Immunotherapy Research Articles

Inclusion body myositis and immunosenescence: current evidence and future perspectives.

Inclusion body myositis (IBM) remains an enigmatic and complex muscle disorder where a deeper understanding of disease pathomechanisms and the identification of potential genetic contributors represent an unmet need. The absence of effective treatments has spurred endeavours to reassess the interplay between degeneration, including autophagy, mitochondrial dysfunction and proteasomal dysregulation, and autoimmunity. IBM is unique among the other idiopathic inflammatory myopathies owing to its molecular signature involving highly differentiated cytotoxic T cells that evade immune regulation. This has led to a resurgence of interest in the development of immunomodulatory therapy. This review discusses the potential role of cellular immunosenescence in sustaining inflammation and/or fibrotic remodelling observed in IBM and appraises the rationale for some potential therapeutic approaches to mitigate disease progression.

IgA Vasculitis (Henoch–Schönlein Purpura): An Update on Treatment

Objective: IgA vasculitis (IgAV), previously named as Henoch–Schönlein purpura, is the most frequent systemic vasculitis in children. In adults, IgAV is less common although it is associated with more severe disease. In fact, the frequency of glomerulonephritis (referred to as IgAV nephritis) in adults is higher than in children and tends to present more severely, with around 10–30% of those affected eventually progressing to end-stage renal disease. In this review, we describe the pathophysiology, main clinical features, diagnosis of the disease, and latest clinical data regarding IgAV therapy. Methods: A narrative literature review, primarily based on articles published in PubMed, was conducted. In addition to discussing the main aspects of glucocorticoids and conventional disease-modifying drugs used in the management of IgAV, this review focuses on the latest information reported regarding biologics and potential future therapies. Results: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. Colchicine, dapsone, and methotrexate can be useful for controlling minor manifestations. Several immunomodulatory agents, such as cyclosporine A, tacrolimus, and mycophenolate mofetil, have shown favorable results as glucocorticoid-sparing agents. Leflunomide has shown promising results but requires further study. The use of rituximab has demonstrated efficacy in reducing relapse frequency, lowering the cumulative glucocorticoid burden, and achieving long-term remission of the disease in children and adults with IgAV. Immunoglobulins and plasma exchange therapy can also be useful in difficult and life-threatening situations. Other potential therapies with encouraging results include TRF-budesonide, B-cell-directed therapy, B-cell-depleting agents, sodium–glucose cotransporter-2 inhibitors, endothelin receptor antagonists, and complement pathway inhibitors. Conclusions: Glucocorticoids are the first-line therapy for IgAV, especially in adults with severe manifestations. The role of various immunomodulatory therapies, such as calcineurin inhibitors and mycophenolate mofetil, remains promising, while rituximab reduces the long-term side effects of glucocorticoids and can help achieve disease remission. Other potential therapies with encouraging results require further research.

Impact of Renin-angiotensin system inhibitors on response to PD1/L1 inhibitors in patients with Metastatic Renal Cell Carcinoma

BackgroundThe renin-angiotensin-aldosterone system (RAAS), traditionally associated with blood pressure and fluid regulation, also plays a role in tumorigenesis. Renin-angiotensin-aldosterone system inhibitors (RAASI), including angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown to improve outcomes in various malignant neoplasms. In metastatic urothelial cancer, the use of RAASI have been associated with higher rates of tumor regression in patients receiving immunotherapy (IO) with PD1/L1 inhibitors. This is thought to be due to RAASI-induced downregulation of TGF-beta, for which increased expression is a known mechanism of PD1/L1 inhibitor resistance. We hypothesized that concurrent RAASI in patients with mRCC receiving IO is associated with increased tumor regression. MethodsWe conducted a retrospective analysis of patients with mRCC receiving IO as a first- or second-line therapy from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RAASI on tumor regression. The primary endpoint was any regression of tumor on imaging. ResultsData were available for 128 patients with mRCC who received IO as a first- (n=91, 71.0%) or second- (n=37, 28.9%) line treatment. Patients who received RAASI during IO were more likely to have tumor regression compared to patients who were not on concurrent RAASI (OR 3.84 [95% CI 1.81-8.47, p=<0.001). This held true regardless if patients received IO as a first-line (OR 2.83 [95% CI 1.2-6.94], p=0.0173) or second-line (OR 9.5 [95% CI 1.89-73.1], p=0.005) treatment. ConclusionsOur hypothesis generating study suggests that in our mRCC population, concurrent use of RAASI in patients receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RAASI in combination with IO for mRCC patients. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population. MicroAbstractRenin-angiotensin-aldosterone system inhibitors (RAASI) have been shown to improve outcomes in various malignancies. In this retrospective, single-center study, we found that concurrent use of RAASI in patients with mRCC receiving IO is associated with a significantly increased likelihood of tumor regression. Our findings suggest the potential therapeutic advantage of RAASI in combination with IO for mRCC patients.

