Combo Therapy Research Articles

Strengths and Weaknesses of Different Therapeutic Strategies for the Treatment of Patients with Multiple Myeloma Who Progress After the Frontline Use of Lenalidomide: A Narrative Review

Background/Objectives: Patients with multiple myeloma (MM) who relapse after exposure to lenalidomide in the context of their first-line therapy are becoming a growing and clinically relevant population. We performed a systematic review of available clinical trials evaluating the efficacy and safety of different therapeutic strategies for the treatment of patients with MM at first relapse after the frontline use of lenalidomide. Methods: Publications of interest were searched on the PubMed database. The following search terms were employed: relapsed multiple myeloma, refractory multiple myeloma, first relapse, second-line therapy, lenalidomide-refractory (Len-R) and lenalidomide-exposed (Len-Exp). Results: Overall, triplet regimens that included anti-CD38 antibodies, carfilzomib and dexamethasone achieved a more favorable PFS regardless of the number of prior therapies. Other trials also demonstrated a non-negligible benefit with combinations containing pomalidomide, particularly in early lines of therapy. However, the variable number of patients with Len-Exp/Len-R disease enrolled in these studies and the limited number of those analyzed after progression following frontline lenalidomide make it difficult to select an “optimal” choice for the treatment of patients with MM at first relapse. Promising results have been more recently obtained by using combo therapies, including belantamab mafodotin and, above all, immunotherapies with CAR-T cells, and ongoing clinical trials are exploring the role of bispecific antibodies and CELMoDs in this population of patients. Conclusions: In the absence of clear-cut data regarding the specific effects of available regimens on patients with MM who are refractory or have relapsed after first-line therapies including lenalidomide, novel approaches based on different types of immune strategies are expected to further improve the clinical outcome of these patients.

Hyphenating sustainability with chemometrics in chromatographic analysis of COVID combo therapy, nirmatrelvir and Molnupiravir, in presence of their overlapping degradation products; blue-green dual evaluation tools

Our manuscript managed to hyphenate the novelty and sustainability in one method. A novel combination of molnupiravir (MNP) and nirmatrelvir (NTV) was found to be a potential symbiotic therapy against SARS-CoV-2. Yet, there is no analytical method published for either determination or stability investigation of this combination simultaneously. So, the proposed HPLC technique focused on determination of MNP and NTV in presence of their degradation products. The sustainability was achieved in our method by using chemometrics tools to quantify NTV in presence of its co-eluted degradation product (NTV-D) without excessive time and solvent usage for separation (run time 5 min.). Moreover, the linearity parameters of both MNP and NTV, including correlation coefficient, LOD and LOQ, have been enhanced significantly after chemometrics treatment through convolution of the resultant derivative curves using trigonometric Fourier function. For example, LOQ of MNP decreased from 3.53 to 0.31 µg/mL and for NTV, LOQ decreased from 4.98 to 2.10 µg/mL after chemometrics treatment. The stability results of the proposed method indicates that no interaction or change in stability behavior of both drugs when co-administered with each other. Thus, this can be used as an empirical basis to initiate clinical trials of this combination for the treatment of COVID-19 patients.Additionally, in order to determine the impact of chemometric methods in minimizing analysis time and reducing solvent, energy, and waste consumption, our chemometric methodology is evaluated in terms of greenness and blueness (dichromic assessment) using AGREE and BAGI, respectively. Besides, the method sustainability using Hexagon was evaluated.

Strengths and Bias of the Different Therapeutic Strategies for the Treatment of Multiple Myeloma Patients Who Progress after Front-Line use of Lenalidomide: A Systematic Review of Available Clinical Trials

Purpose: Patients with Multiple Myeloma (MM) who relapse after exposure to lenalidomide in the context of their first line therapeutic strategy are becoming a growing and clinically relevant population. We performed a systematic review of available clinical trials evaluating the efficacy, in terms of Progression-Free Survival (PFS), of different therapeutic strategies for the treatment of MM patients at first relapse after front-line use of lenalidomide. Methods: Publications of interest were searched on the PubMed database. The following search terms were employed: relapsed multiple myeloma, refractory multiple myeloma, first relapse, second line therapy, and lenalidomide-refractory, lenalidomide-exposed. Results: Triplets including anti-CD38 antibodies, carfilzomib and dexamethasone obtained more significant PFS regardless of the number of prior therapies. Other trials also demonstrated a not negligible benefit with combinations containing pomalidomide, particularly in early lines of therapy. However, the variable amount of Len-Exp/Len-R patients enrolled in these studies and the limited number of those analyzed after progression following front-line lenalidomide, makes it difficult to select an “optimal” choice for the treatment of these MM patients at first relapse. Promising results have been more recently obtained by using combo therapies including belantamab-mafodotin and immunotherapies with CAR-T cells. Conclusion: In absence of clear-cut data regarding specifically the effects of currently available regimens in MM patients refractory or relapsed after first-line therapies including lenalidomide, novel approaches based on immune-therapies and focused on this specific population of MM patients would warrant further specific investigation.

