ABSTRACT
INTRODUCTION: Despite its crucial role in Epidermal Growth Factor Receptor (EGFR) activation, and the resulting impact on the health-disease process, epidermal growth factor (EGF) is an underexplored molecule in relation to how its serum concentrations relate to other analytes and clinical variables in pathological contexts. OBJECTIVE: To clarify the possible correlation between EGF and clinical and analytical variables in the context of COVID-19. METHODS: Cross-sectional observational and analytical study, in patients with virological and clinical diagnosis of COVID-19, selected by simple random sampling, admitted between August and September 2021. UMELISA-EGF commercial kits were used. RESULTS: Differences in overall EGF values were observed between groups (566.04 vs. 910.53 pg/ml, p = .0430). In COVID-19 patients, no notable correlations were observed for neutrophil, platelet, triglyceride or liver enzyme values (p > .05). Significant correlations were observed with the neutrophil-lymphocyte indicator (r = 0.4711, p = .0128) as well as with the platelet-lymphocyte index (r = 0.4553, p = .0155). Statistical results of multivariate regression analysis suggest NLR (ß = .2232, p = .0353) and PLR (ß = .2117, p = .0411) are predictors of inflammation in patients with COVID-19. CONCLUSIONS: Serum EGF concentrations in COVID-19 correlate positively with prognostic inflammatory markers of severity and could presumably act as an independent risk factor for the development of inflammation in response to new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Subject(s)
COVID-19 , Epidermal Growth Factor , Inflammation , SARS-CoV-2 , Humans , COVID-19/blood , COVID-19/diagnosis , Epidermal Growth Factor/blood , Male , Female , Cross-Sectional Studies , Middle Aged , Aged , Inflammation/blood , Adult , Biomarkers/blood , Neutrophils/immunologyABSTRACT
BACKGROUND: NeuroEPO plus is a recombinant human erythropoietin without erythropoietic activity and shorter plasma half-life due to its low sialic acid content. NeuroEPO plus prevents oxidative damage, neuroinflammation, apoptosis and cognitive deficit in an Alzheimer's disease (AD) models. The aim of this study was to assess efficacy and safety of neuroEPO plus. METHODS: This was a double-blind, randomized, placebo-controlled, phase 2-3 trial involving participants ≥ 50 years of age with mild-to-moderate AD clinical syndrome. Participants were randomized in a 1:1:1 ratio to receive 0.5 or 1.0 mg of neuroEPO plus or placebo intranasally 3 times/week for 48 weeks. The primary outcome was change in the 11-item cognitive subscale of the AD Assessment Scale (ADAS-Cog11) score from baseline to 48 weeks (range, 0 to 70; higher scores indicate greater impairment). Secondary outcomes included CIBIC+, GDS, MoCA, NPI, Activities of Daily Living Scales, cerebral perfusion, and hippocampal volume. RESULTS: A total of 174 participants were enrolled and 170 were treated (57 in neuroEPO plus 0.5 mg, 56 in neuroEPO plus 1.0 mg and 57 in placebo group). Mean age, 74.0 years; 121 (71.2%) women and 85% completed the trial. The median change in ADAS-Cog11 score at 48 weeks was -3.0 (95% CI, -4.3 to -1.7) in the 0.5 mg neuroEPO plus group, -4.0 (95% CI, -5.9 to -2.1) in the 1.0 mg neuroEPO plus group and 4.0 (95% CI, 1.9 to 6.1) in the placebo group. The difference of neuroEPO plus 0.5 mg vs. placebo was 7.0 points (95% CI, 4.5-9.5) P = 0.000 and between the neuroEPO plus 1.0 mg vs. placebo was 8.0 points (95% CI, 5.2-10.8) P = 0.000. NeuroEPO plus treatment induced a statistically significant improvement in some of clinical secondary outcomes vs. placebo including CIBIC+, GDS, MoCA, NPI, and the brain perfusion. CONCLUSIONS: Among participants with mild-moderate Alzheimer's disease clinical syndrome, neuroEPO plus improved the cognitive evaluation at 48 weeks, with a very good safety profile. Larger trials are warranted to determine the efficacy and safety of neuroEPO plus in Alzheimer's disease. TRIAL REGISTRATION: https://rpcec.sld.cu Identifier: RPCEC00000232.
