as to assist oncologists in their daily practice, helping them decide when an anti-SARS-Cov2 antibody (Ab) dosage should be scheduled after a full two-dose vaccination and, if necessary, propose an early third dose (D3). Such D3 could apply to non-responder patients with anti-Spike (S) Abs titres <40 binding Ab unit (BAU)/mL. For lowresponder patients with anti-S Ab titres between 40 BAU/mL and 100/260 BAU/mL (suggested area of uncertainty), an early D3 may similarly be proposed. Nevertheless, this D3 could be administered in a less urgent manner, taking into account associated comorbidities and regional epidemic incidence rates. This latter strategy may comprise a monthly dosage of anti-S titres so as to better assess the kinetics of waning immunity. For responder patients with anti-S titres above 260 BAU/mL, we suggest to follow the recommendations outlined for the general population. Given this context, patients with anti-S titres above 1000 BAU/mL should be given the possibility to undergo anti-S titre control after three months, designed to assess rapid humoral waning immunity. We strongly recommend that patients with cancer be included into observational serological monitoring studies or clinical trials that are dedicated to severe immunocompromised patients without any humoral seroconversion after D3.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunity, Humoral , Immunization Schedule , Immunization, Secondary , Neoplasms/immunology , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions , Humans , Immunocompromised Host , Monitoring, Immunologic , SARS-CoV-2/pathogenicity , Seroconversion , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Treatment Outcome
4.
J Biol Chem ; 298(5): 101908, 2022 05.
Article in English | MEDLINE | ID: covidwho-1773440

ABSTRACT

Human Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease.


Subject(s)
Intercellular Signaling Peptides and Proteins , Interleukin-18/metabolism , COVID-19/immunology , Humans , Inflammation , Neoplasms/immunology
6.
Epidemiol Infect ; 150: e40, 2022 02 21.
Article in English | MEDLINE | ID: covidwho-1747291

ABSTRACT

Nosocomial transmission of COVID-19 among immunocompromised hosts can have a serious impact on COVID-19 severity, underlying disease progression and SARS-CoV-2 transmission to other patients and healthcare workers within hospitals. We experienced a nosocomial outbreak of COVID-19 in the setting of a daycare unit for paediatric and young adult cancer patients. Between 9 and 18 November 2020, 473 individuals (181 patients, 247 caregivers/siblings and 45 staff members) were exposed to the index case, who was a nursing staff. Among them, three patients and four caregivers were infected. Two 5-year-old cancer patients with COVID-19 were not severely ill, but a 25-year-old cancer patient showed prolonged shedding of SARS-CoV-2 RNA for at least 12 weeks, which probably infected his mother at home approximately 7-8 weeks after the initial diagnosis. Except for this case, no secondary transmission was observed from the confirmed cases in either the hospital or the community. To conclude, in the day care setting of immunocompromised children and young adults, the rate of in-hospital transmission of SARS-CoV-2 was 1.6% when applying the stringent policy of infection prevention and control, including universal mask application and rapid and extensive contact investigation. Severely immunocompromised children/young adults with COVID-19 would have to be carefully managed after the mandatory isolation period while keeping the possibility of prolonged shedding of live virus in mind.


Subject(s)
COVID-19/epidemiology , Cancer Care Facilities , Cross Infection/epidemiology , Day Care, Medical , Infectious Disease Transmission, Professional-to-Patient , Neoplasms/therapy , Adolescent , Adult , Aged , COVID-19/immunology , COVID-19/transmission , Caregivers , Child , Child, Preschool , Cross Infection/immunology , Cross Infection/transmission , Disease Outbreaks , Female , Humans , Immunocompromised Host , Infant , Male , Middle Aged , Neoplasms/immunology , Republic of Korea/epidemiology , SARS-CoV-2 , Young Adult
7.
JAMA Oncol ; 8(5): 748-754, 2022 05 01.
Article in English | MEDLINE | ID: covidwho-1733818