Subcutaneous versus intravenous infliximab therapy - a real-world study: toward higher drug concentrations.

Recently, a formula of subcutaneous infliximab (SC-IFX) has been approved for inflammatory bowel disease (IBD), demonstrating a better pharmacokinetic and immunogenic profiles, compared to intravenous infliximab (IV-IFX), with similar efficacy and safety. The aim of this study is to evaluate the clinical, biochemical, and pharmacological outcomes of IBD patients in clinical remission, who switched from IV-IFX to SC-IFX, with a follow-up period of 6 months. Retrospective cohort study, including IBD patients in clinical remission, previously medicated with IV-IFX, who switched to SC-IFX 120 mg every other week. Biochemical parameters were evaluated before the switch and 6 months after, namely infliximab serum concentrations, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin. Included 41 patients in clinical remission, 32 with Crohn's disease (78.0%) and 9 with ulcerative colitis (22.0%). All patients maintained clinical remission during the 6 months after the switch, with a treatment persistence rate of 100%, and no patients requiring corticosteroid therapy, switching back to IV-IFX, or IBD-related hospitalization. The mean infliximab serum concentrations were significantly higher after 6 months of SC-IFX (17.3 ± 6.6 vs. 9.1 ± 5.5 µg/ml, P < 0.001). However, there were no differences between values of ESR, CRP, and fecal calprotectin, before and after the switch ( P = 0.791, P = 0.246, and P = 0.639). Additionally, none of the patients developed antibodies to infliximab. Switching from IV-IFX to SC-IFX in IBD patients in clinical remission is effective and leads to higher infliximab serum concentrations, regardless of the combination with immunomodulatory therapy.

Structural characterization and potential antitumor and immunostimulatory activities of mycelial polysaccharides from Ophiocordyceps gracilis

Ophiocordyceps gracilis (O. gracilis), the same genus as Ophiocordyceps sinensis, has been used as an edible medicinal fungus for many years. However, the active ingredients of O. gracilis polysaccharides remain relatively unknown. To address this, a 310.1kDa novel polysaccharide (PDP-1a) was isolated from O. gracilis. The structural characteristics of PDP-1a were determined by different spectroscopy analyses, revealing that PDP-1a was α-glucan homologs with →4)-α-Glcp(1→ as the main chain. Furthermore, PDP-1a inhibited tumor cell proliferation, particularly in the A549 cell line, with a cell death mechanism involving cell cycle blockage, mitochondrial membrane potential reduction, and increased reactive oxygen species, thereby leading to apoptosis. Importantly, PDP-1a promotes antitumor cytokine secretion and enhances macrophage phagocytosis concentration-dependently. These findings provide a theoretical foundation for the use of O. gracilis and emphasize the potential application of PDP-1a in antitumor immunomodulatory therapy.

Transapical Transcatheter Aortic Valve Implantation with the J-Valve System in Aortic Regurgitation

BackgroundAortic regurgitation (AR) is a condition associated with significant morbidity and mortality, particularly in severe cases. The J-valve system, next-generation transcatheter heart valve (THV), may overcome the procedural challenges associated with treating pure AR. This study reported the outcome of J-valve for treatment of AR. MethodsThis study observed 47 patients undergoing transcatheter aortic valve implantation (TAVI) with the J-Valve system. Diagnostic evaluation included transthoracic echocardiography and multislice computed tomography to assess AR severity and anatomical characteristics essential for TAVI. Follow-ups were conducted at various intervals post-operation to evaluate outcomes. ResultsThe patients had a mean age of 73.0±9.0 years and a median ejection fraction (EF) of 58.0% (IQR, 45.0%-64.0%). The median EuroSCORE II was 3.0% (IQR, 2.0%-6.7%).The procedural success rate was 100%, with no need for a second valve implantation or conversion to sternotomy. Short-term outcomes showed significant improvements in the New York Heart Association (NYHA) functional classification (P<0.001), left ventricular ejection fraction (LVEF) (P=0.009) and left ventricular end-diastolic diameter (LVEDD) (P<0.001). A singular case of valve migration and severe perivalvular leakage (PVL) due to Behçet's disease prompted a revised approach incorporating immunomodulation therapy. ConclusionsTAVI with the J-Valve system presents a viable alternative for managing severe AR, demonstrating high procedural success and substantial clinical improvement. However, the case of valve migration due to Behçet's disease highlights the need for careful preoperative screening and consideration of autoimmune disorders in differential diagnoses.