Subject(s)
Alzheimer Disease , Cognition Disorders , Cognitive Dysfunction , Aged , Female , Humans , Male , Activities of Daily Living , Alzheimer Disease/drug therapy , Alzheimer Disease/psychology , Cognition Disorders/drug therapy , Double-Blind Method , Treatment OutcomeABSTRACT
INTRODUCTION: Centenarians are considered a model of successful aging. Cuba exhibits one of the oldest populations in Latin America with more than two thousand centenarians. METHODS: This study aimed to evaluate the immune phenotype of forty-three Cuban centenarians, their clinical characteristics such as comorbidities, frailty, body mass index, and some hemochemical parameters. RESULTS: Centenarians had normal body mass indexes, relatively good health status, and 21.95% of them had no comorbidities; 53.6% were classified as frail, and 7% were classified as robust. In addition, 17% of centenarians were independent, and 41.46% were moderately dependent. The seroprevalence against cytomegalovirus was 100%. Concerning pro-inflammatory markers, the majority of them had very low cytokine levels and serum C-reactive protein around the normal limit. We also found the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells. Terminally differentiated CD8+CD28- T cells were higher in frail centenarians than in pre-frail, while CD8+CD57+ and CD8+EMRA T cells were higher in moderately and severely dependent individuals than in independent individuals. Severely dependent centenarians had a lower CD4+/CD8+ ratio. CONCLUSION: This study describes for the first time the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells, as well as its relation to frailty and/or dependency in a group of Cuban centenarians. Further studies are needed to continue understanding the natural biological aging mechanism and the relationship between terminally differentiated lymphocytes and inflammaging in the context of extreme longevity.
Subject(s)
Frailty , Humans , Centenarians , Seroepidemiologic Studies , Aging , CD8-Positive T-Lymphocytes/metabolismABSTRACT
SARS-CoV-2 infection causes a range of clinical presentations and induces changes in both innate and adaptive branches of the immune system. Furthermore, direct viral action to the cells of the lung promotes over-expression of the epidermal growth factor receptor (EGFR) which triggers pro-inflammatory response, contributes to coagulopathy and intravascular thrombi as well as lung fibrosis. Based on the role of this signaling pathway in the pathophysiology of the disease, nimotuzumab, an anti-EGFR monoclonal antibody, was used to treat patients with COVID-19. The aim of this study was to determine IL-6 and PAI-1 concentrations and lymphocyte subpopulations profiles in moderately and severely ill COVID-19 patients diagnosed during the B.1.617.2 variant wave in Cuba and included in a phase I/II trial to evaluate the safety and preliminary effect of nimotuzumab in COVID-19 disease. We observed high serum levels of IL-6, elevated plasma concentration of PAI-1, mean values of neutrophils to lymphocytes ratio (NLR) above three and CD4+ lymphopenia in both groups of patients. PAI-1 and IL-6 circulating levels decreased in patients treated with nimotuzumab. More than 95% of patients in which IL-6 decreased or increased slightly, were alive within 14 days after the monoclonal antibody administration. Patients with moderate and severe disease, were no different regarding the studied parameters, addressing the idea that several immune alterations could be present before the infection becomes clinically relevant. These findings suggest that nimotuzumab could be an attractive therapeutic option to interfere with the negative relationship between cytokines and procoagulant mediators in the inflammatory and prothrombotic phases of the disease.
