Type Of Immunotherapy Research Articles

Immunohistochemical factors of prognosis of immunotherapy for metastatic melanoma: А prospective and retrospective study

Introduction. Anti-PD-1 immunotherapy (IT) is becoming the standard treatment for patients with metastatic melanoma. However, immune checkpoint inhibitors are only effective in a fraction of patients, and studies examining biological markers and their correlation with clinical efficacy are insufficient to draw unambiguous conclusions. Aim. To improve the outcomes of the first-line therapy for disseminated melanoma based on identifying clinical and immunohistochemical predictors of IT efficacy. Materials and methods. Data from 130 patients who were treated with immune checkpoint inhibitors (nivolumab or prolgolimab) in the first-line therapy for disseminated melanoma between 2017 and 2024 were analyzed. Results. Improvement was observed in 24 patients (18.4%): complete response in 18 patients (13.8%), partial response in 6 (4.6%), and stabilization in 71 (54.6%) patients. Progression was reported in 31 (24%) patients. Death occurred in 4 (3%) cases during IT with prolgolimab due to disease progression. The two-year disease-free survival (DFS) during IT was 53% (95% confidence interval [CI] 42–67), p=0.63; the median 2-year overall survival was not reached. In the immunohistochemical study, 47 (63.5%) patients had a predominance of tumor infiltration with CD8 lymphocytes over CD4, regardless of the IT type: 2-year DFS 82% (95% CI 70–96) vs 13% (95% CI 2.7–64) in the absence of CD8 predominance over CD4, p=0.0001; the median DFS was not reached in patients with the predominance of CD8 lymphocytes tumor infiltration over CD4 compared to the other group – 7.6 months in the absence of this feature (95% CI 5.8–0), p=0.001. The peritumoral location of the immune lymphoid infiltrate was observed in all 74 (100%) patients, and the intratumoral location was less common (52 patients, 70%). In the presence of both periand intratumoral location of the immune infiltrate, the 2-year DFS was 83% (95% CI 70–98) compared to the group of patients in whom no intratumoral location was detected – 5.5% (95% CI 0.8–36), p0.0001. The expression of programmed cell death ligand 1 (PD-L1) level 10% was observed in 47 (63.5%) patients. With this level of PD-L1 expression, the one-year DFS was 91% (95% CI 83–100) compared to 29% (95% CI 15–57) with a lower level of PD-L1 expression, p0.0001; the median DFS is reached, and in the group 2, DFS was only 6.6 months. In the case of PD-L110%, the 2-year DFS was high at 78% (95% CI 63–100), p0.0001. Conclusion. Based on the study's results, it can be assumed that immunohistochemical characteristics such as a PD-L1 expression level 10%, the simultaneous presence of periand intratumoral lymphoid tumor infiltration, and the predominance of CD8 over CD4 can be considered predictors of IT efficacy with nivolumab and prolgolimab.

Promising Therapeutic Impact of Immune Checkpoint Inhibitors in Type II Endometrial Cancer Patients with Deficient Mismatch Repair Status.

Type II endometrial cancer (EC) is responsible for most endometrial cancer-related deaths due to its aggressive nature, late-stage detection, and high tolerance to standard therapies. Thus, novel treatment strategies for type II EC are imperative. For patients with mismatch repair-deficient (dMMR) tumors, immunotherapy with immune checkpoint inhibitors represents a promising therapeutic strategy. However, the prevalence of dMMR tumors in type II EC patients remains unclear. In this study, using immunohistochemistry, we evaluated the expression of mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1) in 60 patients with type II EC (16, 5, 17, and 22 were endometrioid G3, serous, de-differentiated, and carcinosarcoma cases, respectively) to investigate the therapeutic effect of immune checkpoint inhibitors. Approximately 24 cases (40%) had a loss of MMR protein expression. The positivity rate of CD8+ (p = 0.0072) and PD-L1 (p = 0.0061) expression was significantly associated with the dMMR group. These results suggest immune checkpoint inhibitors (anti-PD-L1/PD-1 antibodies) could effectively treat type II EC with dMMR. The presence of dMMR might be a biomarker for a positive response to PD-1/PD-L1 immunotherapy in type II EC.