ABSTRACT

Importance: Patients with cancer experience high rates of morbidity and mortality after SARS-CoV-2 infection. Immune response to mRNA-1273 vaccination across multiple cancer types and treatments remains to be established. Objective: To quantitate antibody responses after mRNA-1273 vaccination among patients with solid tumors and hematologic cancer and to assess clinical and treatment factors associated with vaccine response. Design, Setting, and Participants: This cohort study included patients with cancer who were aged 18 years or older, spoke English or Spanish, had received their first mRNA-1273 dose between January 12 and 25, 2021, and agreed to blood tests before and after vaccination. Exposures: Receipt of 1 and 2 mRNA-1273 SARS-CoV-2 vaccine doses. Main Outcomes and Measures: Seroconversion after each vaccine dose and IgG levels against SARS-CoV-2 spike protein obtained immediately before the first and second vaccine doses and 57 days (plus or minus 14 days) after the first vaccine dose. Cancer diagnoses and treatments were ascertained by medical record review. Serostatus was assessed via enzyme-linked immunosorbent assay. Paired t tests were applied to examine days 1, 29, and 57 SARS-CoV-2 antibody levels. Binding antibody IgG geometric mean titers were calculated based on log10-transformed values. Results: The 515 participants were a mean (SD) age of 64.5 (11.4) years; 262 (50.9%) were women; and 32 (6.2%) were Hispanic individuals and 479 (93.0%) White individuals; race and ethnicity data on 4 (0.7%) participants were missing. Seropositivity after vaccine dose 2 was 90.3% (465; 95% CI, 87.4%-92.7%) among patients with cancer, was significantly lower among patients with hematologic cancer (84.7% [255]; 95% CI, 80.1%-88.6%) vs solid tumors (98.1% [210]; 95% CI, 95.3%-99.5%), and was lowest among patients with lymphoid cancer (70.0% [77]; 95% CI, 60.5%-78.4%). Patients receiving a vaccination within 6 months after anti-CD20 monoclonal antibody treatment had a significantly lower seroconversion (6.3% [1]; 95% CI, 0.2%-30.2%) compared with those treated 6 to 24 months earlier (53.3% [8]; 95% CI, 26.6%-78.7%) or those who never received anti-CD20 treatment (94.2% [456]; 95% CI, 91.7%-96.1%). Low antibody levels after vaccination were observed among patients treated with anti-CD20 within 6 months before vaccination (GM, 15.5 AU/mL; 95% CI, 9.8-24.5 AU/mL), patients treated with small molecules (GM, 646.7 AU/mL; 95% CI, 441.9-946.5 AU/mL), and patients with low lymphocyte (GM, 547.4 AU/mL; 95% CI, 375.5-797.7 AU/mL) and IgG (GM, 494.7 AU/mL; 95% CI, 304.9-802.7 AU/mL) levels. Conclusions and Relevance: This cohort study found that the mRNA-1273 SARS-CoV-2 vaccine induced variable antibody responses that differed by cancer diagnosis and treatment received. These findings suggest that patients with hematologic cancer and those who are receiving immunosuppressive treatments may need additional vaccination doses.


Subject(s)
Antibody Formation , COVID-19 , Neoplasms , /immunology , Aged , COVID-19/epidemiology , COVID-19/prevention & control , Cohort Studies , Female , Florida , Hematologic Neoplasms , Humans , Immunoglobulin G , Male , Middle Aged , Neoplasms/immunology , Prospective Studies , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccination
8.
J Clin Oncol ; 40(1): 12-23, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-1724717

ABSTRACT

PURPOSE: The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS: We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti-SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS: Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses (P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type (P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses (P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION: Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Neoplasms/immunology , SARS-CoV-2/immunology , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Prospective Studies
9.
Transl Res ; 241: 83-95, 2022 03.
Article in English | MEDLINE | ID: covidwho-1720996