Subject(s)
COVID-19 Drug Treatment , Humans , SARS-CoV-2 , Interleukin-6 , Plasminogen Activator Inhibitor 1 , Antibodies, Monoclonal/therapeutic useABSTRACT
EGFR signaling is an important regulator of SARS-CoV induced lung damage, inflammation and fibrosis. Nimotuzumab is a humanized anti-EGFR antibody registered for several cancer indications. An expanded access study was conducted to evaluate the safety and recovery rate of severe and critical patients with confirmed SARS-CoV-2 infection, treated with nimotuzumab in combination with the standard of care in the real-world scenario. The antibody was administered as an intravenous infusions every 72 h, up to 5 doses. In order to assess the impact of nimotuzumab, the recovery rate was compared with a paired retrospective cohort. Control patients received standard treatment according the national protocol but not nimotuzumab. Overall, 1,151 severe or critical patients received nimotuzumab in 21 hospitals of Cuba. Median age was 65 and 773 patients had at least one comorbidity. Nimotuzumab was very well-tolerated and mild or moderate adverse events were detected in 19 patients. 1,009 controls matching with the nimotuzumab patients, were selected using a "propensity score" method. The 14-day recovery rate of the nimotuzumab cohort was 72 vs. 42% in the control group. Controls had a higher mortality risk (RR 2.08, 95% CI: 1.79, 2.38) than the nimotuzumab treated patients. The attributable fraction was 0.52 (95% CI: 0.44%; 0.58), and indicates the proportion of deaths that were prevented with nimotuzumab. Our preliminary results suggest that nimotuzumab is a safe antibody that can reduce the mortality of severe and critical COVID-19 patients.
Subject(s)
COVID-19 Drug Treatment , Cohort Studies , Humans , Retrospective Studies , SARS-CoV-2ABSTRACT
Background: CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods: Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a "3+3" dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings: The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.
ABSTRACT
BACKGROUND: The Center of Molecular Immunology of Cuba has developed a programme for the conducting of multicentre oncology clinical trials in primary healthcare centres since 2009. AIM: To evaluate the ability to conduct oncology clinical trials in primary health care. DESIGN & SETTING: A longitudinal, prospective, analytical study was developed between July 2010 and August 2020 in the Villa Clara province. METHOD: Structure, process, and outcome indicators were evaluated by the methods of a structured interview, direct observation, documentary observation, and databases analysis. The investigators' curricula vitae, the investigator site file, minutes of workshops, the monitoring reports, the clinical trial training records, and databases were employed as sources of information. The following criteria were considered adequate: when the indicator met the standard; and not adequate: when the indicator did not meet the standard. RESULTS: The six structure indicators reached adequate results and showed that the programme has allowed building of capacities to conduct clinical trials in primary care. The eight processes indicators and two outcome indicators were considered adequate too. Trials conducted in primary care showed better indicators of patient recruitment than secondary care. Both scenarios showed similar behaviour for the process indicators: retention, protocol compliance, and safety. Survival and satisfaction with health services were also comparable in both scenarios. CONCLUSION: The evaluation of the programme showed adequate indicators for conducting oncology clinical trials in primary care in Villa Clara and these were comparable to those determined in the secondary care.
ABSTRACT
Lung cancer is the second cause of cancer related deaths worldwide. Chemotherapy and immunotherapy represent the current standard of care for advanced NSCLC. Platinum-based chemotherapy expands late-differentiated T cell populations. Therefore, immune restoration after chemotherapy to adjuvate the immunotherapeutic potential could be crucial. The aim of this study was to evaluate the effect of Biomodulina T (BT), a thymic polypeptide fraction, on peripheral lymphocytes subpopulations in the context of cancer disease. Additionally, whether these effects might induce a better response to CIMAvax-EGF, an epidermal growth factor (EGF) depleting immunotherapy. Eighteen advanced NSCLC patients were evaluated after being treated with platinum-based chemotherapy. We found that the frequency of terminally differentiated effector T cells re-expressing CD45RA (EMRA) CD4+ (p=0.0031) and CD8+ (p=0.0372) T cells decreased with the administration of BT, whereas CD4+ naive T cells increase in more than 70% of the patients. Remarkably, CD4+ and CD8+ T lymphocytes expressing programmed cell death receptor-1 (PD1) significantly decreased after BT administration (p=0.0005 and p<0.0001, respectively). We also found an enhancement of the anti-EGF antibody response with a large percentage of patients treated with CIMAvax-EGF reaching the good antibody response condition after four vaccine doses. Moreover, the median overall survival of patients treated with CIMAvax-EGF was 16.09 months. In conclusion, our results suggest that the immunorestoration generated by the administration of BT after first-line chemotherapy may induce a better immune response to CIMAvax-EGF that could translate into the clinical benefit of patients diagnosed with advanced NSCLC.