Antigen-specific immunotherapy to restore antigen-specific tolerance in Type 1 diabetes and Graves' disease.

Type 1 diabetes and Graves' disease are chronic autoimmune conditions, characterized by a dysregulated immune response. In Type 1 diabetes, there is beta cell destruction and subsequent insulin deficiency whereas in Graves' disease, there is unregulated excessive thyroid hormone production. Both diseases result in significant psychosocial, physiological, and emotional burden. There are associated risks of diabetic ketoacidosis and hypoglycaemia in Type 1 diabetes and risks of thyrotoxicosis and orbitopathy in Graves' disease. Advances in the understanding of the immunopathogenesis and response to immunotherapy in Type 1 diabetes and Graves' disease have facilitated the introduction of targeted therapies to induce self-tolerance, and subsequently, the potential to induce long-term remission if effective. We explore current research surrounding the use of antigen-specific immunotherapies, with a focus on human studies, in Type 1 diabetes and Graves' disease including protein-based, peptide-based, dendritic-cell-based, and nanoparticle-based immunotherapies, including discussion of factors to be considered when translating immunotherapies to clinical practice.

339 A serum exocrine enzyme as a biomarker of response to immunotherapy in type 1 diabetes.

OBJECTIVES/GOALS: We assessed the relationship between C-peptide preservation and a serum exocrine pancreatic enzyme (trypsin) in a recently concluded clinical trial. We hypothesized that immunomodulatory treatment resulting in improved beta-cell function would be associated with improved trypsin levels in subjects with recent-onset type 1 diabetes (T1D). METHODS/STUDY POPULATION: In a three-arm, randomized, double-masked, placebo-controlled trial 'Antithymocyte Globulin (ATG) and pegylated granulocyte colony stimulating factor (GCSF) in New Onset Type 1 Diabetes’ 89 subjects with recent-onset T1D (duration <100 days) were enrolled and randomized to 3 groups: low-dose ATG (2.5 mg/kg IV) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), low-dose ATG alone, and placebo. We compared longitudinal serum levels of an exocrine enzyme (trypsin) in a subset of responders to therapy (defined as subjects with at least 60% of baseline area under the curve (AUC) C-peptide levels at 96 weeks, n=4) versus placebo 'responders’ (n=2) and non-responders (n=25), and treated (n=19) versus placebo (n=12) subjects at baseline, 2 weeks, and 6 months after treatment. RESULTS/ANTICIPATED RESULTS: There was no observed difference in treated (n=20) versus placebo (n=12) longitudinal trends in trypsin levels when compared to baseline levels. However, responders to immunotherapy (n=4) had 6 month trypsin levels that were 114% of baseline whereas placebo subject 'responders’ (n=2), placebo subjects (n=10), and non-responders to immunotherapy (n=15) had trypsin levels that were 81-93% of baseline (unpaired T test p=0.05). Overall, we found that serum trypsin, a marker of exocrine pancreatic function, had a normal upward trend in new-onset T1D subjects who responded clinically to immunotherapy but declined in subjects who did not respond or who were not treated. These results were bordering on statistical significance but did not reach significance, likely due to the small sample size. DISCUSSION/SIGNIFICANCE: An improvement in trypsin, a marker of exocrine function, after response to immunotherapy in new-onset T1D may be due to a direct impact on exocrine function versus an indirect effect from improved beta cell function. Future studies will be needed to confirm our findings in a larger sample and evaluate the mechanism for improved exocrine function.

Nanotechnology in Immunotherapy for Type 1 Diabetes: Promising Innovations and Future Advances.