Review article: Optimisation of biologic (monoclonal antibody) therapeutic response in inflammatory bowel disease.

There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents. To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM). An extensive review of the published literature. TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure-response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non-TNF inhibitors demonstrate less robust exposure-response relationships, and TDM may not prove as beneficial. In the treat-to-target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control.

The Supportive Care Needs of Individuals Living With Advanced or Metastatic Lung Cancer Receiving Targeted or Immunotherapies.

Lung cancer is associated with the highest incidence and mortality of all cancers. New treatments, called targeted therapies (TT) and immunotherapies (IO), offer higher treatment efficacy and fewer side effects compared to traditional treatments but are accompanied by uncertainty and an unpredictable treatment course. There is a paucity of research on the experiences of individuals living with advanced or metastatic lung cancer receiving TT/IO, and even less is known about the supportive care needs of this population. Twenty four participants from across Canada participated in semi-structured interviews regarding their supportive care needs. Thematic analysis was utilized to identify their supportive care needs. Qualitative coding identified unmet needs and challenges. All participants indicated difficulties with unmet supportive care needs, including psychological, informational, and practical needs. The exploration of supportive care experiences of patients receiving TT/IO exposes high distress and unmet needs. Results indicate the need for timely and accessible supportive cancer care. Results can inform patient advocacy efforts and the development of new services.

Advancing Immunotherapy in Pancreatic Cancer

Pancreatic cancer remains one of the deadliest malignancies, with a consistently low five-year survival rate for the past several decades. This is in stark contrast to other cancers, which have seen significant improvement in survival and prognosis due to recent developments in therapeutic modalities. These modest improvements in pancreatic cancer outcomes have primarily resulted from minor advances in cytotoxic chemotherapeutics, with limited progress in other treatment approaches. A major focus of current therapeutic research is the further development of immunomodulatory therapies characterized by antibody-based approaches, cellular therapies, and vaccines. Although initial results utilizing immunotherapy in pancreatic cancer have been mixed, recent clinical trials have demonstrated significant improvements in patient outcomes. In this review, we detail these three approaches to immunomodulation, highlighting their common targets and distinct shortcomings, and we provide a narrative summary of completed and ongoing clinical trials that utilize these approaches to immunomodulation. Within this context, we aim to inform future research efforts by identifying promising areas that warrant further exploration.

The diagnostic challenge of coexisting systemic lupus erythematosus and multiple sclerosis in a young male: Rare but real.

The coexistence of multiple sclerosis (MS) and systemic lupus erythematosus (SLE) is exceptionally rare, especially in males. This case highlights the importance of early diagnosis and treatment with immunomodulatory therapies like rituximab, which can lead to sustained remission in patients with overlapping autoimmune disorders.

Management and long-term outcome of recurrent idiopathic FSGS in pediatric kidney transplant recipients

Focal segmental glomerulosclerosis (FSGS) is a major cause of pediatric kidney failure. Most cases of FSGS in children are idiopathic and have a high risk of post-transplantation recurrence and graft loss. Common treatments for recurrent FSGS (rFSGS) post-transplantation include plasmapheresis, immunoadsorption, and/or immunomodulatory therapy. This study retrospectively evaluated the efficacy and safety of early plasmapheresis followed by rituximab for inducing and maintaining remission in rFSGS. Between 2014 and 2023, 8 of 65 pediatric kidney transplant recipients at our center were diagnosed with idiopathic FSGS. rFSGS was diagnosed based on nephrotic range proteinuria with no other cause and managed with plasmapheresis. Rituximab therapy was used for those who did not achieve complete remission with prolonged plasmapheresis or remained plasmapheresis dependent. 6 of 8 (75%) transplant recipients with idiopathic FSGS experienced rFSGS. All patients achieved partial or complete remission with plasmapheresis, with response times ranging from 8 to 379 days (median 13 days). Rituximab therapy was introduced for 5 plasmapheresis-dependent patients, leading to sustained remission and cessation of plasmapheresis in 3 patients, while 2 showed improved proteinuria and reduced plasmapheresis frequency. Adverse effects included rituximab-induced serum sickness in one patient and one mild allergic reaction. One patient experienced graft loss due to humoral rejection, but no grafts were lost to rFSGS, and all other grafts remained functional over an average follow-up of 50 months. Early plasmapheresis followed by rituximab therapy effectively induces remission in most post-transplantation rFSGS cases, is well tolerated, and prevents graft loss. Larger studies are needed to confirm these findings.

