Immunotherapy Schedule Research Articles

Low-dose immunotherapy for patients with cancer in low- and middle-income countries (LMIC): A needs assessment.

112 Background: Immune checkpoint inhibitors are unavailable or unaffordable to many patients in LMIC, including Mexico. Some proposed strategies to improve access include weight-based dosing, vial sharing, or using low-dose IO (immunotherapy) schedules. Despite the potential advantages of low-dose IO to increase access and improve outcomes, there is limited information regarding the use of low-dose IO in real-world clinical practice in LMICs. Methods: We conducted a cross-sectional online survey of medical oncologists and hematologists practicing in Mexico. The survey was distributed via email using databases from the Mexican Society of Oncology and the Mexican Society of Hematology, and through physician Whatsapp groups in April and May 2024. The primary objective was to examine the prevalence and reasons of low-dose IO use in real-world clinical practice across Mexico. The survey assessed provider characteristics, prevailing attitudes, and potential barriers to low-dose IO adoption. Results: A total of 154 specialists answered the online survey, of which 77 completed it. The median age was 41 years (range 30-73); forty-five (58.4%) were men, thirty-one were women (40.2%), and two were non-binary. Fifty-nine (77%) were medical oncologists and 18 (23%) were hematologists. Twenty-two (29.3%) worked in private practice, nine (12%) in public institutions, and forty-four (58.7%) practiced in both. Seventy-two percent of respondents reported barriers in acquiring IO and forty-eight percent reported utilizing low-dose IO. For low-dose IO users, nivolumab was the most frequently prescribed drug (76%), followed by pembrolizumab (43%). The most frequent reason for using low-dose IO was reducing treatment-related cost (83% of respondents). Common barriers to low-dose IO use included concerns regarding the efficacy and safety of lower doses and a lack of knowledge about dosing protocols. Fifty respondents (67%) reported complete or moderate confidence in the efficacy of low-dose IO for patients with advanced disease, while only 36 respondents (49%) reported confidence on its efficacy for patients with localized disease. Conclusions: Despite its potential benefits of low-dose IO and a need to improve access to treatment, there are concerns about the efficacy and safety of this strategy among Mexican cancer specialists. Addressing these barriers and identifying facilitators could improve the acceptability of prospective trials studying low-dose IO in Mexico.

Mechanistic in silico explorations of the immunogenic and synergistic effects of radiotherapy and immunotherapy: a critical review.

Immunotherapy is a rapidly evolving field, with many models attempting to describe its impact on the immune system, especially when paired with radiotherapy. Tumor response to this combination involves a complex spatiotemporal dynamic which makes either clinical or pre-clinical in vivo investigation across the resulting extensive solution space extremely difficult. In this review, several in silico models of the interaction between radiotherapy, immunotherapy, and the patient's immune system are examined. The study included only mathematical models published in English that investigated the effects of radiotherapy on the immune system, or the effect of immuno-radiotherapy with immune checkpoint inhibitors. The findings indicate that treatment efficacy was predicted to improve when both radiotherapy and immunotherapy were administered, compared to radiotherapy or immunotherapy alone. However, the models do not agree on the optimal schedule and fractionation of radiotherapy and immunotherapy. This corresponds to relevant clinical trials, which report an improved treatment efficacy with combination therapy, however, the optimal scheduling varies between clinical trials. This discrepancy between the models can be attributed to the variation in model approach and the specific cancer types modeled, making the determination of the optimum general treatment schedule and model challenging. Further research needs to be conducted with similar data sets to evaluate the best model and treatment schedule for a specific cancer type and stage.

A modified schedule of multiple aeroallergen ultra-rush immunotherapy in perennial allergic rhinitis: safety, efficacy, and T lymphocyte cell population studies.

This study assessed whether a modified immunotherapy schedule for allergic rhinitis could be safe and efficient. Ultra-rush immunotherapy (URIT) rapidly desensitizes patients to aeroallergens. We aimed to develop a modified URIT protocol in 3 days to achieve the target dose while observing whether it could improve this situation and decrease the time to achieve the maintenance dose. The URIT was exercised in 21 patients with perennial allergic rhinitis. Premeditations were given to the patients 3 days prior to the immunotherapy and during the 3 days injections immunotherapy: pred nisolone, ranitidine, and Airokast/montelukast. Finally, the T cell population frequencies of patients prior to and after immunotherapy, including T helper 1, T helper 2, cytotoxic T lymphocytes, and regulatory T cells, were studied using flow cytometry. During the URIT protocol, 21 patients received 291 injections. Six patients (28.6%) showed systemic reactions in our study. All systemic reactions occurred on the third day by the 1:1 dilution of the maintenance dose. These systemic reactions occurred in three patients after 13 injections, and the three remaining patients showed systemic reactions following the last injection. No systemic reaction was observed on the first and second day of the therapy, and the risk of systemic reaction with every injection was about 2%. Among the T cell populations, CD3+ and CD8+ cells decreased significantly. The findings emphasized that URIT, alongside premedication with a high dose of antihistamine, helped to achieve the maintenance dose and control clinical manifestations.