ABSTRACT
In COVID-19, the inflammatory cytokine-release syndrome is associated with the progression of the disease. Itolizumab is a monoclonal antibody that recognizes human CD6 expressed in activated T cells. The antibody has shown to be safe and efficacious in the treatment of moderate to severe psoriasis. Its effect is associated with the reduction of pro-inflammatory cytokines release, including IFN-γ, IL-6 and TNF-α. Here, we report the outcome of three severe and critically ill COVID-19 patients treated with itolizumab as part of an expanded access protocol. Itolizumab was able to reduce IL-6 concentrations in all the patients. Two of the three patients showed respiratory and radiological improvement and were fully recovered. We hypothesize this anti-inflammatory therapy in addition to antiviral and anticoagulant therapy could reduce COVID-19 associated morbidity and mortality.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , COVID-19 Drug Treatment , Cytokine Release Syndrome/drug therapy , Aged, 80 and over , Biomarkers/blood , COVID-19/pathology , Critical Illness , Cytokine Release Syndrome/pathology , Drug Therapy, Combination , Female , Humans , Interleukin-6/blood , Male , Middle Aged , SARS-CoV-2 , Treatment OutcomeABSTRACT
Aging is considered the single most significant risk factor for the majority of common malignances including lung cancer. Together immunosenescence, changes occurring with aging in the immune system, and inflammaging, characterizes by a chronic, subclinical accumulation of pro-inflammatory factors, are suggested to stand at the origin of most of the diseases of the elderly, such as cancer. The aim of this study was to determine associations among lymphocyte subpopulations, pro-inflammatory cytokines and epidermal growth factor (EGF) in patients diagnosed with non-small cell lung cancer (NSCLC). Forty-six advanced NSCLC patients were enrolled. Sixteen patients with newly diagnosed and before treatment and 30 patients after first-line platinum-based chemotherapy. Peripheral blood subpopulations were studied by flow cytometry and serum concentrations of soluble factors by ELISA. The frequency of naïve CD4+ T cells, naïve B cells and central memory CD8+ T cells were significantly lower in NSCLC patients after chemotherapy, while effector memory CD4+ T cells and terminally differentiated CD8+ T cells were significantly higher. IL-1ß and TNFα significantly correlated among them before and after platinum-based chemotherapy. Terminally differentiated T cells expressing CD57+ significantly correlated with TNFα and IL-1ß. For the first time, associations between EGF serum levels and terminally differentiated CD4+ T cells, and memory B cells were detected. This study confirms the association among terminally differentiated lymphocytes and pro-inflammatory cytokines in patients diagnosed with lung cancer, reinforcing the interconnection between terminally differentiated lymphocytes and pro-inflammatory cytokines. Clinical trial registration number: RPCEC00000205, http://registroclinico.sld.cu/.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/pathology , Cytokines/metabolism , Epidermal Growth Factor/metabolism , Lung Neoplasms/pathology , Lymphocyte Subsets/immunology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/metabolism , Clinical Trials, Phase IV as Topic , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , PrognosisABSTRACT
OBJECTIVES: COVID-19 can lead to a hyperinflammatory state. CD6 is a glycoprotein expressed on mature T lymphocytes which is a crucial regulator of the T-cell activation. Itolizumab is a humanised antibody targeting CD6. Nonclinical and clinical data in autoimmune diseases indicate that it lowers multiple cytokines primarily involving the Th1/Th17 pathway. The primary objective of this study was to assess the impact of itolizumab in arresting the lung function deterioration of COVID-19 patients. Secondary objectives included safety, duration of ventilation, 14-day mortality and evaluation of interleukin 6 concentration. METHODS: Patients with confirmed SARS-CoV-2 received itolizumab in combination with other therapies included in the national protocol for COVID-19. RESULTS: Seventy critical, severe or moderate patients were treated with itolizumab in 10 