ABSTRACT

Patients with cancers have been severely affected by the COVID-19 pandemic. This is highlighted by the adverse outcomes in cancer patients with COVID-19 as well as by the impact of the COVID-19 pandemic on cancer care. Patients with cancer constitute a heterogeneous population that exhibits distinct mechanisms of immune dysfunction, associated with distinct systemic features of hot (T-cell-inflamed/infiltrated) and cold (Non-T-cell-inflamed and/or infiltrated) tumors. The former show hyper immune activated cells and a highly inflammatory environment while, contrastingly, the latter show the profile of a senescent and/or quiescent immune system. Thus, the evolution of SARS-CoV-2 infection in different types of cancers can show distinct trajectories which could lead to a variety of clinical and pathophysiological outcomes. The altered immunological environment including cytokines that characterizes hot and cold tumors will lead to different mechanisms of immune dysfunction, which will result in downstream effects on the course of SARS-CoV-2 infection. This review will focus on defining the known contributions of soluble pro- and anti-inflammatory mediators on immune function including altered T-cells and B-cells responses and as well on how these factors modulate the expression of SARS-CoV-2 receptor ACE2, TMPRSS2 expression, and lymph node fibrosis in cancer patients. We will propose immune mechanisms that underlie the distinct courses of SARS-CoV-2 infection in cancer patients and impact on the success of immune based therapies that have significantly improved cancer outcomes. Better understanding of the immune mechanisms prevalent in cancer patients that are associated to the outcomes of SARS-CoV-2 infection will help to identify the high-risk cancer patients and develop immune-based approaches to prevent significant adverse outcomes by targeting these pathways.


Subject(s)
COVID-19/complications , Neoplasms/immunology , COVID-19/immunology , COVID-19/virology , Humans , Outcome Assessment, Health Care , SARS-CoV-2/isolation & purification
10.
Eur J Cancer ; 160: 243-260, 2022 01.
Article in English | MEDLINE | ID: covidwho-1719651

ABSTRACT

BACKGROUND: Patients with cancer are considered a priority group for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination given their high risk of contracting severe Coronavirus Disease 2019 (COVID-19). However, limited data exist regarding the efficacy of immunisation in this population. In this study, we assess the immunologic response after COVID-19 vaccination of cancer versus non-cancer population. METHODS: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched from 01st March 2020 through 12th August 12 2021. Primary end-points were anti-SARS-CoV-2 spike protein (S) immunoglobulin G (IgG) seroconversion rates, T-cell response, and documented SARS-CoV-2 infection after COVID-19 immunisation. Data were extracted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Overall effects were pooled using random-effects models. RESULTS: This systematic review and meta-analysis included 35 original studies. Overall, 51% (95% confidence interval [CI], 41-62) and 73% (95% CI, 64-81) of patients with cancer developed anti-S IgG above the threshold level after partial and complete immunisation, respectively. Patients with haematologic malignancies had a significantly lower seroconversion rate than those with solid tumours after complete immunisation (65% vs 94%; P < 0.0001). Compared with non-cancer controls, oncological patients were less likely to attain seroconversion after incomplete (risk ratio [RR] 0.45 [95% CI 0.35-0.58]) and complete (RR 0.69 [95% CI 0.56-0.84]) COVID-19 immunisation schemes. Patients with cancer had a higher likelihood of having a documented SARS-CoV-2 infection after partial (RR 3.21; 95% CI 0.35-29.04) and complete (RR 2.04; 95% CI 0.38-11.10) immunisation. CONCLUSIONS: Patients with cancer have an impaired immune response to COVID-19 vaccination compared with controls. Strategies that endorse the completion of vaccination schemes are warranted. Future studies should aim to evaluate different approaches that enhance oncological patients' immune response.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/adverse effects , COVID-19/drug therapy , Neoplasms/immunology , SARS-CoV-2/drug effects , T-Lymphocytes/immunology , Vaccination/adverse effects , Antibodies, Viral/blood , COVID-19/virology , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Neoplasms/chemically induced , Neoplasms/drug therapy , Neoplasms/virology , SARS-CoV-2/immunology , Seroconversion , Spike Glycoprotein, Coronavirus/immunology
11.
Eur J Cancer ; 159: 259-274, 2021 12.
Article in English | MEDLINE | ID: covidwho-1719650