Nondaily dosing schedule of allergen-specific sublingual immunotherapy: efficacy and safety.

Sublingual immunotherapy is currently promoted by various companies, with administration schedules variable in the different products even though almost all are standardized immunologically. So, this study was planned to examine the efficacy of simple nondaily dosing of sublingual immunotherapy instead of the widely used daily schedule. Fifty-two patients with allergic rhinitis and bronchial asthma were enrolled. Sublingual immunotherapy (manufactured at the allergen immunotherapy preparation unit at Mansoura University) was given in suitable bottles with a dropper mechanism that permits comfortable dosing under the tongue. The physician recommended that the patient put the drops under his/her tongue and leave the drops beneath the tongue for 2 minutes before swallowing. This was repeated every 3 days, with the drop number and concentration gradually rising. After 2 months of follow-up, 65.8% responded partially to the symptom score and 26.3% responded completely to the medication score. There was a significant decline in the symptom and medication scores from the baseline scores (p<0.0001). After 4 months of follow-up, 95.8% responded partially to symptom scores and no one has not responded; 54.2% responded completely to medication scores; and 81% of studied patients had no side effects. However, the most frequent side effect was a sore throat. Our nondaily schedule of sublingual immunotherapy is tolerable, safe, and effective in patients with allergic rhinitis and bronchial asthma.

Observational Study on The Efficacy and Effects in The Quality of Life of Cluster Immunotherapy Schedule in Patients with Asthma Sensitized to House Dust Mites

Background: The conventional schedule administration of subcutaneous allergen immunotherapy (SCIT) for Acaroid®, requires eight weeks to get the maintenance dose. To reduce the duration of the build-up phase, the cluster schedules have been introduced. The objective was to analyze the one-year efficacy of Acaroid® in a cluster schedule, as well as the effect on the patient’s quality of life. Methods: A real-world observational study was designed, with one-year follow-up. Patients 5-65 years-old with allergic bronchial asthma, sensitized to house dust mites and treated with Acaroid®, in cluster schedule 2/2/2 were included. The main efficacy endpoint was the Asthma Control Test (ACT) score at month 12 compared to baseline. The patient’s quality of life was measured with the Asthma Quality of Life Questionnaire (AQLQ) and ESPRINT-15 questionnaire. Results: A total of 81 patients, 55.6% female, were included with a mean age of 29.7 years old. The ACT score from baseline-12 months significantly improved (p=0.003) 1.4 points (95%CI 0.4-2.4). The proportion of patients with a good asthma control increased significantly from baseline-6-12 months (p&lt;0.05). AQLQ (p=0.014) and ESPRINT-15 quality of life domains significantly improved at 12 months. Conclusions: The cluster schedule 2/2/2 of SCIT with Acaroid® was effective and allowed shortening the build-up phase to three weeks, instead of the conventional schedule of eight weeks. This resulted in the benefit of the patient in terms of comfort and could reduce the costs related to SCIT administration while maintaining patient efficacy and safety of the conventional schedules.

Risk of anaphylaxis in cluster vs standard subcutaneous multiallergen immunotherapy

BackgroundCluster schedules for subcutaneous allergen immunotherapy (AIT) require significantly fewer injections, but there have been conflicting reports regarding the risk of systemic reactions (SR). ObjectiveTo compare the incidence of SRs during the build-up stages of multiallergen standard vs cluster immunotherapy. MethodsData on SRs were collected prospectively from 91 urban adult patients who underwent either standard or cluster AIT at the Johns Hopkins Allergy and Asthma Center from 2014 to 2022. The SRs were recorded during the build-up phase and compared for both protocols using Pearson's χ2, Fisher exact test, and multivariate logistic regression models. ResultsOverall, SR rates were 21% for patients in the standard schedule and 37% for patients in the cluster immunotherapy schedule, which was not statistically different (P = .08). However, the SR rate for each injection was 0.69% per injection in the standard protocol and 2.29% per injection in the cluster schedule (incident rate ratio = 3.3). All SRs (100%) in both groups occurred in the second half of the build-up phase. Multivariate regression revealed that the target prescription protein nitrogen units and the number of allergens in the treatment vial did not influence SR rates (odds ratio = 1.00 and 1.06, respectively). ConclusionThe overall incidence of SR was not statistically different for cluster and standard AIT protocols. However, because cluster patients received approximately half the number of injections, the risk for SR per individual injection is more than 3-fold higher than that of standard immunotherapy.