Immunomodulation by the combination of statin and matrix-bound nanovesicle enhances optic nerve regeneration

Modulating inflammation is critical to enhance nerve regeneration after injury. However, clinically applicable regenerative therapies that modulate inflammation have not yet been established. Here, we demonstrate synergistic effects of the combination of an HMG-CoA reductase inhibitor, statin/fluvastatin and critical components of the extracellular matrix, Matrix-Bound Nanovesicles (MBV) to enhance axon regeneration and neuroprotection after mouse optic nerve injury. Mechanistically, co-intravitreal injections of fluvastatin and MBV robustly promote infiltration of monocytes and neutrophils, which lead to RGC protection and axon regeneration. Furthermore, monocyte infiltration is triggered by elevated expression of CCL2, a chemokine, in the superficial layer of the retina after treatment with a combination of fluvastatin and MBV or IL-33, a cytokine contained within MBV. Finally, this therapy can be further combined with AAV-based gene therapy blocking anti-regenerative pathways in RGCs to extend regenerated axons. These data highlight novel molecular insights into the development of immunomodulatory regenerative therapy.

Lock, stock, and Leuconostoc: an unusual presentation of a rare pathogen

Leuconostoc mesenteroides is a Gram-positive bacterium in the Lactobacillaceae family. This species is rarely encountered clinically and in the past was regarded as a contaminant when cultured. Recently it is being recognized as a pathogen responsible for opportunistic infections in immunocompromised patients. Compared to other Gram-positive cocci, Leuconostoc spp. carry intrinsic resistance to vancomycin. It is not common for clinical microbiology laboratories to isolate this organism and instead incorrectly report enterococcus and streptococcus organisms. Here, we present a case of bacteremia resulting in febrile illness and pneumonia in an 81-year-old woman with a history of rheumatoid arthritis and a notable lapse between immunomodulator therapy exposure. She was successfully treated when this organism was identified, and her antibiotic therapy was switched from vancomycin to ampicillin-sulbactam. This case highlights the importance of considering L. mesenteroides as a source of infection in patients predisposed to an immunocompromised state despite this organism’s being a rare pathogen. Keywords: Leuconostoc mesenteroides, rheumatoid arthritis, immunomodulators; vancomycin resistance

Efficacy and tolerability of subcutaneous repository corticotropin injection in refractory ocular inflammatory diseases

Abstract Background Repository corticotropin injection (RCI) has been suggested to exert immunomodulatory and anti-inflammatory effects in ocular inflammation. The index retrospective study aimed to evaluate the efficacy and tolerability of subcutaneous RCI in patients with active scleritis or uveitis. Main body Medical records of patients who were diagnosed with different types of active scleritis or uveitis and received RCI for more than six months at a tertiary eye center were reviewed. Patient characteristics including age, sex, comorbidities, clinical findings, treatment details, and adverse events were recorded. A total of 17 eyes of 17 patients were included. Median age was 43 years old and 53% of patients were male. Mean treatment duration was 25.4 ± 15.5 months. Indications for RCI therapy were scleritis (7 anterior and 1 posterior) (47.8%), panuveitis (17.4%), retinal vasculitis (17.4%), chronic/recurrent anterior uveitis (13%), and posterior uveitis (4.35%). RCI was initiated at a dose of 40 to 80 units 3 times weekly. Given the adequate control of inflammation, RCI was successfully discontinued in four patients (23.5%). Prior to RCI therapy, 14 (82.3%) patients were on oral prednisone at an average of 10 mg daily (range 2.5–40 mg), and two (11.7%) patients discontinued prednisone immediately before initiating RCI due to side effects. After six months of therapy, the prednisone dose was reduced in four (23.5%) patients to an average of 3 mg daily (range 1–5 mg) and was stopped in eight (53%) patients. Concomitant immunomodulatory therapies (IMTs) included mycophenolate mofetil (23.5%) and methotrexate (23.5%), and adalimumab (23.5%). Ten patients were on IMTs prior to using RCI, and during the course of treatment, IMT was stopped in two patients and reduced in one. Side effects included insomnia (23%), hypertension (11.7%), lower extremity edema (11.7%), hyperglycemia (11.7%), weight gain (11.7%), and infection (5.8%). Conclusion RCI may be considered as a potential therapy with acceptable tolerability for patients with non-infectious scleritis or uveitis.