ABSTRACT

BACKGROUND: Efficacy and safety data of COVID-19 vaccines among cancer populations have been limited; however, preliminary data from recent studies have emerged regarding their immunogenicity and safety in this population. In this review, we examined current peer-reviewed publications containing serological and safety data after COVID-19 vaccination of patients with cancer. METHODS: This analysis examined 21 studies with a total of 5012 patients with cancer, of which 2676 (53%) had haematological malignancies, 2309 (46%) had solid cancers and 739 were healthy controls. Serological responses by anti-SARS-CoV-2 spike protein S1/S2 immunoglobulin G antibody levels and post-vaccination patient questionnaires regarding vaccine-related side-effects after the first and second dose were collected and analysed. RESULTS: In general, a single dose of the COVID-19 vaccine yields weaker and heterogeneous serological responses in both patients with haematological and solid malignancies. On receiving a second dose, serological response rates indicate a substantial increase in seropositivity to the SARS-CoV-2 spike protein in all cancer cohorts, but antibody titres remain reduced in comparison with healthy controls. Furthermore, seroconversion in patients with haematological malignancies was significantly lower than that in patients with solid tumours. COVID-19 vaccines are safe and well-tolerated in patients with cancer based on current data of local and systemic effects. CONCLUSION: Together, these data support the prioritisation of patients with cancer to receive their first and second doses to minimise the risk of COVID-19 infection and severe complications in this vulnerable population. Additional prophylactic measures must be considered for high-risk patients where current vaccination programs may not mount sufficient protection against SARS-CoV-2 infection.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunogenicity, Vaccine , Neoplasms/therapy , SARS-CoV-2/immunology , Vaccination , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/immunology , Risk Factors , SARS-CoV-2/pathogenicity , Seroconversion , Treatment Outcome , Vaccination/adverse effects , Young Adult
12.
Eur J Cancer ; 159: 105-112, 2021 12.
Article in English | MEDLINE | ID: covidwho-1719647

ABSTRACT

PURPOSE: Initial findings in patients with cancer suggest a lower seroconversion to SARS-CoV-2 vaccination possibly related to myelo-immunosuppressive therapies. We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunisation (AEFI) to the BNT162b2 vaccine in patients on active treatment. PATIENTS AND METHODS: Cancer patients, candidates to two doses of BNT162b2 SARS-CoV-2 vaccination, were enrolled. Patients on active surveillance served as controls. The primary endpoint was poor seroconversion (anti S1/S2 IgG < 25 AU/mL) after 21 days from the second dose. RESULTS: Between March and July 2021, 320 subjects were recruited, and 291 were assessable. The lack of seroconversion at 21 days from the second dose was 1.6% (95% CI, 0.4-8.7) on active surveillance, 13.9% (8.2-21.6) on chemotherapy, 11.4% (5.1-21.3) on hormone therapy, 21.7% (7.5-43.7) on targeted therapy and 4.8% (0.12-23.8) on immune-checkpoint-inhibitors (ICI). Compared to controls, the risk of no IgG response was greater for chemotherapy (p = 0.033), targeted therapy (0.005) and hormonotherapy (p = 0.051). Lymphocyte count < 1 × 109/L (p = 0.04) and older age (p = 0.03) also significantly predicted poor seroconversion. Overall, 43 patients (14.8%) complained of AEFI, mostly of mild grade. Risk of AEFI was greater in females (p = 0.001) and younger patients (p = 0.009). CONCLUSION: Chemotherapy, targeted therapy, hormone therapy, lymphocyte count < 1 × 109/L, and increasing age predict poor seroconversion after two doses of BNT162b2 in up to 20% of patients, indicating the need for a third dose and long-term serological testing in non-responders. AEFI occur much more frequently in women and younger subjects who may benefit from preventive medications. CLINICALTRIALS. GOV IDENTIFIER: NCT04932863.