A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer.

Cuproptosis, or copper-induced cell death, has been reported as a novel noncanonical form of cell death in recent times. However, the potential roles of cuproptosis in the alteration of tumor clinicopathological features and the formation of a tumor microenvironment (TME) remain unclear. In this study, we comprehensively analyzed the cuproptosis-related molecular patterns of 1,274 colorectal cancer samples based on 16 cuproptosis regulators. The consensus clustering algorithm was conducted to identify cuproptosis-related molecular patterns and gene signatures. The ssGSEA and ESTIMATE algorithms were used to evaluate the enrichment levels of the infiltrated immune cells and tumor immune scores, respectively. The cuproptosis score was established to assess the cuproptosis patterns of individuals with principal component analysis algorithms based on the expression of cuproptosis-related genes. Three distinct cuproptosis patterns were confirmed and demonstrated to be associated with distinguishable biological processes and clinical prognosis. Interestingly, the three cuproptosis patterns were revealed to be consistent with three immune infiltration characterizations: immune-desert, immune-inflamed, and immune-excluded. Enhanced survival, activation of immune cells, and high tumor purity were presented in patients with low cuproptosisScore, implicating the immune-inflamed phenotype. In addition, low scores were linked to high tumor mutation burden, MSI-H and high CTLA4 expression, showing a higher immune cell proportion score (IPS). Taken together, our study revealed a novel cuproptosis-related molecular pattern associated with the TME phenotype. The formation of cuproptosisScore will further strengthen our understanding of the TME feature and instruct a more personalized immunotherapy schedule in colorectal cancer.

Compared Efficacy of Adjuvant Intravesical BCG-TICE vs. BCG-RIVM for High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC): A Propensity Score Matched Analysis.

Simple SummaryIntravesical immunotherapy with bacillus Calmette–Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer. Different BCG strains are currently available and the superiority of any BCG strain over another could not be demonstrated yet. We compared the efficacy of two BCG strains: RIVM and TICE, respectively. In this propensity-score matched cohort study, we showed no particular survival benefit of TICE vs RIVM in the case of high-risk disease. Nevertheless, stratifying our data for re-staging procedures and for those who received BCG maintenance, we identified BCG TICE to improve RFS independently. Herein, we corroborated the importance of performing a routine secondary resection followed by an adequate maintenance course of BCG. Future larger prospective randomized head-to-head trials are needed to further elucidate this important topic, especially in this era of BCG shortage.Background: Intravesical immunotherapy with bacillus Calmette–Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC). The superiority of any BCG strain over another could not be demonstrated yet. Methods: Patients with NMIBCs underwent adjuvant induction ± maintenance schedule of intravesical immunotherapy with either BCG TICE or RIVM at two high-volume tertiary institutions. Only BCG-naïve patients and those treated with the same strain over the course of follow-up were included. One-to-one (1:1) propensity score matching (PSM) between the two cohorts was utilized to adjust for baseline demographic and tumor characteristics imbalances. Kaplan–Meier estimates and multivariable Cox regression models according to high-risk NMIBC prognostic factors were implemented to address survival differences between the strains. Sub-group analysis modeling of the influence of routine secondary resection (re-TUR) in the setting of the sole maintenance adjuvant schedule for the two strains was further performed. Results: 852 Ta-T1 NMIBCs (n = 719, 84.4% on TICE; n = 133, 15.6% on RIVM) with a median of 53 (24–77) months of follow-up were reviewed. After PSM, no differences at 5-years RFS, PFS, and CSS at both Kaplan–Meier and Cox regression analyses were detected for the whole cohort. In the sub-group setting of full adherence to European/American Urology Guidelines (EAU/NCCN), BCG TICE demonstrated longer 5-years RFS compared to RIVM (68% vs. 43%, p = 0.008; HR: 0.45 95% CI 0.25–0.81). Conclusion: When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to RIVM for RFS outcomes. However, no significant differences were detected for PFS and CSS, respectively.