Diabetes is a chronic condition which affects the glucose metabolism in the body. In lieu of any clinical “cure,” the condition is managed through the administration of pharmacological aids, insulin supplements, diet restrictions, exercise, and the like. The conventional clinical prescriptions are limited by their life-long dependency and diminished potency, which in turn hinder the patient’s recovery. This necessitated an alteration in approach and has instigated several investigations into other strategies. As Type 1 diabetes (T1D) is known to be an autoimmune disorder, targeting the immune system in activation and/or suppression has shown promise in reducing beta cell loss and improving insulin levels in response to hyperglycemia. Another strategy currently being explored is the use of nanoparticles in the delivery of immunomodulators, insulin, or engineered vaccines to endogenous immune cells. Nanoparticle-assisted targeting of immune cells holds substantial potential for enhanced patient care within T1D clinical settings. Herein, we summarize the knowledge of etiology, clinical scenarios, and the current state of nanoparticle-based immunotherapeutic approaches for Type 1 diabetes. We also discuss the feasibility of translating this approach to clinical practice.

Safety of the use of gold nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in type 1 diabetes.

Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune β-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies

Immunotherapy for type 1 diabetes.

Despite advances in technology including the development of more sophisticated methods of monitoring blood glucose and delivering insulin, many individuals with type 1 diabetes continue to experience significant challenges in optimizing glycaemic control. Alternative treatment approaches to insulin are required. Increasing efforts have focused on developing treatments aimed at targeting the underlying disease process to modulate the immune system, maximize beta cell function and enhance endogenous insulin production and action. Literature searches with keywords 'Type 1 diabetes and immunotherapy', publications relating to clinical trials of immunotherapy in type 1 diabetes. Insulin therapy is insufficient to achieve optimal glycaemic control in many individuals with type 1 diabetes, and new treatment approaches are required. Studies have showed promising results for the use of immunotherapy as a means of delaying disease onset and progression. The optimal way of identifying individuals most likely to benefit from immunotherapies. A better understanding of the natural history of type 1 diabetes has made it possible to identify individuals who have developed autoimmunity but have not yet progressed to clinical diabetes, offering opportunities not only to develop treatments that delay disease progression, but prevent its development in the first place. A consensus on how to identify individuals who may benefit from immunotherapy to prevent disease onset is needed. The development of optimal strategies for preventing and delaying progression of type 1 diabetes, and monitoring the response to immunointervention.

Timing of Immunotherapy in Type 1 Diabetes: The Earlier, the Better?

In 1986, The New England Journal of Medicine published George Eisenbarth's (Eisenbarth. 1986. N. Engl. J. Med. 314: 1360-1368) model of type 1 diabetes (T1D) as a chronic autoimmune disease. In 2019, the same journal published the results of the teplizumab trial, which showed the anti-CD3 mAb delayed T1D progression in high-risk individuals. Although teplizumab is the first immunomodulatory agent to demonstrate significant delay in disease progression, it is also one of the few tested prior to clinical disease onset. Is it possible, then, that this trial's success is as much about the agent as it is about its timing? This commentary will review the landscape of immune intervention in T1D since 1986, discuss the teplizumab trial results, and finally, speculate on whether current paradigms for T1D immune intervention should focus less on disease development as a continuum and more on the stages of T1D progression as distinct disease processes.

60-LB: Dendritic Cells Engineered with Tailored Multiepitopes-Encoding mRNA as Precision Medicine for Immunotherapy of Type 1 Diabetes

Type 1 diabetes (T1D) is a complex autoimmune disease characterized by heterogeneity in genetic risk factors and immune profiles of patients and for which a cure or approved treatment is not yet available. Antigen-specific immunotherapy (ASIT) offers a targeted treatment of T1D that selectively inhibits autoreactive T cells. So far, ASIT trials showed limited efficacy, as only a subset of patients is responsive. Thus, approaches that consider the genetic and immunological heterogeneity of T1D patients to provide more tailored treatments are needed. Using mRNA encoding multiple epitopes tailored to the NOD mouse (model of T1D), we engineered bone marrow-derived dendritic cells (DCs) by mRNA electroporation (mRNA-DCs). The mRNA is designed to enable optimal presentation of epitopes to both CD4 and CD8 T cells. Antigen presentation persisted at least three days in vivo. Markers of anergy as well as IL-10 expression were found to be upregulated in antigen-specific CD4 and CD8 T cells after treating NOD mice with mRNA-DCs. T1D development was significantly suppressed with 3 biweekly treatments with 106 DCs containing 2 µg of antigen mRNA. Moreover, efficacy of the mRNA-DCs was enhanced when mRNAs encoding antigens and IL-27 were co-delivered into DCs by electroporation or when DCs were treated with rapamycin during differentiation. Endogenous expression of antigens may enable post-translational modifications and more prolonged presentation. Thus, we developed a promising and customizable ASIT platform to deliver multiple epitopes to exogenous tolerogenic DCs (or to endogenous APCs using a nanoparticle-based platform not covered here) that will consider the patient’s immune profile for a precision medicine treatment of T1D. Disclosure R. Fite: None. R. J. Creusot: None. Funding American Diabetes Association (1-19-PMF-022 to R.F.F.)