Subject(s)
Antibodies, Viral/blood , COVID-19/prevention & control , Immunogenicity, Vaccine , Neoplasms/therapy , SARS-CoV-2/immunology , Vaccination , Aged , /immunology , Biomarkers/blood , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Female , Humans , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/immunology , Prospective Studies , Risk Factors , SARS-CoV-2/pathogenicity , Seroconversion , Time Factors , Treatment Outcome , Vaccination/adverse effects
13.
Int Immunopharmacol ; 105: 108531, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1712710

ABSTRACT

Immunoediting is a well-known concept that occurs in cancer through three steps of elimination, equilibrium, and escape (3Es), where the immune system first suppresses the growth of tumor cells and then promotes them towards the malignancy. This phenomenon has been conceptualized in some chronic viral infections such as HTLV-1 and HIV by obtaining the resistance to elimination and making a persistent form of infected cells especially in untreated patients. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a heterogeneous disease characterizing from mild/asymptomatic to severe/critical courses with some behavioral aspects in an immunoediting setting. In this context, a coordinated effort between innate and adaptive immune system leads to detection and destruction of early infection followed by equilibrium between virus-specific responses and infected cells, which eventually ends up with an uncontrolled inflammatory response in severe/critical patients. Although the SARS-CoV-2 applies several escape strategies such as mutations in viral epitopes, modulating the interferon response and inhibiting the MHC I molecules similar to the cancer cells, the 3Es hallmark may not occur in all clinical conditions. Here, we discuss how the lesson learnt from cancer immunoediting and accurate understanding of these pathophysiological mechanisms helps to develop more effective therapeutic strategies for COVID-19.


Subject(s)
COVID-19/immunology , SARS-CoV-2 , Animals , COVID-19/drug therapy , Host-Pathogen Interactions , Humans , Neoplasms/immunology
14.
Front Immunol ; 13: 832533, 2022.
Article in English | MEDLINE | ID: covidwho-1705491

ABSTRACT

Immunoproteomics has emerged as a versatile tool for analyzing the antibody repertoire in various disease contexts. Until recently, characterization of antibody molecules in biological fluids was limited to bulk serology, which identifies clinically relevant features of polyclonal antibody responses. The past decade, however, has seen the rise of mass-spectrometry-enabled proteomics methods that have allowed profiling of the antibody response at the molecular level, with the disease-specific serological repertoire elucidated in unprecedented detail. In this review, we present an up-to-date survey of insights into the disease-specific immunological repertoire by examining how quantitative proteomics-based approaches have shed light on the humoral immune response to infection and vaccination in pathogenic illnesses, the molecular basis of autoimmune disease, and the tumor-specific repertoire in cancer. We address limitations of this technology with a focus on emerging potential solutions and discuss the promise of high-resolution immunoproteomics in therapeutic discovery and novel vaccine design.


Subject(s)
Antibodies/analysis , Immunoproteins/analysis , Proteomics/methods , Animals , Autoimmune Diseases/immunology , Humans , Mass Spectrometry , Neoplasms/immunology , Vaccines/immunology
15.
Eur J Med Res ; 27(1): 23, 2022 Feb 12.
Article in English | MEDLINE | ID: covidwho-1703609