Advances in Immunotherapy for Cancer Treatment: Targeting the Immune System to Fight Tumors

A revolutionary new method for treating cancer, immunotherapy uses the immune system to specifically target and kill tumor cells. Recent developments in immunotherapy and its function in cancer treatment are summarized in this article. This article provides a comprehensive overview of immunotherapeutic techniques, including bispecific antibodies, cancer vaccines, immune checkpoint combo therapy, checkpoint inhibitors, TIL therapy, CAR T-cell therapy, and cancer vaccines. It also discusses the mechanisms of action of these strategies and their clinical uses. Immunotherapy has shown tremendous promise in the treatment of many malignancies, according to recent important advances in the area as well as clinical data and case studies.

Multidimensional tumor profiling and its meaningful impact on personalized therapy outcomes: Insights from a real-world study.

e15064 Background: This real-world study underscores the transformative potential of multidimensional tumor profiling, including tissue and blood-based markers, in guiding personalized oncology treatments. We established a robust link between comprehensive diagnostics and improved clinical outcomes by correlating extensive profiling data with progression-free survival (PFS), the ratio of PFS2 to PFS1, and comparing these with treatment modalities. Methods: Over five years, 44 patients with advanced-stage solid tumors underwent comprehensive tumor profiling, including genetic markers from tissue and blood, mRNA expression, circulating tumor cells, pharmacogenomics, and immunohistochemistry, to tailor therapies. These multidimensional datasets were rigorously analyzed applying machine learning algorithms against responses to target, chemo, and combo therapies, using robust statistical frameworks to elucidate the impact of advanced diagnostics on therapy effectiveness. Results: Multidimensional tumor testing markedly extended progression-free survival, with median PFS1 and PFS2 at 22.5 and 30 weeks, respectively t(43) = 1.76, p = 0.043, and a significant median PFS2/1 ratio of 1.31. Targeted therapies achieved the highest median PFS2 at 61 weeks, surpassing chemo alone (10.5 weeks) and combination therapy (29.5 weeks) significantly. Patients treated based on gene expression, including mRNA profiling and immunohistochemistry/immunocytochemistry (n = 22), had a median PFS of 37.5 weeks, outperforming those treated based on NGS (n = 12) with 27.5 weeks significantly. Those not fully adhering to guideline treatments due to divergent findings had a median PFS2 of 16.5 weeks. Notably, 26 out of 44 patients with critical illness had a PFS2 over 6 months. Conclusions: A clear linkage was established between comprehensive profiling indicators, including genetic, molecular, and cellular markers, and the observed therapeutic outcomes. The study reaffirms the critical importance of multidimensional tumor profiling in the era of precision oncology. However, we proceed monitoring this growing group of patients to establish a clearer picture how to adapt complex diagnostic tools into modern oncological practice.

An antioxidant and anti-ER stress combination therapy elevates phosphorylation of α-Syn at serine 129 and alleviates post-TBI PD-like pathology in a sex-specific manner in mice

Clinical studies have shown that traumatic brain injury (TBI) increases the onset of Parkinson's disease (PD) in later life by >50%. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are the major drivers of both TBI and PD pathologies. We presently evaluated if curtailing oxidative stress and ER stress concomitantly using a combination of apocynin and tert-butylhydroquinone and salubrinal during the acute stage after TBI in mice reduces the severity of late-onset PD-like pathology. The effect of multiple low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on post-TBI neurodegeneration was also evaluated. The combo therapy elevated the level of phosphorylation at serine 129 (pS129) of α-Syn in the pericontusional cortex of male mice at 72 h post-TBI. Motor and cognitive deficits induced by TBI lasted at least 3 months and the combo therapy curtailed these deficits in both sexes. At 3 months post-TBI, male mice given combo therapy exhibited significantly lesser α-Syn aggregates in the SN and higher TH+ cells in the SNpc, compared to vehicle control. However, the aggregate number was not significantly different between groups of female mice. Moreover, TBI-induced loss of TH+ cells was negligible in female mice irrespective of treatment. The MPTP treatment aggravated PD-like pathology in male mice but had a negligible effect on the loss of TH+ cells in female mice. Thus, the present study indicates that mitigation of TBI-induced oxidative stress and ER stress at the acute stage could potentially reduce the risk of post-TBI PD-like pathology at least in male mice, plausibly by elevating pS129-α-Syn level.

Combination Therapy: A New Tool for the Management of Obesity.