A century later, still fighting back: antigen‐specific immunotherapies for type 1 diabetes

Type 1 diabetes (T1D) is a chronic metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. Ever since the 1920s, the fate of patients suffering from T1D was dramatically improved owing to the isolation and production of insulin, and the scientific field has largely progressed as a result of the evidence gathered about its underpinnings and mechanisms. The last years have seen this knowledge transformed into actual antigen-specific immunotherapies with potential to restore selectively the breach of tolerance to β-cell autoantigens and halt the autoimmune aggression. However, so far, the results of both prevention and reversion trials in T1D have been rather discouraging, so there is still an urgent need to optimize those immunotherapies and their associated factors, for example, posology and administration patterns, route and timing. In this review, we look back on what has been achieved in the last century and identify the main autoantigens driving the autoimmune attack in T1D. Then, we take a deep dive into the numerous antigen-specific immunotherapies trialed and the ones still at a preclinical phase, ranging from peptides, proteins and agent combinations to gene transfer, nanoparticles, cell-based strategies and novel approaches exploiting naturally occurring tolerogenic processes. Finally, we provide insight into the several features to be considered in a T1D clinical trial, the ideal time point for intervention and the biomarkers needed for monitoring the successful regulatory effect of the antigen-specific immunotherapy. Although further research and optimization remain imperative, the development of a therapeutic armamentarium against T1D autoimmunity is certainly advancing with a confident step.

Immunogenomic classification of gastric cancer based on the tumor microenvironments expression of PD-L1 and CD8+ T-cell infiltration.

e16578 Background: Previous data has shown that a positive response to immunotherapy usually relies on active interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). The aim of this study was to classify gastric cancer (GC) subsets based on the TME immune status according to the expression of PD-L1 and infiltration of CD8+ T cells. Methods: One hundred and eighty-six tumor tissue from gastric cancer patients with a curative D2 gastrectomy were examined for evaluating PD-L1 and CD8+ T cells status using histopathologic analysis. The molecular characteristics of 289 GC samples in TCGA network were further analyzed to distinguish the genetic features of four immune subtypes depending on the presence of PD-L1/CD8+T cell. Results: GC samples were categorized into four types, type I (CD8+/PD-L1+, 60.3%), II (CD8-/PD-L1-, 11.8%), III (CD8-/PD-L1+, 0%), and IV (CD8+/PD-L1-, 27.9%), basing on PD-L1/CD8 expression. The PD-L1 expressing level was geographically associated with the intensity of CD8+ T cell infiltration which was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.003 and p = 0.006). Distinct patterns of genetic profile were described in four types of GC from TCGA database. Type I and III which PD-L1 were overly expressed had comparatively higher MSI and TMB, with EBV mainly enriched in Type I, whereas CIN was more likely to occur in PD-L1 aberrant types II and IV. SNV analysis illustrated higher gene mutations in oncogenes (PIK3CA and ERBB2), and in DNA damage repair related pathway, such as PRKDC, ATM, and SWI/SNF complexes (e.g. ARID1A) in Type I. However, TP53 mutations tend to enrich in Type II and IV. Similar results were obtained by transcriptome analysis. Conclusions: The genetic features of four immune subtypes proof that PD-L1 and CD8+ T cells status are reasonable immunogenomic classification of gastric cancer. SNV analysis prompts a potential mechanism for effectiveness of immunotherapy in Type I patients. Overall, the results may be useful for the development of clinical treatments for the blockade of immune checkpoints.