ABSTRACT

BACKGROUND: Immunocompromised (IC) patients are at higher risk of severe SARS-CoV-2 infection, morbidity, and mortality compared to the general population. They should be prioritized for primary prevention through vaccination. This study aimed to evaluate the efficacy of COVID-19 mRNA vaccines in IC patients through a systematic review and meta-analysis approach. METHOD: PubMed-MEDLINE, Scopus, and Web of Science were searched for original articles reporting the immunogenicity of two doses of mRNA COVID-19 vaccines in adult patients with IC condition between June 1, 2020 and September 1, 2021. Meta-analysis was performed using either random or fixed effect according to the heterogeneity of the studies. Subgroup analysis was performed to identify potential sources of heterogeneity. RESULTS: A total of 26 studies on 3207 IC patients and 1726 healthy individuals were included. The risk of seroconversion in IC patients was 48% lower than those in controls (RR = 0.52 [0.42, 0.65]). IC patients with autoimmune conditions were 54%, and patients with malignancy were 42% more likely to have positive seroconversion than transplant recipients (P < 0.01). Subgroup meta-analysis based on the type of malignancy, revealed significantly higher proportion of positive seroconversion in solid organ compared to hematologic malignancies (RR = 0.88 [0.85, 0.92] vs. 0.61 [0.44, 0.86], P = 0.03). Subgroup meta-analysis based on type of transplantation (kidney vs. others) showed no statistically significant between-group difference of seroconversion (P = 0.55). CONCLUSIONS: IC patients, especially transplant recipients, developed lower immunogenicity with two-dose of COVID-19 mRNA vaccines. Among patients with IC, those with autoimmune conditions and solid organ malignancies are mostly benefited from COVID-19 vaccination. Findings from this meta-analysis could aid healthcare policymakers in making decisions regarding the importance of the booster dose or more strict personal protections in the IC patients.


Subject(s)
COVID-19 Vaccines/immunology , Immunocompromised Host , Vaccines, Synthetic/immunology , /immunology , Autoimmune Diseases/immunology , COVID-19 Vaccines/therapeutic use , Case-Control Studies , Humans , Neoplasms/immunology , Organ Transplantation , Vaccines, Synthetic/therapeutic use , /therapeutic use
16.
Cancer Treat Res Commun ; 31: 100537, 2022.
Article in English | MEDLINE | ID: covidwho-1693708

ABSTRACT

This overview describes the research of Nobutu Yamamoto (Philadelphia) concerning immunotherapy with GcMAF for patients with cancer and for patients infected with pathogenic envelope viruses. GcMAF (Group-specific component Macrophage-Activating Factor) is a mammalian protein with an incredible potency to directly activate macrophages. Since the late 1980s Yamamoto's investigations were published in numerous journals but in order to understand the details of his research, a minute survey of many of his patents was required. But even then, regrettably, a precise description of his experiments was sometimes lacking. This overview tries to summarize all of Yamamoto's research on GcMAF, as well as some selected more recent papers from other investigators, who tried to verify and/or reproduce Yamamoto's reports. In my opinion the most important result of the GcMAF research deserves widespread renewed attention: human GcMAF injections (100 ng per week, intramuscular or intravenous) can help to cure patients with a great variety of cancers as well as patients infected with pathogenic envelope viruses like the human immunodeficiency virus 1 (HIV-1), influenza, measles and rubella (and maybe also SARS-CoV-2). From Yamamoto's data it can be calculated that GcMAF is a near-stoichiometric activator of macrophages. Yamamoto monitored the progress of his immunotherapy via the serum level of an enzyme called nagalase (α-N-acetylgalactosaminidase activity at pH 6). I have extensively discussed the properties and potential catalytic site of this enzyme activity in an Appendix entitled: "Search for the potential active site of the latent α-N-acetylgalactosaminidase activity in the glycoproteins of some envelope viruses".