Cuban hospitals. Median age was 68, and 94% had comorbidities. After 72 h, most patients improved the PO2/FiO2 ratio and reduced FiO2 requirements. Ventilation time was 8 days for critical and 1 day for severe cases. Ten patients had related adverse events while 3 subjects developed related serious events. In 30 patients, interleukin 6 decreased in individuals with high level and did not change in those with lower concentration. Fourteen-day lethality rate was 4% and 18% for moderate and severe patients, respectively. The proportion of moderate or severe patients with ventilation or death at day 14 was 9.8%. Time to treatment, neurological manifestations and biomarkers such as NLR were significantly associated with higher lethality. CONCLUSIONS: The opportune administration of itolizumab might interrupt the hyperinflammatory cascade and prevent COVID-19 morbidity and mortality.
ABSTRACT
BACKGROUND: Since the COVID-19 outbreak an unprecedented challenge for healthcare systems around the world has been placed. In Cuba, the first case of COVID-19 was reported on March 11. Elderly with multiple comorbidities have been the most risky population. Although most patients present a mild to moderate disease, some have developed severe symptoms. One of the possible mechanisms underlying rapid disease progression is a cytokine storm, in which interleukin (IL) -6 seems to be a major mediator. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody (MAb), with the ability of reducing serum interferon gamma (INF-γ), tumour necrosis factor alpha (TNFα) and IL-6. Based on these previous results in patients with psoriasis and rheumatoid arthritis, an expanded access clinical trial was approved by the Cuban regulatory agency for COVID-19 critically, severely and moderately ill patients. RESULTS: We show here a short kinetic of IL-6 serum concentration in the first 24 COVID-19 patients treated with itolizumab. Most of patients were elderly with multiple comorbidities. We found that with one itolizumab dose, the circulating IL-6 decreased in critically and severely ill patients, whereas in moderately ill patients the values didn't rise as compared to their low baseline levels. CONCLUSION: These findings suggest that itolizumab could be an attractive therapeutic option to decrease the negative outcome of the cytokine storm in COVID-19 patients. TRIAL REGISTRATION: CECMED IIC RD-EC 179, RPCEC00000311. Registered 4 May 2020 - Retrospectively registered, http://rpcec.sld.cu/ensayos/RPCEC00000311-Sp or http://rpcec.sld.cu/trials/RPCEC00000311-En.
ABSTRACT
BACKGROUND: Quality of Life Core Questionnaire of the European Organization for the Research and Treatment of Cancer (EORTC QLQ-C30) is one of the most used quality of life questionnaires in cancer studies. It provides scores for five functional scales, nine symptom scales, and two single items which assess overall health status and quality of life. However, high correlations among QLQ-C30 items suggest a reduced dimensionality for the scale. OBJECTIVE: To assess the dimensionality of the EORTC QLQ-C30 using item response theory (IRT) in a training sample and confirmatory factor analysis (CFA) in a test sample. METHODS: We analyzed responses to QLQ-C30 from 1,107 patients with advanced lung cancer who were included in five clinical trials of immunotherapy. We used non-parametric and parametric IRT models (Mokken, and Samejima's graded response) in a random training set (n = 332) for initial assessment of dimensions and item characteristics of the QLQ-C30. Finally, we used CFA in the test set (n = 775) to confirm the measurement domains. RESULTS: Mokken model showed that QLQ-C30 fits a unidimensional scale, whereas Samejima model showed that most QLQ-C30 items present adequate difficulty and discrimination. All items showed adequate scalability indexes with an overall scalability of 0.47 (medium scale). The QLQ-C30-reduced dimensionality was confirmed by CFA (comparative fit index = 0.98, root mean square error of approximation = 0.055) with all items presenting factorial loadings > 0.40. CONCLUSIONS: The EORTC QLQ-C30 fits a unidimensional latent construct identified with perceived quality of life in advanced lung cancer patients. TRIAL REGISTRATION: RPCEC00000161, RPCEC00000181 and RPCEC00000205.