Obesity is a chronic lifestyle issue with devastating results. Behavioral changes are one of the initial lines of management strategies for obesity, but they are not very efficient management strategies. Many people also use surgical intervention to maintain a healthy weight, now considered to be the most common and effective obesity management. Chemically synthesized medicines fill the gap between lifestyle interventions and minimally invasive surgical management of obesity. The most common issue associated with monotherapy without side effects is its moderate effectiveness and higher dose requirement. Combination therapy is already used for many serious and complicated disease treatments and management and has shown efficacy as well. Generally, we use two or more medicines with different mechanisms of action for a better effect. The commonly used combination therapy for obesity management includes low-dose phentermine and prolonged and slow-releasing mechanism topiramate; naltrexone, and bupropion. Phentermine with inhibitors of Na-glucose cotransporter-2 or glucagon-like peptide-1 (GLP-1) agonists with gastric hormone or Na-glucose cotransporter-2 are two more viable combo therapy. This combination strategy aims to achieve success in bariatric surgery and the scientific community is working in this direction.

Abstract 951: 3D-PREDICT - An ex vivo precision oncology and clinical trial enrichment platform by Nilogen Oncosystems

Abstract Background: Immuno-oncology (IO) therapy with checkpoint inhibitors has demonstrated a higher response rate, duration of response, and overall survival than chemotherapy. However, predicting which FDA approved IO therapies or pharmaceutical agents, as well as best combinations and delivery sequence, will have optimal patient response remains a significant challenge for personalized medicine. Nilogen Oncosystem’s 3D-PREDICT is a novel ex vivo therapeutic investigative platform that provides a functional model of a patient’s tumor to investigate susceptibility to different therapeutic approaches directly. Derived from core biopsies, the 3D-PREDICT model captures the tumor heterogeneity while preserving the tumor microenvironment by retaining stromal components and cell-cell and cell-extracellular matrix interactions. Here, we employed the 3D-PREDICT platform to compare the efficacy of different immunotherapeutic approaches in various solid tumor indications ex vivo. Methods: Tumoroids from 18-gauge core biopsies from solid tumors were generated using Nilogen Oncosystems’s proprietary mechanical process forgoing any enzymatic digestion or propagation while keeping the spatial contexture of stroma intact. Pooled tumoroids were treated ex vivo for 72 hours with various standard-of-care mono or combo therapy (carboplatin, anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab, anti-CD47 antibody magrolimab, anti-programmed cell death receptor-1 (PD-1) antibody nivolumab, or a combination of magrolimab and atezolizumab). Treatment-mediated immune modulation in tumor microenvironment were analyzed to predict patient response to subjected therapies. Results: Treatment-mediated tumor cell killing activity was evaluated using 3D high throughput confocal imaging and Nilogen Oncosystems’s proprietary algorithm for data analysis. The ex vivo response to checkpoint inhibitors was correlated with retrospective patient clinical information. Tumoroid samples treated with atezolizumab and magrolimab demonstrated enhanced tumor cell killing. Approximately 20% of tumors showed increased CD8 T-cell activation upon ex vivo treatment, correlating with proinflammatory cytokine release in conditioned media. Conclusions: The 3D-PREDICT ex vivo tumoroid platform provides a unique resource to predict patients’ response to treatment, potentially serving as a clinical diagnostic to guide clinical care and stratifying patient procurement into clinical trials. This would allow prospective assessment of therapeutic efficacy ex vivo to match each patient to the most effective and least toxic, to improving outcomes, reducing costs, and assigning therapeutics on a more rational basis. Citation Format: Jared Ehrhart, Seth Currlin, Michelle Ataya, Alliyah Humphrey, Rikhia Chakraborty. 3D-PREDICT - An ex vivo precision oncology and clinical trial enrichment platform by Nilogen Oncosystems [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 951.

Abstract 6870: Immunological aging in triple negative breast cancer leads to a chronic interferon phenotype and immune cell exhaustion that impedes response to therapy