MAGE-A3 Recombinant Protein (recMAGE-A3) Immunotherapy and Autologous Peripheral Blood Lymphocyte (PBL) Infusion Is Safe and Induces Robust Humoral Immune Responses In Multiple Myeloma (MM) Patients Undergoing Autologous Stem Cell Transplantation (autoSCT)

▪ BackgroundMAGE-A3 is a cancer-testis antigen expressed in various human cancers, including MM, but not in normal non-gonadal tissues. MAGE-A3 expression inhibits apoptosis in MM cells, and has been associated with a more aggressive clinical course, making it a rational target for immunotherapy. Pre-autoSCT myeloablative conditioning provides tumor antigen release and a lymphopenic environment that may be ideal for expansion of primed PBL and generation of anti-myeloma immune responses. Patients and methodsEligibility for this pilot study required symptomatic MM within 1 year of diagnosis; MAGE-A+ MM cells by immunohistochemistry (IHC); at least VGPR following induction therapy; and meeting institutional criteria for autoSCT. The immunotherapy consists of a recombinant protein containing full-length MAGE-A3 fused to part of H. influenzae Protein D antigen, mixed with the AS15 immunostimulant (containing MPL, QS21, and CpG7909). Six weeks prior to SCT, patients received their 1st injection (300 µg recMAGE-A3 intramuscularly), followed 3 weeks later by steady-state leukopheresis to collect primed PBL. They then underwent stem cell mobilization and a melphalan 200 mg/m2-conditioned autoSCT, followed by re-infusion of unmanipulated PBL on day +3 after SCT, and 7 post-SCT injections (days +10, 31, 52, 73, 94, 180, and 270). Lenalidomide maintenance was permitted. The primary objectives were safety and tolerability. The secondary objectives were cellular and humoral immune responses and clinical outcomes. Humoral immunity was assessed by ELISA using baculovirus-generated recombinant MAGE-A3 protein. ResultsOf 93 pre-screened patients, 30 (32%) were MAGE-A+ by IHC. Of these, 13 (43%) enrolled. Reasons for non-enrollment were: did not achieve VGPR (n=6), declined/received other therapy (n=7), other (n=4). For enrolled patients, median age was 56; ISS stages I/II/III were 58%/25%/17%; 45% had high-risk cytogenetics at diagnosis (n=11 tested). Responses at enrollment were 12 VGPR and 1 CR; most (83%) had received VRD-based induction. All patients had adequate PBL collections (median 1.4 x 108 CD3+ cells/kg, range 1.0-2.6), and all collected stem cells successfully (median 11.4 x 106 CD34+ cells/kg, range 8.3 – 37.2). Autologous PBL infusions were well-tolerated, with no engraftment-like syndromes. Time to neutrophil recovery (median 11 days) and SCT-related toxicities were typical. The immunotherapy schedule was feasible with only 1 missed dose to date. Potential immunotherapy-related AE's (all grade 1 or 2) include injection site pain/reaction (n=6), myalgia/flu-like symptoms (n=5), fever/chills (n=2), fatigue (n=1), and rash (n=1). Three SAE's were observed: 1 immunotherapy-related (grade 2 myalgia requiring a 24-hour hospitalization), and 2 unrelated (grade 3 diarrhea, grade 3 atrial fibrillation with pulmonary edema). There have been no autoimmune toxicities and no deaths on study. Four patients initiated lenalidomide maintenance with no unexpected toxicities. Regarding immune responses, 12 of 12 (100%) evaluable patients have developed high-titer (>104) IgG antibodies against MAGE-A3 (Fig.). Responses were seen in all but 2 patients by day +31 post-SCT, and in all patients by day +75, persisting at 1 year post-SCT in both patients reaching this timepoint so far. All patients also developed strong IgG responses against Protein D. Clinically, at 3 months post-SCT, 50% of patients had achieved CR (33% stringent CR). With a median follow-up of 10 months post-SCT (range 1-20), 92% are progression-free, with follow-up ongoing. ConclusionsMAGE-A3 protein immunotherapy plus autologous PBL transfer is feasible, has an acceptable safety profile, and is strongly immunogenic, capable of overcoming the profound immune suppression typically seen in MM patients post-autoSCT. The presence of IgG-type anti-MAGE antibodies implies the generation of a CD4 T cell response to induce Ig class-switching, though formal assessment of T cell responses against MAGE-A3 and other antigens are needed to confirm this, and are ongoing. Importantly, the use of an “off-the-shelf” immunotherapy product and unmanipulated autologous PBL transfer allows the treatment to be given at any transplant center. Further study of this approach as a strategy to consolidate post-autoSCT responses and potentially eliminate minimal residual disease is warranted. [Display omitted] Disclosures: Cohen:Bristol Meyers Squibb: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria; Millennium: Honoraria. Bertolini:Ludwig Institute for Cancer Research: Employment. Pan:Ludwig Institute for Cancer Research: Employment. Venhaus:Ludwig Institute for Cancer Research: Employment. Fellague-Chebra:GlaxoSmithKline Vaccines: Employment. Gruselle:GlaxoSmithKline Vaccines: Employment.