Subject(s)
Carcinoma, Non-Small-Cell Lung/epidemiology , Lung Neoplasms/epidemiology , Quality of Life/psychology , Cuba , Female , Humans , MaleABSTRACT
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a recent outbreak of coronavirus disease (COVID-19). In Cuba, the first case of COVID-19 was reported on March 11, 2020. Elderly individuals with multiple comorbidities are particularly susceptible to adverse clinical outcomes in the course of SARS-CoV-2 infection. During the outbreak, a local transmission event took place in a nursing home in Villa Clara province, Cuba, in which 19 elderly residents tested positive for SARS-CoV-2. METHODS: Based on the increased susceptibility to cytokine release syndrome, inducing respiratory and systemic complications in this population, 19 patients were included in an expanded access clinical trial to receive itolizumab, an anti-CD6 monoclonal antibody. RESULTS: All patients had underlying medical conditions. The product was well tolerated. After the first dose, the course of the disease was favorable, and 18 of the 19 patients (94.7%) were discharged clinically recovered with negative real-time reverse transcription polymerase chain reaction test results at 13 days. After one dose of itolizumab, circulating IL-6 decreased within the first 24-48 h in patients with high baseline values, whereas in patients with low levels, this concentration remained over low values. To preliminarily assess the effect of itolizumab, a control group was selected among the Cuban COVID-19 patients that did not receive immunomodulatory therapy. The control subjects were well matched regarding age, comorbidities, and severity of the disease. The percentage of itolizumab-treated, moderately ill patients who needed to be admitted to the intensive care unit was only one-third of that of the control group not treated with itolizumab. Additionally, treatment with itolizumab reduced the risk of death 10 times as compared with the control group. CONCLUSION: This study corroborates that the timely use of itolizumab in combination with other antivirals reduces COVID-19 disease worsening and mortality. The humanized antibody itolizumab emerges as a therapeutic alternative for patients with COVID-19. Our results suggest the possible use of itolizumab in patients with cytokine release syndrome from other pathologies.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/therapeutic use , COVID-19 Drug Treatment , Aged , Aged, 80 and over , Cuba , Female , Humans , Male , Middle Aged , SARS-CoV-2/drug effectsABSTRACT
We previously reported that CIMAvax-EGF vaccine is safe, immunogenic and efficacious to treat advanced non-small-cell lung cancer (NSCLC) patients. A phase III trial was designed using an optimized immunization schedule. It included higher antigen dose and injections at multiple sites. Immune response and circulating biomarkers were studied in a subset of patients. EGF-specific antibody titers, IgG subclasses, peptide immunodominance and circulating biomarkers were assessed by ELISA. In vitro EGF-neutralization capacity of immune sera and EGF-IgG binding kinetics was evaluated by Western Blot and Surface Plasmon Resonance (SPR) technology, respectively. We show that CIMAvax-EGF elicited mainly IgG3/IgG4 antibodies at titers exceeding 1:4000 in 80% of vaccinated patients after 3 months of treatment. The EGF-specific humoral response was directed against the central region of the EGF molecule. For the first time, the kinetic constants of EGF-specific antibodies were measured evidencing affinity maturation of antibody repertoire up to month 12 of vaccination. Notably, the capacity of post-immune sera to inhibit EGFR phosphorylation significantly increased during the course of the immunization scheme and was related to clinical outcome (P = .013, log-rank test). Basal concentrations of EGF and TGFα in the serum were affected by EGF-based immunization. In conclusion, the CIMAvax-EGF vaccine induces an EGF-specific protective humoral response in a high percent of NSCLC vaccinated patients, the quantity and quality of which were associated with clinical benefit (clinical trial registration number: RPCEC00000161, http://registroclinico.sld.cu/). Abbreviations: EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; Ab: antibody; AR: amphiregulin; NSCLC: non-small-cell lung cancer; rhEGF: recombinant human epidermal growth factor; BSC: best supportive care; TGFα: tumor growth factor alpha; IL-8: interleukin 8; MAb: monoclonal antibody; SPR: surface plasmon resonance.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Biomarkers , Carcinoma, Non-Small-Cell Lung/drug therapy , Epidermal Growth Factor , Female , Humans , Immunization Schedule , Immunotherapy, Active , Lung Neoplasms/drug therapy , Male , Treatment Outcome , VaccinationABSTRACT