Abstract Age is the biggest risk factor for developing most forms of cancer, and understanding how age impacts cancer progression is critical to improving responses to therapy. As we age immune function declines suggesting that therapeutic responses, particularly to immunotherapies, will also change with age. Early clinical trial data suggests that there are age-associated responses to immunotherapies. Clinical trials, however, are not designed to reflect patient chronological and immunological ages - over 50% of breast cancer patients are over the age of 60, yet less than 25% of patients in clinical trials are in this age range. Here, we utilize a preclinical mouse model of immunological aging to understand how aging impacts immune responses to triple-negative breast cancer (TNBC). Immunologically young (8 weeks old) and aged (~12 months old) FVB mice were orthotopically injected with syngeneic Met1 TNBC cells. We previously established that this preclinical model mimics human immunological aging and enables us to better understand how age impacts disease progression and therapeutic responses. Once tumors became palpable, mice were treated with paclitaxel or vehicle control and/or anti-PDL1 to mimic first-line therapeutic strategies. Tumors grew significantly faster in young control mice compared to aged, but young mice had a more robust response to therapy. Notably, only young mice had a significant benefit of combo therapy (paclitaxel + anti-PDL1) over monotherapy alone. Tumors in aged mice had significantly more infiltration of CD8+ cytotoxic T cells and FOXP3+ inhibitory T-regulatory cells compared to young control mice, yet only tumors in young mice exhibited an increase in T cell infiltration with chemo or immunotherapy. Depletion of either CD8+ or CD4+ T cells in immune-competent FVB mice both led to a complete loss of age-associated differences in tumor growth. RNA sequencing analysis indicated that the infiltrating T cells in aged mice may be exhausted due to a chronic interferon phenotype, as indicated by enrichments of interferon alpha, interferon gamma, and IL2 signaling pathways, as well as expression of RIPK1, TNFa, and the immune exhaustion markers PD1, CTLA4, TIM3, and LAG3. Analysis of published single cell RNAseq data indicated the same interferon response pathways enriched with age in human TNBC, particularly in the T cell compartment. Our findings show that the aging immune microenvironment significantly impacts tumor progression and that a chronic interferon phenotype with age may lead to T cell exhaustion and impaired therapeutic responses. This work suggests that targeting interferon signaling may lead to improved therapeutic responses. Together these findings demonstrate how immunological aging can impact disease progression and response to therapy and highlight the importance of developing age-stratified treatment strategies. Citation Format: Milos Spasic, Adrienne Parsons, Gregory Goreczny, Qiuchen Guo, Abigail Recko, Elizabeth Mittendorf, Peter van Galen, Sandra McAllister. Immunological aging in triple negative breast cancer leads to a chronic interferon phenotype and immune cell exhaustion that impedes response to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6870.

Spatiotemporal modeling of nano-delivered chemotherapeutics for synergistic microwave ablation cancer therapy

Background and objectiveThe effectiveness of current microwave ablation (MWA) therapies is limited. Administration of thermosensitive liposomes (TSLs) which release drugs in response to heat has presented a significant potential for enhancing the efficacy of thermal ablation treatment, and the benefits of targeted drug delivery. However, a complete knowledge of the mechanobiological processes underlying the drug release process, especially the intravascular drug release mechanism and its distribution in response to MWA needs to be improved. Multiscale computational-based modeling frameworks, integrating different biophysical phenomena, have recently emerged as promising tools to decipher the mechanobiological events in combo therapies. The present study aims to develop a novel multiscale computational model of TSLs delivery following MWA implantation. MethodsDue to the complex interplay between the heating procedure and the drug concentration maps, a computational model is developed to determine the intravascular release of doxorubicin from TSL, its transvascular transport into the interstitium, transport in the interstitium, and cell uptake. Computational models can estimate the interplays among liposome and drug properties, tumor perfusion, and heating regimen to examine the impact of essential parameters and to optimize a targeted drug delivery platform. ResultsResults indicated that the synergy of TSLs with MWA allows more localized drug delivery with lower side effects. The drug release rate and tumor permeability play crucial roles in the efficacy of TSLs during MWA treatment. The computational model predicted an unencapsulated drug lime around the ablated zone, which can destroy more cancer cells compared to MWA alone by 40%. Administration of TSLs with a high release rate capacity can improve the percentage of killed cancer cells by 24%. Since the heating duration in MWA is less than 15 min, the presented combination therapy showed better performance for highly permeable tumors. ConclusionThis study highlights the potential of the proposed computational framework to address complex and realistic scenarios in cancer treatment, which can serve as the future research foundation, including advancements in nanomedicine and optimizing the pair of TSL and MWA for both preclinical and clinical studies. The present model could be as a valuable tool for patient-specific calibration of essential parameters.

Drug-Loaded Bacillus Calmette-Guérin Bacteria for Immuno-Chemo Combo Therapy in Bladder Cancer.

Intravesical Bacillus Calmette-Guérin (BCG) is a well-established strategy for managing high-risk nonmuscle-invasive bladder cancer (NMIBC); however, over half of patients still experience disease recurrence or progression. Although the combined intravesical instillation of various chemotherapeutic drugs is implemented in clinical trials to enhance the BCG therapy, the outcome is far from satisfying due to severe irritative effects and treatment intolerance at high doses. Therefore, it is adopted the "biotin-streptavidin strategy" to doxorubicin (DOX)-encapsulated nanoparticles within live BCG bacteria (DOX@BCG) to improve treatment outcomes. Adherence of BCG to the bladder epithelium helps precisely target DOX@BCG to the local tumor cells and simultaneously increases intratumoral transport of therapeutic drugs. DOX@BCG effectively inhibits cancer progression and prolongs the survival of rats/mice with orthotopic bladder cancer owing to synergism between BCG-immunotherapy, DOX-chemotherapy, and DOX-induced immunogenic tumor cell death; furthermore, it exhibits improved tolerance and biosafety, and establishes antitumor immunity in the tumor microenvironment. Therefore, the drug-loaded live BCG bacterial delivery system holds considerable potential for clinical translation in the intravesical treatment of bladder cancer.