Subject(s)
Immunotherapy , Macrophage-Activating Factors , Neoplasms , Vitamin D-Binding Protein , Animals , Humans , Macrophage-Activating Factors/therapeutic use , Neoplasms/immunology , Neoplasms/therapy , Neoplasms/virology , Virus Diseases/drug therapy , Virus Diseases/immunology , Virus Diseases/virology , Vitamin D-Binding Protein/therapeutic use , alpha-N-Acetylgalactosaminidase/immunology
17.
Life Sci Alliance ; 5(6)2022 06.
Article in English | MEDLINE | ID: covidwho-1689580

ABSTRACT

SARS-CoV-2 vaccination has proven effective in inducing an immune response in healthy individuals and is progressively us allowing to overcome the pandemic. Recent evidence has shown that response to vaccination in some vulnerable patients may be diminished, and it has been proposed a booster dose. We tested the kinetic of development of serum antibodies to the SARS-CoV-2 Spike protein, their neutralizing capacity, the CD4 and CD8 IFN-γ T-cell response in 328 subjects, including 131 immunocompromised individuals (cancer, rheumatologic, and hemodialysis patients), 160 health-care workers (HCW) and 37 subjects older than 75 yr, after vaccination with two or three doses of mRNA vaccines. We stratified the patients according to the type of treatment. We found that immunocompromised patients, depending on the type of treatment, poorly respond to SARS-CoV-2 mRNA vaccines. However, an additional booster dose of vaccine induced a good immune response in almost all of the patients except those receiving anti-CD20 antibody. Similarly to HCW, previously infected and vaccinated immunocompromised individuals demonstrate a stronger SARS-CoV-2-specific immune response than those who are vaccinated without prior infection.


Subject(s)
COVID-19 Vaccines/immunology , Immunocompromised Host/immunology , T-Lymphocytes/immunology , /immunology , Aged , Antibodies, Neutralizing/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Humans , Immunization, Secondary , Middle Aged , Neoplasms/immunology , Renal Dialysis
18.
Cancer Discov ; 12(2): 303-330, 2022 02.
Article in English | MEDLINE | ID: covidwho-1685769

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic has left patients with current or past history of cancer facing disparate consequences at every stage of the cancer trajectory. This comprehensive review offers a landscape analysis of the current state of the literature on COVID-19 and cancer, including the immune response to COVID-19, risk factors for severe disease, and impact of anticancer therapies. We also review the latest data on treatment of COVID-19 and vaccination safety and efficacy in patients with cancer, as well as the impact of the pandemic on cancer care, including the urgent need for rapid evidence generation and real-world study designs. SIGNIFICANCE: Patients with cancer have faced severe consequences at every stage of the cancer journey due to the COVID-19 pandemic. This comprehensive review offers a landscape analysis of the current state of the field regarding COVID-19 and cancer. We cover the immune response, risk factors for severe disease, and implications for vaccination in patients with cancer, as well as the impact of the COVID-19 pandemic on cancer care delivery. Overall, this review provides an in-depth summary of the key issues facing patients with cancer during this unprecedented health crisis.


Subject(s)
COVID-19/epidemiology , Neoplasms/complications , COVID-19/complications , COVID-19/therapy , Humans , Neoplasms/immunology , Neoplasms/therapy , Pandemics
19.
Front Immunol ; 12: 838082, 2021.
Article in English | MEDLINE | ID: covidwho-1674340