The dysfunction of complement and coagulation in diseases: the implications for the therapeutic interventions.

The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.

Efficacy and safety of rituximab in the treatment of pediatric myasthenia gravis

Objective: To evaluate the efficacy and safety of rituximab in pediatric myasthenia gravis (MG). Methods: Case series study. The clinical manifestations, laboratory tests, treatment plans and prognosis of 27 pediatric MG patients treated with rituximab from June 2013 to June 2023 at Children's Medical Center of Peking University First Hospital were retrospectively collected. Results: There were 5 males and 22 females in 27 MG children. The onset age was 2.1 (1.6, 4.8) years, ranging from 8 months to 11 years. The clinical classification included 20 children (74%) of ocular MG and 7 children (26%) of generalized MG. Seventeen children (63%) had positive MG-related pathogenic antibodies, including 17 children of anti-AchR antibody and 1 of them also had anti-MuSK antibody. Rituximab was used as first-line immunosuppressant in 13 children, second-line immunosuppressant in 13 children and third-line immunosuppressant in 1 child. Immunosuppressants used before rituximab including 8 children of cyclosporine, 3 children of tacrolimus, 1 child of azathioprine, 1 child of mycophenolate mofetil and 1 child of cyclosporine combined with azathioprine. Rituximab was used for at least half a year with a follow-up period of more than 12 months. At the last follow-up after rituximab treatment, all children achieved improved or above, 14 children (52%) achieved complete stable remission, 7 children (26%) achieved pharmacologic remission, 1 child (4%) achieved minimal manifestations, and 5 children (18%) improved. After rituximab treatment, 27 children all could reduce the immunomodulation therapy and shorten the course of glucocorticoid therapy, and 22 children (81%) had stopped the glucocorticoid therapy. Among the 14 children with poor efficacy of other immunosuppressants, rituximab had complete stable remission of 7 children. The most common adverse reaction was respiratory infection (4 children (15%)). Only 2 children had allergic reaction to rituximab and got better after symptomatic treatment. Conclusions: Rituximab has good efficacy and tolerance in pediatric MG. Early application of rituximab can improve the prognosis and shorten the course of glucocorticoid treatment.

Blinded independent central review versus local investigator assessment of PFS in RCTs of immunotherapy in advanced cancers: A systematic review and meta-analysis

BackgroundAssessment of Progression-free survival (PFS) events by investigators might be inaccurate in randomized controlled trials (RCTs) with open-label design. We explored differences in PFS evaluated by blinded independent central review (BICR) or local investigator assessment (IA) in trials testing immunotherapy (IO) in advanced cancers. MethodsWe systematically reviewed articles of RCTs investigating IO in advanced tumors, published in PubMed-indexed journals up to December 2023. For each RCT, we collected PFS results by BICR and by local IA. We calculated the discrepancy index (DI) as the ratio of BICR and IA Hazard Ratios (HRBICR/HRIA) for PFS. An overall DI and relative confidence interval (CI) were calculated using a fixed-effect model weighted for the inverse of variance. FindingsOnly 32/140 (22.9 %) RCTs reported both BICR and local IA PFS data, including 17,054 patients. PFS was the sole primary endpoint in 19/32 (59.4 %) and a co-primary endpoint 9/32 (28.2 %) trials. The study design was open label or double-blind in 17/32 (53.1 %) and 15/32 (46.9 %) RCTs, respectively. The overall DI was 1.07 (95 % CI 1.01–1.13; I2 =0, p = 0.02), revealing a more optimistic analysis of results in favor of local IA. In the 17 open-label trials, the overall DI was 1.09 (95 % CI 1.02–1.17, I2 =0, p = 0.02), revealing a more favorable interpretation of PFS results by local investigators. InterpretationWe found a statistically significant difference between BICR and local IA of PFS in trials of IO in cancer. These results suggest that the double assessment is recommended in RCTs testing IO, especially in open-label trials. FundingThis work was supported by the MFAG27826–2022 grant (Dr. Alberto Servetto).