The Long-Term Effects of Olmesartan Combined Amlodipine among Hypertensive Patients in a Tertiary Care Hospital – A Retrospective Study

Introduction: Hypertension, commonly known as high blood pressure, stands as a pervasive global health concern, often referred to as the "silent killer" due to its asymptomatic nature. The management of hypertension is critical to prevent cardiovascular complications and other associated health risks. This study aimed to observe the long-term effects of olmesartan combined with amlodipine among hypertensive patients. Methods: This was a retrospective observational study conducted in the Department of Medicine, Popular Medical College Hospital, Dhaka, Bangladesh during the period from January, 2023 to December, 2023. In our study, we included 210 hypertensive patients who were divided into three groups: Group A -Patients who received Olmesartan (OM 40 mg), Group B -Patients who received Amlodipine (AML 5 mg), and Group C -Patients who received the combination of Olmesartan (OM 40 mg) and Amlodipine (AML 5 mg). Result: We found the mean age was 52.8 ± 11.3 years. Most of our patients were male (68.10%). The majority of patients in Group B had ≤140⁄90 mmHg blood pressure than the other groups at the end of our study. Patients with ≤130⁄85 mmHg, were higher in Group A. Patients with ≤130⁄80 mmHg blood pressure during the last week of the study were highest in Group C. Drowsiness/dizziness, headache, nausea/vomiting, and stomach /abdominal pain were the most common side effects. Conclusion: In our study, we discovered that Olmevas AM (OM/AML) 40/5 mg was more effective at decreasing blood pressure than either OM (Olmesartan) 40 mg or AML (Amlodipine) 5 mg. There were no unexpected or unusual safety concerns found with OM/AML combo therapy.

Peripheral blood cell counts as biomarkers of clinical benefit in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) receiving immune checkpoint inhibitor (ICI) combination (combo) therapies.

446 Background: Numerous combos of ICIs and Tyrosine Kinase Inhibitors (TKIs) have received approval for the management of mccRCC. Specific peripheral blood cell counts reflect inflammation and impact anti-tumor immunity, and here we investigated their role as biomarkers of clinical benefit to ICI combos in RCC. Methods: We performed a retrospective study of 179 mccRCC patients treated with ICI combos ≥ 4 weeks (2013-2023), where we examined baseline and 6-week post-treatment Neutrophil to Lymphocyte ratio (NLR), Red cell Distribution Width (RDW), and eosinophil values. We categorized these values as High (H) or Low (L) based on baseline medians. Our analysis included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to next treatment (TNT). Kaplan-Meier methods and the log-rank test were used to evaluate time from start of ICI combos to the event of interest. Results: Our analysis included 111 eligible ICI-naïve mccRCC patients median age 63, 76% male. IMDC risk scores categorized 22% as favorable, 53% intermediate, and 25% poor risk. Treatment included 50 (45%) patients on ICI+ICI combos with a median therapy duration of 6.3 months, and 61 (55%) on ICI+TKI with a median duration of 8.8 months. In the ICI+ICI group, median OS was 28.2 months (95% CI 20.7-38.4), PFS 5.5 months (95% CI 3.7-7.8), and TNT 12.7 months (95% CI 7.4-20.4). In the ICI+TKI group, median OS was 21.7 months (95% CI 17.1-25.4), PFS 7.4 months (95% CI 5.6-11.1), and TNT 12.5 months (95% CI 9.7-16.4). The ORR was 38% in the ICI+ICI group, and 56% in the ICI+TKI group (p=0.062). No differences were seen with NLR. In the ICI+ICI group, higher baseline RDW levels were correlated with a shorter TNT, while higher eosinophil levels at week 6 were correlated with longer PFS and TNT (significant results highlighted in the table below). Conclusions: Eosinophil levels and RDW are potentially readily available biomarkers in the clinic for predicting and monitoring ICI combo treatment outcomes in mccRCC patients. Validation of these results in larger cohorts is warranted. [Table: see text]

P1070 Utilization of HLA-DQA1*05 haplotype testing in routine clinical practice to stratify advanced therapies: A prospective pilot study