The COVID-19 pandemic has called attention to the contribution of comorbidities, including cancer and brought additional challenges to previously existing programs for cancer treatment and control. The COVID-19 pandemic in Cuba was addressed through an integrated all-society action plan that to date has been largely successful with a low incidence of COVID-19 and mortality rates several-fold lower than worldwide averages. Despite downsizing many other health components all oncology services were maintained. Between March 11, when the first case was detected, until July 23, Cuba reported 2,449 cases of COVID-19 that included 28 (1.14%) with a diagnosis of cancer. Distribution among cancer diagnoses did not deviate from that expected according to cancer epidemiology in Cuba. However, although the probability of getting infected with the coronavirus for a cancer patient (0.012%), was not higher than that of the general population (0.020%), 9 of the 28 (32.1%) died, a lethality higher than that of COVID-19 patients without cancer (3.5%) a difference that is statistically significant (P< .001). We argue that going forward scientific research on the relationship of aging, inflammation and cancer, including identification of biomarkers and the development of novel therapeutic interventions, should become one of the priorities in the post-COVID agenda of both oncologists and infectious disease scientists.
Subject(s)
COVID-19/therapy , Neoplasms/therapy , COVID-19/diagnosis , COVID-19/epidemiology , Comorbidity , Cuba/epidemiology , Female , Humans , Male , Neoplasms/epidemiology , PandemicsABSTRACT
BACKGROUND: Immunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non-Small Cell Lung Cancer Patients. METHODS: Data from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success. RESULTS: The mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders. CONCLUSIONS: Peripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biomarkers, Tumor/blood , Cancer Vaccines/administration & dosage , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Models, Statistical , Aged , Biomarkers, Tumor/immunology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/mortality , Clinical Trials, Phase III as Topic , Combined Modality Therapy/methods , Epidermal Growth Factor/blood , Epidermal Growth Factor/immunology , Female , Humans , Immunosenescence , Lung Neoplasms/blood , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Male , Middle Aged , Predictive Value of Tests , Prognosis , Randomized Controlled Trials as Topic , Retrospective StudiesABSTRACT
The changes that occur in the immune system with aging are commonly termed immunosenescence. Immunosenescence affects almost all components and functions of the immune response. The most commonly described change is a decrease in numbers and proportions of naïve T cells combined with the increase of terminally differentiated T lymphocytes, mainly affecting CD8+ T cells. The changes in the naïve T cell compartment are principally attributed to thymic involution and lifelong chronic antigen stimulation, among other triggers. Several strategies such as hormonal products, thymic peptides, or cytokines have been proposed for the restoration of the immune system. Here we show the effects of Biomodulina T (BT) on several populations of the immune system when administered to elderly patients diagnosed with recurrent respiratory infections. BT is a polypeptide fraction of bovine thymus, a Cuban product that obtained sanitary registration in 1994 for its immunomodulatory effects. We found that CD4+ naïve T, CD8+ stem cell-like memory (SCM) T, CD4+ recent thymic emigrants (RTE) T and CD4+ CD31+ naïve T cells increased with the administration of BT, whereas CD4+ and CD8+ T cells expressing PD1 decreased after the treatment with BT. Additionally, the proliferative capacity of CD4+ T cells measured by Ki67 expression, and the CD4+ T cell ability to produce IFN-γ were also improved by BT. Moreover, BT did not increase CD4+ Tregs. Altogether, these findings suggest that BT administration is a promising strategy for immune restoration in elderly patients and improvement of immunotherapeutic potential in cancer patients.