COVID-19 et cancer bronchique : adaptation des schémas d’immunothérapie et qualité de vie

IntroductionLa première vague de COVID-19 a nécessité des modifications des pratiques médicales selon les recommandations des sociétés savantes. En oncologie thoracique, le pembrolizumab a été doublé à 400 mg toutes les 6 semaines, le nivolumab à 480 mg toutes les 4 semaines. L’objectif de notre étude était d’évaluer l’impact sur la qualité de vie, l’état psychologique et la tolérance de ce nouveau schéma d’administration.MéthodesDurant la première vague, nous avons inclus des patients suivis en oncologie thoracique chez qui le schéma d’administration de l’immunothérapie avait été modifié et utilisé le Quality of Life Questionnaire-30 pour mesurer leur qualité de vie et l’échelle Hospital Anxiety Depression (HAD) pour évaluer l’état psychologique. Nous avons également précisé les préférences des patients concernant le schéma d’administration et les effets indésirables présentés.RésultatsChez les 30 patients inclus la qualité de vie globale était conservée (score médian 75 [33–100]), les scores HAD étaient < 8 chez 23/30 patients pour la dépression, 22/30 pour celui d’anxiété. La tolérance était acceptable. Vingt et un sur 30 patients préféraient le nouveau schéma d’administration .ConclusionsCe nouveau schéma d’administration d’immunothérapie a montré une bonne tolérance avec une qualité de vie préservée. Cela est une option thérapeutique possible en contexte de pandémie.

Final survival follow-up and translational associations using interval indirect immunization with oregovomab (O) and poly ICLC in patients (pts) with recurrent platinum-resistant ovarian cancer (PROC).

e17545 Background: Indirect immunization with tumor specific antibody is an approach to triggering therapeutic immunity to cancer through activated immune cells. O is a monoclonal IgG1 specific to CA125 (MUC16). O is currently in phase III evaluation of front-line chemoimmunotherapy (CIT), having shown benefit relative to chemotherapy alone in a randomized phase II study (Brewer, Gyn Onc 2020). H is a TLR3 agonist used as a stimulatory immune adjuvant. The dosing phase of the protocol established safety and compatibility of this combination. The primary safety and response outcomes were reported at IGCS-2019. Immune parameters and long-term outcome associations are the focus of this final update. Methods: Pts with heavily treated RECIST evaluable platinum resistant ovarian cancer (median of 5 prior Rx) received 4 IV infusions with 2 mg O followed by 2mg H IM 30 min &amp; 48 hrs post O at wks 0, 3, 6, 9. At wk 12 imaging was performed and elective salvage Rx allowed. A fifth O+H was optional at wk 16. Study endpoints included immune associations after O+H, after second-line chemotherapy, and survival outcomes. Results: 17 pts were enrolled at 2 centers; 15 patients were dosed and 13 completed the specified minimum 3 infusions. The treatment was well tolerated with local reactions and mild flu like symptoms (13/15 pts) as the only reported adverse events. There was no treatment related serious adverse events. Median survival was 15.0 m [95% CI:10.8m-NE] and 4 patients remained alive at data lock (median 26.5 m). H stimulated an early humoral antibody response to O at wk 6 in 7 of 9 pts (78%). Interval administration of second-line Rx (bevacizumab, paclitaxel, carboplatin, &amp;/or doxorubicin) and O were associated with further antibody spikes. Baseline neutrophil monocyte to lymphocyte ratio (NMLR), a measure of myeloid-derived immune suppression was inversely associated with survival. PROC patients with baseline NMLR ≤4x (n = 8) had median OS 19.6m [15.0 m -NE] vs median OS 10.8m [3.6m-NE] HR 2.44 [0.73-8.15], ( p= 0.13) for pts with NMLR &gt; 4.0 (n = 7). Conclusions: H is a viable immune adjuvant for combination with O suitable for further study in immune resistant settings. Immune responsiveness was similar to that observed in a prior study of same day schedule of carboplatin-paclitaxel front-line immunotherapy (Braly, JIT 2009; Battaglia, Cll, 2020). Patterns of immune response to O in the setting of recurrent ovarian cancer are influenced by concomitant anti-neoplastic therapy. Clinical outcomes appear sensitive to myeloid burden (NMLR &gt; 4) which may be more prevalent in patients with treatment resistant disease than in chemotherapy naïve patients, as previously observed in front-line CIT trials. A phase III study to further evaluate these associations in the front-line setting is currently underway NCT04498117. Clinical trial information: NCT03162562.