Abstract Background A potential association between HLA-DQA1*05 allele and development of anti-drug antibodies in Anti-TNF treated Crohn’s Disease patients is reported in the PANTS study. The utility of stratifying treatment based on the HLA-DQA1*05 status has not been evaluated in a biomarker stratified clinical trial and there are no prospective studies evaluating the impact of using HLADQA1*05 in routine clinical practice to decide on monotherapy versus combo therapy while initiating on anti-TNFs. We aimed to determine the impact of carriage of HLADQA1*05 allele to guide the need for concomitant immunomodulators in IBD patients planned for Infliximab therapy. Methods In our prospective study, 97 adult IBD patients were included. All patients were screened for HLADQ2 haplotype as part of their routine pre-biologic screen. Stratification was done according to the presence of HLA-DQA1*05 haplotype. HLADQA1*05 positive patients were assigned combo therapy with Infliximab combined with either methotrexate or azathioprine. HLADQA1*05 negative patients were given infliximab monotherapy unless another indication for concomitant immunomodulation was present. Patients were followed for a minimum of one year after drug initiation. Primary outcome was drug persistence, expressed as time to discontinuation of infliximab, segregated by the treatment decision based on HLA-DQA1*05 status. Secondary outcomes were proportion of patients developing anti-drug antibodies and time to antibody development. Statistical analysis was done using Kaplan-Meier curves and log-rank test. Results Baseline characteristics are detailed in Table 1. HLA-DQA1*05 was positive in 41/97(42%) of patients and combo therapy was offered to 33/41(80%) of those patients. Immunomodulators were avoided in 39/97(40.2%) patients representing the subset of patients with negative HLADQA*105 to whom no immunomodulator was offered. There was no statistically significant difference in drug persistence rates between the groups treated based on HLA-DQA*105 status. 54/97(55.6%) of the patients developed anti-infliximab antibodies during their follow-up (25/41(60.9 %) in HLA positive and 29/56 (51.7%) in HLA negative). Neutralizing drug antibodies with absent drug levels were detected in 15/97(15.5%) of patients (8/41(19.5%) in HLA positive, 7/56(12.5%) in HLA negative). The median time to antibody development was 33.5 weeks (IQR 22-46.7). Conclusion This is the first prospective study suggesting HLA-DQA1*05 haplotype testing can be used in routine clinical practice to stratify therapy based on the need for immunomodulators in infliximab treated IBD patients. HLA-DQA1*05 negative patients may be started on monotherapy with potential for improving safety and reducing costs of immunomodulator monitoring.

P1056 T cell responses to repeated SARS-CoV-2 vaccination and breakthrough infections in patients with inflammatory bowel disease on TNF inhibitor treatment, a prospective cohort study

Abstract Background Understanding T cell responses to SARS-CoV-2 immunisation in patients on immunosuppressive treatment is important for future vaccine recommendations. Our aim was to investigate the magnitude and quality of T cell responses following repeated SARS-CoV-2 vaccine doses and COVID-19 (breakthrough infections). Methods In this prospective, observational study of responses to SARS-CoV-2 vaccines (Nor-vaC)1, patients with inflammatory bowel disease (IBD) on TNF inhibitor (TNFi) therapy receiving up to four SARS-CoV-2 vaccine doses, and healthy controls receiving three vaccine doses were included. CD4 and CD8 T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks following vaccination and breakthrough infection. Antibodies to the receptor binding domain (RBD) of the Wuhan-Hu-1 and BA.1 (omicron) strains were measured. Results Between March 2, 2021, and December 20, 2022, 118 IBD patients, and 21 healthy controls were included in the study (Table). Following three vaccine doses, the humoral immune response was attenuated in IBD patients compared to healthy controls (median 3954 BAU/ml vs. 6280 BAU/ml, p=0.008). However, both the percentage of spike-specific T cells (CD4 median 0.11% vs. 0.10%, p=0.259, CD8 0.030% vs. 0.046%, p=0,333) and T cell polyfunctionality scores (a measure of quality of vaccine response) (CD4 median 0.403 vs. 0.371, p=0.386, CD8 0.105 vs. 0.101, p=0.871), showed comparable quality in IBD patients and controls following three doses. CD4 T cell responses increased rapidly and plateaued after two vaccine doses whereas CD8 T cell responses continued to improve up to four vaccine doses (Figure). Breakthrough infection in patients following the third or fourth vaccine dose increased CD8 polyfunctionality and generated broad CD4 and CD8 T cell responses against non-spike peptides. There was no difference in T cell responses between patients using TNFi mono- and combo therapy after primary vaccination (three vaccine doses) (p=0.648). Conclusion Despite attenuated antibody responses, IBD patients on TNFi treatment demonstrated T cell responses comparable to healthy controls following three SARS-CoV-2 vaccine doses. Repeated vaccination and breakthrough infection increased the quality and breadth of T cell responses, reaching a plateau. Distinguishing between CD4 and CD8 immune compartments and dynamics of activation after SARS-CoV-2 immunisation may provide nuanced understanding of protective cellular responses The study results indicate that IBD patients on TNFi treatment may in future follow the same recommendations for further SARS-CoV-2 vaccines as the general population. 1Clinialtrials.gov NCT04798625

P883 Impaired long-term quantitative cellular response to SARS-COV-2 vaccine in thiopurine-treated IBD patients