ABSTRACT

Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications. Furthermore, they do not solely represent a substitute for monoclonal antibodies but their unique features allow expanding the applications of biotherapeutics and changes the pattern of disease treatment. Nanobodies possess the double advantage of being small and simple to engineer. This combination has promoted extremely diversified approaches to design nanobody-based constructs suitable for particular applications. Both the format geometry possibilities and the functionalization strategies have been widely explored to provide macromolecules with better efficacy with respect to single nanobodies or their combination. Nanobody multimers and nanobody-derived reagents were developed to image and contrast several cancer diseases and have shown their effectiveness in animal models. Their capacity to block more independent signaling pathways simultaneously is considered a critical advantage to avoid tumor resistance, whereas the mass of these multimeric compounds still remains significantly smaller than that of an IgG, enabling deeper penetration in solid tumors. When applied to CAR-T cell therapy, nanobodies can effectively improve the specificity by targeting multiple epitopes and consequently reduce the side effects. This represents a great potential in treating malignant lymphomas, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma and solid tumors. Apart from cancer treatment, multispecific drugs and imaging reagents built with nanobody blocks have demonstrated their value also for detecting and tackling neurodegenerative, autoimmune, metabolic, and infectious diseases and as antidotes for toxins. In particular, multi-paratopic nanobody-based constructs have been developed recently as drugs for passive immunization against SARS-CoV-2 with the goal of impairing variant survival due to resistance to antibodies targeting single epitopes. Given the enormous research activity in the field, it can be expected that more and more multimeric nanobody molecules will undergo late clinical trials in the next future. Systematic Review Registration.


Subject(s)
Single-Domain Antibodies/chemistry , Single-Domain Antibodies/therapeutic use , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Communicable Diseases/immunology , Communicable Diseases/therapy , Humans , Immunomodulation , Molecular Imaging , Molecular Targeted Therapy , Neoplasms/diagnostic imaging , Neoplasms/immunology , Neoplasms/therapy , Recombinant Proteins/chemistry , Recombinant Proteins/immunology , Recombinant Proteins/therapeutic use , Single-Domain Antibodies/immunology
20.
Viruses ; 14(2)2022 01 25.
Article in English | MEDLINE | ID: covidwho-1667339

ABSTRACT

In 2014 and 2021, two nucleic-acid vaccine candidates named MAV E2 and VGX-3100 completed phase III clinical trials in Mexico and U.S., respectively, for patients with human papillomavirus (HPV)-related, high-grade squamous intraepithelial lesions (HSIL). These well-tolerated but still unlicensed vaccines encode distinct HPV antigens (E2 versus E6+E7) to elicit cell-mediated immune responses; their clinical efficacy, as measured by HSIL regression or cure, was modest when compared with placebo or surgery (conization), but both proved highly effective in clearing HPV infection, which should help further optimize strategies for enhancing vaccine immunogenicity, toward an ultimate goal of preventing malignancies in millions of patients who are living with persistent, oncogenic HPV infection but are not expected to benefit from current, prophylactic vaccines. The major roadblocks to a highly efficacious and practical product remain challenging and can be classified into five categories: (i) getting the vaccines into the right cells for efficient expression and presentation of HPV antigens (fusion proteins or epitopes); (ii) having adequate coverage of oncogenic HPV types, beyond the current focus on HPV-16 and -18; (iii) directing immune protection to various epithelial niches, especially anogenital mucosa and upper aerodigestive tract where HPV-transformed cells wreak havoc; (iv) establishing the time window and vaccination regimen, including dosage, interval and even combination therapy, for achieving maximum efficacy; and (v) validating therapeutic efficacy in patients with poor prognosis because of advanced, recurrent or non-resectable malignancies. Overall, the room for improvements is still large enough that continuing efforts for research and development will very likely extend into the next decade.


Subject(s)
Cancer Vaccines/therapeutic use , Cervical Intraepithelial Neoplasia/therapy , Neoplasms/therapy , Papillomavirus Infections/therapy , Papillomavirus Vaccines/therapeutic use , Uterine Cervical Neoplasms/therapy , Vaccines, DNA/therapeutic use , Animals , Cervical Intraepithelial Neoplasia/immunology , Clinical Trials as Topic , Female , Humans , Immunogenicity, Vaccine , Neoplasms/immunology , Neoplasms/virology , Papillomavirus Infections/immunology , Papillomavirus Vaccines/immunology , Squamous Intraepithelial Lesions of the Cervix/therapy , Uterine Cervical Neoplasms/virology , Vaccines, DNA/immunology , /therapeutic use
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