Efficacy of three BCG strains (Connaught, TICE and RIVM) with or without secondary resection (re-TUR) for intermediate/high-risk non-muscle-invasive bladder cancers: results from a retrospective single-institution cohort analysis

Purpose(I) To evaluate the clinical efficacy of three different BCG strains in patients with intermediate-/high-risk non-muscle-invasive bladder cancer (NMIBC). (II) To determine the importance of performing routine secondary resection (re-TUR) in the setting of BCG maintenance protocol for the three strains.MethodsNMIBCs who received an adjuvant induction followed by a maintenance schedule of intravesical immunotherapy with BCG Connaught, TICE and RIVM. Only BCG-naïve and those treated with the same strain over the course of follow-up were included. Cox proportional hazards model was developed according to prognostic factors by the Spanish Urological Oncology Group (CUETO) as well as by adjusting for the implementation of re-TUR.Resultsn = 422 Ta-T1 patients (Connaught, n = 146; TICE, n = 112 and RIVM, n = 164) with a median (IQR) follow-up of 72 (60–85) were reviewed. Re-TUR was associated with improved recurrence and progression outcomes (HRRFS: 0.63; 95% CI 0.46–0.86; HRPFS: 0.55; 95% CI 0.31–0.86). Adjusting for CUETO risk factors and re-TUR, BGC TICE and RIVM provided longer RFS compared to Connaught (HRTICE: 0.58, 95% CI 0.39–0.86; HRRIVM: 0.61, 95% CI 0.42–0.87) while no differences were identified between strains for PFS and CSS. Sub-analysis of only re-TUR cases (n = 190, 45%) showed TICE the sole to achieve longer RFS compared to both Connaught and RIVM.ConclusionRe-TUR was confirmed to ensure longer RFS and PFS in intermediate-/high-risk NMIBCs but did not influence the relative single BCG strain efficacy. When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to the other strains for RFS outcomes.

A Potent Inhibitor of IL-10/STAT3 Axis Signaling Modulates Anti-Inflammatory Responses and Boosts Anti-Tuberculosis Immunity in rBCG30 Immunized Mice

Aims and Objectives: In the present study we tried to improve anti-TB immunity offered by 2nd generation rBCG30 vaccine. We attempted to bolster rBCG30 invoked anti-TB immunity in mice through modulation of the IL-10/STAT3 interaction mediated anti-inflammatory program. The study was aimed towards generating optimum activated APCs, early either after vaccination (with rBCG30) or infection (with Mtb), which can process and present mycobacterial antigens more efficiently to T cells. It was envisage that downmodulating IL-10/STAT3 signaling may improve immunity and protection offered by rBCG30 vaccine. Methods: A small molecule immunomodulator aimed at disrupting anti-inflammatory signaling orchestrated by IL-10/STAT3 axis was administered in rBCG30 immunized mice. The comparative expansion of pathogen permissive Alternatively Activated Monocytes/Macrophages/DCs (AAMs/AADCs) and Classically Activated Monocytes/Macrophages/DCs (CAMs/CADCs), the cells that resist establishment of successful Mtb infection, was profiled in both peritoneal and splenic compartment. To assess innate and adaptive T cell responses, splenocytes cytokine production was checked ex vivo using sandwich ELISA. We also checked polyfunctional T cell response, T cell memory response and comparative Th17/Treg cells expansion using flow cytometry. Finally, to assess the real time efficacy of the employed immunotherapeutic strategy, in vivo protection study was undertaken in BALB/c mice challenge with aerosolized Mtb (H37 Rv). Results: The small molecule mediated inhibition of IL-10/STAT3 signaling was resulted in improved pro inflammatory immune responses in both post-vaccination and post-infection immunotherapy schedules. The improved immune profile in rBCG30 vaccinated and immunotherapy administered mice was accompanied with enhanced expansion of CAMs/CADCs, elevated production of polyfunctional T cells producing signature Th1 cytokines, long lasting CD4+ and CD8+ memory T cell response and balanced Th17/Treg cells ratio. Interestingly, post-infection, and not post-vaccination immunotherapy, was able to significantly reduce mycobacterial loads in spleen and lungs of experimentally infected mice. Conclusions: Small molecule mediated transient disruption of anti-inflammatory effectors, such as IL-10/STAT3, during vaccination or post infection with Mtb, may serve to enhance the efficacy of existing and forthcoming TB vaccines. The strategy can also be tested concomitantly with standard chemotherapy (either in vaccinated or unvaccinated host) to enhance the efficacy of therapeutic regimen and to reduce the treatment length.