Abstract Background SARS-CoV-2 mRNA vaccine induces a robust immune response in most patients with inflammatory bowel disease (IBD). However, humoral short-term response appears to be reduced in patients receiving anti-TNF agents or tofacitinib, even after booster doses. Data on long-term immune response is limited. We aimed to assess short and long-term humoral and T-cell response to SARS-CoV-2 mRNA vaccine in IBD patients receiving anti-TNF and/or thiopurines. Methods A prospective, longitudinal study was carried out in IBD patients receiving thiopurines, anti-TNF mono, or combo therapy. Patients had received between 2 and 4 doses of mRNA SARS-CoV-2 vaccine. Cellular and humoral response to the vaccine was assessed by serum interferon-gamma release assay (IGRA) and antibody SARS-CoV-2, respectively. We defined short-term response as humoral and T-cell response six weeks after the second vaccine and long-term response 6 to 12 months after that. Primary outcome was to determine if T-cell immune response differs in IBD patients receiving anti-TNF versus thiopurines. Results We recruited 148 IBD patients, 57 treated with anti-TNF monotherapy, 53 with anti-TNF combo, and 38 with thiopurines. Short-term T-cell and humoral responses were similar between the three groups. However, long-term T-cell concentration was reduced in thiopurine-treated (median 0.7 UI/mL [0.26-2.35]; p<0.05) and anti-TNF-combo-treated patients (median 0.4 UI/mL [0.22-1.13]; p<0.01) when compared to anti-TNF monotherapy (median 2.2 UI/mL [1-4.15]). Multivariate analysis showed that anti-TNF monotherapy (-0.93, p<0.05) and decreased time between vaccination and T-cell response measurement (0.04 [.00005-.078] p=0.05) were associated with increased T-cell concentration long-term when compared to the other groups of patients. Conclusion We found a diminished long-term quantitative cellular response in our cohort of IBD patients vaccinated for SARS-CoV-2 treated with thiopurines or combo therapy compared with anti-TNF monotherapy. These findings highlight the recommendation to receive booster doses in IBD patients, specially those receiving thiopurines.

A real-world study of the effectiveness and safety of apatinib-based regimens in metastatic triple-negative breast cancer

PurposeThis investigation sought to examine the efficacy and safety of low-dose apatinib used alongside chemotherapy in the clinical management of patients with metastatic triple-negative breast cancer (TNBC) within a real-world setting, whilst comparing the outcomes with those treated solely with chemotherapy.MethodsThis case series study analyzed clinical data and treatment outcomes of 163 patients with metastatic TNBC who underwent rescue treatment at the Medical Oncology Department of Clinical Oncology, Fujian Cancer Hospital, School of Fujian Medical University, China, between October 2011 and January 2023. All the patients underwent rescue treatment with either chemotherapy alone or apatinib (250 mg/day) combined with chemotherapy. The study’s primary outcome was progression-free survival (PFS), whereas the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles.ResultsThe study was designed to compare two groups [1]. Out of the 163 TNBC patients who participated in the study, 107 individuals (65.6%) received treatment based on chemotherapy, whereas 56 patients (34.4%) were given treatment based on a combination of low-dose apatinib (250 mg/day) and other treatments, including chemotherapy. After propensity score matching (PSM), the objective response rate (ORR) and disease control rate (DCR) of patients with advanced triple-negative breast cancer (TNBC) who received apatinib-based treatment were 50.0 and 90.0%, respectively, while they were 6.7 and 20.0%, respectively, for the chemotherapy-based group (P < 0.001). The group that received apatinib-based treatment showed superior results in both PFS and OS compared to the group that received chemotherapy. The median PFS and OS for the apatinib-based group were 7.8 and 20.3 months, respectively, while they were only 2.2 months and 9.0 months, respectively, for the chemotherapy-based group (P < 0.001) [2]. Patients who were administered combo therapies, including PD-1 inhibitors, were excluded. In total, 97 patients received chemotherapy alone, while 34 patients were treated with apatinib in combination with chemotherapy. After propensity score matching (PSM), the ORR and DCR for the total group who received combo therapies were 44.4 and 81.5%, respectively, while they were 11.1 and 22.2%, respectively, for the chemotherapy alone group (P < 0.001). The group receiving both apatinib and chemotherapy displayed notable advantages over the group solely receiving chemotherapy in regards to PFS and OS for the entirety of the population. The PFS was found to be 7.8 months in comparison to 2.1 months (P < 0.001) and the OS was 21.1 months in contrast to 9.0 months (P < 0.001). Apatinib combined with chemotherapy induced grade 3/4 hematological toxicities, including neutropenia (8.8%) and thrombocytopenia (2.9%). Additionally, non-hematological toxicities were commonly observed, such as Hand-foot syndrome (35.3%), proteinuria (26.5%), hypertension (61.8%), higher alanine aminotransferase levels (26.5%), and fatigue (35.3%). The most frequent non-hematological grade 3/4 toxicities were Hand-foot syndrome (2.9%) and hypertension (5.9%). The study did not report any fatal adverse effects.ConclusionsThe combination of low-dose apatinib with chemotherapy has proven to be more effective than chemotherapy alone in treating metastatic triple-negative breast cancer (TNBC). Additionally, the occurrence of grade 3/4 non-hematologic toxicities was significantly lower compared to the recommended dose of apatinib.