Subject(s)
Biological Products/therapeutic use , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Immunosenescence , Thymus Gland/drug effects , Aged , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cytokines/immunology , Female , Humans , Immunologic Memory , Lymphocyte Activation , Male , Middle Aged , Peptides/therapeutic use , Thymus Gland/immunologyABSTRACT
One of the most known oncogenes is the epidermal growth factor receptor (EGFR) family. It activates multiple signaling cascades that promote carcinogenesis and immune evasion. Therefore, these molecules have been extensively targeted in cancer immunotherapy. Beyond EGFR signaling cascade inhibition, some of these agents are able to induce T-cell activation, transforming a passive therapy into a vaccine-like effect. Nimotuzumab is an IgG1 humanized monoclonal antibody directed against the extracellular domain of the EGFR blocking the binding to its ligands. It possesses unique pharmacodynamic properties, which allow treating patients for long-term periods and with very low toxicity. Based on its clinical effect, nimotuzumab has been approved in Cuba and abroad for the treatment of different epithelial tumors. Recently, new potential mechanisms of action of nimotuzumab involving the activation of the innate and adaptive immune response have been reported. This review summarizes the main properties of nimotuzumab in comparison with other EGFR-specific monoclonal antibodies, highlighting its capacity to activate an effective immune response. In addition, differential clinical effects of this antibody and ongoing clinical trials to deeply characterize the biomarkers of clinical benefit are shown.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , ErbB Receptors/antagonists & inhibitors , Neoplasms/drug therapy , Signal Transduction/drug effects , Antibodies, Monoclonal, Humanized/immunology , Antibody-Dependent Cell Cytotoxicity/drug effects , Antibody-Dependent Cell Cytotoxicity/immunology , Antineoplastic Agents, Immunological/immunology , Antineoplastic Agents, Immunological/therapeutic use , Dendritic Cells/immunology , ErbB Receptors/immunology , Humans , Killer Cells, Natural/immunology , Models, Immunological , Neoplasms/immunology , Neoplasms/pathology , Signal Transduction/immunologyABSTRACT
Lung cancer remains one of the leading causes of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most common histologic type of lung cancer. Medical and scientific progress has led to longer survival in an increasing number of patients suffering from cancer. Concerning patients with advanced NSCLC, there is a subgroup with long-term survival. The human epidermal growth factor receptor (EGFR) family plays a key role in tumor development. This cluster of genes is associated with augmented angiogenesis and enhanced proliferation, survival, and migration of tumor cells. The CIMAvax-EGF vaccine consists of a chemical conjugate of the EGF with the P64 protein derived from the Meningitis B bacteria and the Montanide ISA 51, as adjuvant. The vaccine induces antibodies against EGF that results in EGF withdrawal. CIMAvax-EGF has been demonstrated to be safe and immunogenic in advanced NSCLC patients. Here we summarize the current knowledge of the mechanism of action of CIMAvax-EGF, highlighting the impact of this anti-EGF-based vaccine on the long-term survival of advanced NSCLC patients.