Observational study on the tolerability of cluster immunotherapy schedules in patients sensitized to house dust mites

Observational study on the tolerability of cluster immunotherapy schedules in patients sensitized to house dust mites

Gaps in allergen immunotherapy administration and subcutaneous allergen immunotherapy dose adjustment schedules: Need for prospective data

Gaps in allergen immunotherapy administration and subcutaneous allergen immunotherapy dose adjustment schedules: Need for prospective data

Protocol for a double-blind, randomized controlled trial on the dose-related efficacy of omalizumab in multi-food oral immunotherapy

BackgroundPrevious proof-of-concept studies have shown that a short course of omalizumab can safely accelerate the oral immunotherapy schedule for multiple allergens simultaneously. Considering the high cost of medication, the dose-related efficacy of omalizumab at decreasing the duration of oral immunotherapy up-dosing phase must be objectively quantified before cost–benefit analyses can be performed. The primary objective of this trial will be to compare the efficacy of 2 omalizumab dosages to placebo at decreasing time-to-maintenance dose during a symptom-driven multi-food OIT protocol.MethodsA total of 90 participants aged 6 to 25 with multiple food allergies (3 or more) will be enrolled at four sites in Canada. Participants will be randomized to: (A) Omalizumab 8 mg/kg per month (n = 36); (B) Omalizumab 16 mg/kg per month (n = 36); or (C) Placebo (n = 18). Study drug will be administered at full dosage for 12 weeks, then progressively tapered at 50% dosage (8 mg/kg vs 4 mg/kg vs placebo) for 4 weeks and at 25% dosage (4 mg/kg vs 2 mg/kg vs placebo) for another 4 weeks. After a pre-treatment period of 8 weeks, participants will undergo an initial food escalation (IFE) to an OIT mix containing 3 allergens and start daily home dosing with biweekly increases until a target daily maintenance of 1500 mg protein is achieved. The amount escalated at each visit will vary based on treatment tolerance according to a standardized up-dosing algorithm. Participants will be followed for at least 12 months following the initial food escalation. The primary endpoint will be time from IFE to the target maintenance dose of 1500 mg protein. Time-to-event analytic methods, including the log-rank test, will be used to compare the 3 arms.DiscussionThis trial uses a novel pragmatic approach to compare OIT with omalizumab to OIT without omalizumab in a blinded manner, which allows to single out the effect of this anti-IgE medication on treatment effectiveness speed without the recourse to predetermined schedules. The innovative patient-centered up-dosing algorithm allows to maximise treatment effectiveness speed without compromising patient safety, regardless of whether the patient is on omalizumab or not. This study will also provide novel prospective data to inform on the optimal and most cost-effective dosage for this indication.Trial registration ClinicalTrials.gov, NCT04045301, Registered 5 August 2019, https://clinicaltrials.gov/ct2/show/NCT04045301

A new immunotherapy schedule in addition to first-line hormone therapy for metastatic breast cancer patients in a state of clinical benefit during hormone therapy.

Acquired resistance occurs in metastatic hormone receptor-positive breast cancer patients. The addition of interferon beta/interleukin-2 immunotherapy to first-line salvage hormone therapy (HT) prolonged progression-free (PFS) and overall survivals (OS) in 26 patients, as compared with 30 historical controls and literature data. This was a 2 : 1 ratio case-control retrospective observational study. The cases were from an open pilot study, started in 1992, and controls were recruited in 2006. The planned mean follow-up time was the time at which more than 80% of controls progressed. The median PFS was significantly longer in the cases than that in controls, 33.1 (95% CI 24.5-41.8) vs 18 (95% CI 12.1-23.8) months (p < 0.0001). Also, median OS was significantly longer in the cases, 81 vs 62 (95% CI 48.1-75.9) months (p < 0.0029). When analysis of the 2 groups was adjusted for the disease-free interval (DFI), hormone receptor status, HER2, site of metastases and molecular-targeted therapies, the hazard ratio for PFS and for OS in the cases increased from 2.347 to 3.090 and from 1.874 to 2.147, respectively. This occurred in spite of the higher proportion of controls (82% vs 7.1%) treated with aromatase inhibitors (AIs), while selective oestrogen receptor modulators (SERMs) were given to 92.9% of the cases and to 18% of the control group (p < 0.0001). Immunotherapy significantly prolonged PFS and OS during conventional first-line HT. A multi-centre randomised clinical trial is advised to enter this immunotherapy into clinical practice. KEY MESSAGES: • Acquired resistance occurs in metastatic endocrine-dependent breast cancer patients. • Interferon beta-interleukin-2 immunotherapy added to first-line salvage hormone therapy prolonged progression-free (PFS) and overall (OS) survivals in 26 patients of a pilot study as compared with 30 historical controls. • In this 2:1 ratio case-control prospective observational study, the PFS median time was significantly longer in the study group than that in controls, 33.1 (95% CI 24.5-41.8) vs 18 (95% CI 12.1-23.8) months (p < 0.0001). • Also, the OS median time was significantly longer in the study group, 81 vs 62 (95% CI 48.1-75.9) months (p < 0.0029).