Infliximab Monotherapy vs Combination Therapy for Pediatric Crohn's Disease Exhibit Similar Pharmacokinetics.

The use of concomitant azathioprine may improve efficacy and pharmacokinetic (PK) properties of infliximab (IFX) but is also associated with an increased risk of adverse events. Proactive therapeutic drug monitoring (pTDM) of IFX monotherapy is an alternative strategy to improve PK. The aim of this study was to evaluate whether IFX with an immunomodulator (combo) has PK benefits over IFX-pTDM (mono) in pediatric Crohn's disease (CD). This PK analysis included pediatric CD patients who started either IFX combo (TISKids study) or IFX mono with pTDM (REFINE cohort). Combo and mono IFX trough levels (TLs) and antibodies-to-infliximab were assessed at infusion 3, 4, and 5. A population PK model was built to compare IFX PK outcomes (clearance [CL], TLs and cumulative exposure) between combo and mono groups at infusion 4 and 5. Clinical response and steroid-free clinical remission (SFCR) was assessed at infusion 4 and 5. This study included 128 pediatric CD patients (66 mono and 62 combo). At infusion 5, there was no significant difference between mono and combo median TLs 4.1 µg/mL (2.1, 7.8) vs 5.9 µg/mL (3.2, 9.4; P = .14) or median CL 0.26 L/d (0.21, 0.32) vs 0.26 L/d (0.21, 0.33; P = .81). Mono patients had a lower SFCR rate at infusion 5 (53% [31 of 59] vs 80% [32 of 40]; P = .01). Clinical response rates were significantly higher among combo than mono patients at both infusion 4 and 5. This study suggests that there are no PK differences (TLs and CL) between combo and mono therapy in pediatric CD patients who started IFX.

An Investigation into the Reasoning for the Ban on Fixed Dosage Combinations

Either a single treatment or the sequential administration of multiple medications can be used to treat an aberrant situation. Utilising fixed dose combinations—specific dosage forms including two or more medications is another strategy. A fixed dose combination is a pharmacological administration method that combines two or more active ingredients into one. Because of all the benefits these products offer, prescribers and consumers alike are quite interested in using them. There are unavoidable intrinsic disadvantages as well. Popular antibiotics, pain relievers, and multivitamins are among the 156 FDC medications that the Health Ministry has prohibited over safety concerns. By outlawing certain potentially dangerous drug combinations, the government hopes to safeguard the public's health. The health concerns connected with these pharmaceuticals have led to their prohibition on production, marketing, and distribution, according to a gazette notice published by the Health Ministry on August 21, 2024. The prohibited FDCs included in the notice include antibiotics, anti-allergic drugs, painkillers, multivitamins, and fever and hypertension combo therapies. This article examines both the advantages and disadvantages of FDCs associated with the ban by the Government of India, as outlined in the gazette. The primary focus is on identifying the underlying causes for the ban.

MicroRNA and granulocyte-monocyte adsorption apheresis combotherapy after inadequate response to anti-TNF agents in ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract, affecting millions of individuals throughout the world, and producing an impaired health-related quality of life. Granulocyte and monocyte apheresis (GMA) is a therapeutic option for UC management to induce remission by selective removal of activated leukocytes from bloodstream. Despite the knowledge of the important role of epigenetics in UC pathogenesis, and in the response to different treatments, nothing is known about the role of microRNAs in GMA therapy in UC patients. Seven consecutively UC patients who started GMA in combo therapy with infliximab were recruited. Peripheral blood samples were taken before the apheresis session, at the start of the induction (S0) and at the end (S10). They were follow-up during the induction phase (10 sessions: 2 sessions for a week during 3 wk and 1 session for a week during 4 wk) of the treatment at a tertiary hospital (Hospital la Fe) and 6 mo after finishing the GMA induction therapy. MiRNA was extracted and analyzed by RT-PCR. R software and GraphPad were used. Clinical disease activity significantly decreased after induction therapy with GMA (median partial Mayo score 2 (IQR, 1-6) (P < .05). Fecal calprotectin value and CRP value significantly decreased after induction therapy. Five microRNAs modified their expression during GMA (unsupervised analysis): miR-342-3p, miR-215-5p, miR-376c-3p, miR-139-5p, and miR-150-5p. When a sub-analysis was performed in those patients who showed good response to apheresis treatment (n = 5), two microRNAs showed to be implicated: miR-215-5p and miR-365a-3p. These are preliminary but promising and novel results, as it is the first time, to our knowledge that microRNA profiles have been studied in the context of GMA treatment for IBD.