Molecular mechanisms of resistance and new therapeutic approaches in the treatment of colorectal cancer - a review of the literature

CRC occupies one of the leading positions among gastrointestinal malignancies and is a significant problem in Europe since it is the third most frequently diagnosed cancer. Recent developments in diagnostic techniques have led to higher chances of early diagnosis and survival; nevertheless, CRC is highly likely to relapse in the survivorably younger individuals. The importance of the current chemotherapy treatment and potential key therapeutic targets are identified in this review so that the molecular alterations causing drug resistance in CRC can be studied.Current literature formed the basis of this review by reviewing the molecular processes that underlie CRC, with emphasis on the mutational alterations in genes such as SENP1, KRAS, APC, TP53, and BRAF that play critical roles in CRC and resistance to treatment. Chemotherapy for CRC, targeting therapies, and immuno therapies have been discussed particularly with reference to their effectiveness for treatment and overcoming resistance.Genomic alterations in some important genes are involved in the onset of CRC and also determined the response to therapies. The KRAS mutations are associated with the resistance to EGFR inhibitors; however, BRAF mutations require BRAF/MEK inhibitors. Lack of MMR system SSR as a trigger for MSI-H status suggests a better response to immunotherapies. In addition, new molecules including SENP1, which involved the DNA repair pathway, and combination using CDK4/6 inhibitors are currently under development to overcome resistance and enhance the patients’ benefits.Colorectal cancer is still a problem, primarily because of its genetic character and high rates of recurrence. Even though chemotherapy and targeted therapies offer helpful results, the problem of resistance stands in the way. Subsequent studies should aim at symptomatic treatment outcomes and combine different drugs in order to enhance long-term treatment outcomes.

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.

Correction of immune disorders under the influence of pharmacotherapy and extracorporeal magnetic stimulation with patients after surgical treatment of prostate adenoma

BACKGROUND: The course of benign prostatic hyperplasia is associated with immunological disorders at the systemic and local level. Despite the wide arsenal of pharmacological agents for the treatment of benign prostatic hyperplasia, some patients undergo surgical treatment. Postoperative management programmes should be aimed at reducing the risks of complications, including infectious-inflammatory complications. In this regard, the inclusion of immunomodulatory pharmacotherapy and therapeutic physical factors in the course of reconstructive treatment is reasonable and justified. AIM: To study the role of the complex effect of pharmacotherapy and extracorporeal magnetic stimulation in the correction of immune disorders with the patients after surgical treatment of benign prostatic hyperplasia. MATERIALS AND METHODS: There have been observed 88 patients after surgical treatment of benign prostatic hyperplasia, who underwent a medical rehabilitation at stages II and III. At stage II 43 patients in the comparison group underwent standardized drug therapy, individual exercise therapy; in the main group 45 patients additionally were prescribed immunomodulatory therapy with Tameritis. At stage III the patients of the comparison group continued pharmacotherapy, exercise therapy, and transrectal magnetic therapy; in the main group 45 patients were additionally prescribed extracorporeal magnetic stimulation. A method of enzyme-linked immunosorbent assay was used to study the content of interleukins (IL); IPSS-QOL (International Prostate Symptom Score – Quality-of-Life) and SF-36 (The Short Form-36) were used to assess the quality of life. Confidence level (р) 0.05. RESULTS: After the second inpatient stage of rehabilitation the patients of the main group after surgical treatment of benign prostatic hyperplasia had a decrease the level of pro-inflammatory IL by 47.5% on average (p 0.01) with an increase in the level of anti-inflammatory IL-10 by 36.2% (p 0.01). After the III outpatient rehabilitation stage, a positive dynamics significantly increased and amounted to 63.2% (p 0.01) and 51.9% (p 0.01), reaching the normative values in the population. It should be noted that the achieved results have been preserved in a long time. In the comparison group the positive dynamics was significantly lower (p 0.05; p 0.01) in all the cases after the II and III stages of rehabilitation. The patients of the main group were observed a decrease in the severity of urinary disorders (p 0.01), restoration of quality of life (p 0.05) according to IPSS-QOL and SF-36 questionnaires at significant inter-group values (p 0.05) with the same confidence. CONCLUSION: The integrated use of pharmacotherapy and extracorporeal magnetic stimulation with the patients after surgical treatment of benign prostatic hyperplasia provides significant correction of immune disorders, restoration of physical and mental health.