Does Mantoux Test Result Predicts BCG Immunotherapy Efficiency and Severe Toxicity in Non-Muscle Invasive Bladder Cancer.

To evaluate on a large group of patients whether Mantoux tuberculin skin test (TST) result is associated with BCG immunotherapy effectiveness and whether it can predict occurrence of moderate to severe toxicity. We analysed group of 823 patients with intermediate and high risk NMIBCs who were treated with BCG. The study included 412 patients with the history TST and 411 without TST. A standard dose of Statens Serum Institute tuberculin RT23 was used. The reaction was read 48-72 hours later by evaluating the diameter of palpable induration. The size of the induration was considered positive when the measurement was greater than or equal to 6 mm and excessively positive when bigger than 26 mm. Whole BCG immunotherapy schedule consisted of 27 instillations. The patients were followed for median 61 months. The 5-year recurrence and progression free survival (RFS, PFS) did not differ between the groups in both total study population and in tumour subgroup analysis. TST result in both total study population and in subgroups was not statistically associated with RFS, PFS and cancer specific survival.The moderate-to-severe toxicity was observed in 181(44%) TST patients, and in 196(47%) patients without TST. Incidence of toxicity was not statistically different and also not statistically associated with TST result in any of the tumour subgroups of TST group. This study shows, that TST does not have value in prediction of bladder cancer recurrence, progres-sion nor cancer specific survival. Also it doesn't have a value in predicting therapy toxicity.

Early Efficacy Analysis of Cluster and Conventional Immunotherapy in Patients With Allergic Rhinitis.

Specific immunotherapy is an important immune-modifying treatment for patients with allergic rhinitis (AR). We compared the early efficacy and safety of cluster and conventional immunotherapies for patients with AR. One hundred forty-nine patients with persistent AR were enrolled in a randomized and open-label trial and were divided into the following 4 groups: 60 children treated conventionally, 33 children treated using the cluster schedule, 23 adults treated conventionally, and 33 adults treated using the cluster schedule. Patients in the cluster groups reached the maintenance dose within 6 weeks, while those receiving conventional therapy reached the maintenance dose within 14 weeks. Symptom scores and skin prick test scores (SPTs) were used to evaluate clinical efficacy and adverse reactions. After buildup phase of treatment, symptom scores, and SPTs were significantly lower than those prior to treatment in each group (P < .05). No significant differences were found in the efficacy of nasal symptoms scores among four groups (P > .05).However, the efficacy of SPTs using conventional schedule was higher than cluster schedule in children groups (group A and B, 57.7 vs 30.2%, P = .001). Besides, the efficacy of SPTs in adults was higher than children when using the cluster treatment (group D and B, 53.0 vs 30.2%, P = .008). No severe adverse reaction occurred. Conventional and cluster immunotherapy schedules have similar efficacies, which do not vary with age; both schedules are safe and reliable. Also, SPT facilitate evaluation of clinical efficacy.

Comparison of adverse events between cluster and conventional immunotherapy for allergic rhinitis patients with or without asthma: A systematic review and meta-analysis

Cluster schedule of allergen-specific immunotherapy (AIT) is a cost-effective choice for allergic rhinitis (AR) patients, but its safety has been questioned due to the greater dosages required at each treatment compared with conventional immunotherapy. It remains a question that whether cluster schedule leads to a higher risk of side effects. This study was designed to update the evidence and investigate whether cluster schedule leads to a higher risk of local adverse reactions (LARs) and systemic adverse reactions (SARs) than cluster schedule does. We searched the Cochrane Central Register of Controlled Trials, EMBASE and Medline thoroughly and included studies comparing cluster and conventional schedules. A meta-analysis of 5 outcomes related to adverse events was performed after bias and heterogeneity assessments. And as a result of language limitations, we considered only articles in Chinese and English. 5 observational studies and 6 interventional studies were included in the meta-analysis. There were no differences between cluster and conventional schedules when analyzing SARs by the number of patients, delayed SARs, grade 2 SARs and LARs. Analyses of SARs by injection, grade 1 SARs and LARs by injection in observational studies showed that cluster schedule had a lower risk of adverse events than did conventional schedule. Our data suggest that cluster schedule is as safe as or even safer than conventional schedule for AR patients with or without asthma (AS).