Sporadic Late Onset Nemaline Myopathy with a Monoclonal Gammopathy: Comparative Effectiveness of Immuno- and Chemotherapy

Introduction A rare subset of sporadic late-onset nemaline myopathy (SLONM) is associated with monoclonal gammopathy of unknown significance (MGUS). The role of monoclonal protein (M-protein) in SLONM is unknown, but SLONM with MGUS (SLONM+MGUS) demonstrates an aggressive disease course with severe muscular weakness, early development of respiratory failure, and is often fatal. Whether SLONM+MGUS represents a malignant or dysimmune disease remains unclear. Currently, two approaches are used to treat SLONM+MGUS: 1) immunosuppression ± plasmapheresis/exchange; or 2) chemotherapy (ChT) ± autologous stem cell transplantation (ASCT). Unfortunately, due to the rare occurrence of the disease, the best treatment modality is unknown. Methods We conducted a literature search to identify previous treatment modalities for patients diagnosed with SLONM+MGUS using PubMed, Elsevier, Medline, and CINAHL databases from 1975 to 2019. All publications were carefully reviewed to remove "duplicate" patients. Overall, 28 reports were included for the final analysis. Results We identified 38 unique patients diagnosed with SLONM+MGUS treated either with immunotherapy (IT) (n=19) or ChT ± ASCT (n=19). The median age was 49 years [range: 26-75] in the IT group and 47 years [range: 24-64] in the ChT group. There was a slight male preponderance in the IT group [n=14 (74%)] than in the ChT group [n=10 (53%)]. Similarly, more cases with kappa light chain restricted M-protein were observed in the IT group [n=12 (67%)] than in the ChT group [n=8 (42%)]. In the IT group, M-protein values were only reported in two patients (mean: 0.42 g/L), while M-protein values were reported for 14 patients in the ChT group (mean: 6.54 g/L). In the IT group 16 patients (84%) received steroids, 5 (26%) plasmapheresis, 10 (53%) steroid-sparing immunosuppressants (low dose cyclophosphamide, azathioprine, cytarabine, and mycophenolate mofetil), 2 (11%) rituximab, and 10 (53%) IVIG. Twelve (63%) patients received oral prednisone (mean dose: 67 mg) and 3 (16%) received pulse methylprednisolone (1 g). Patients received IT modalities sequentially or in parallel. Six patients (32%) received 1 and 13 patients (68%) received 2 or 3 (median = 2) IT types. Neurological improvement was observed in 10 patients, a 53% overall response rate (ORR) with 3 (16%) patients in complete remission (CR), and 7 (37%) patients in partial response (PR). No improvement or progression was observed in 9 (47%) patients (Figure 1). In 2 patients, neurological CR was associated with complete disappearance of M-protein. Mean time to best response was 19 months in a follow-up duration of 23 months. The ChT group included three categories: 1) 10 (53%) patients received ASCT with high dose melphalan (mean: 164 mg/m2); 2) 3 patients (16%) were treated with Cyclophosphamide/Bortezomib/Dexamethasone (CyBorD), cyclophosphamide/Thalidomide/Dexamethasone and Lenalidomide and Dexamethasone (Ld) chemotherapy without ASCT; and 3) 6 (31%) patients underwent induction chemotherapy with CyBorD (n=2) and Ld (n=4), followed by consolidative ASCT. Neurological improvement was achieved in 18 patients, a 94.7% ORR with CR in 14 (73.7%) and PR in 3 (21.0%) patients. Only one patient did not respond to therapy. The best neurological improvement correlated with disappearance of M-protein [complete hematological remission (CHR)]. Mean time to best response was 10 months, which was shorter than the IT group. Follow-up duration was 31 months. Conclusion Based on a comprehensive evaluation of existing treatment modalities for patients with SLOMN+MGUS we conclude that the best course of treatment is through consideration of the disease as a malignancy rather than a dysimmune disease. Our review supports that the best method of treatment entails ChT with or without of consolidative ASCT in the pursuit of eliminating the malignant plasma cell clone. In conjunction with nemaline myopathy presence of M-protein has clinical significance and it may be worth considering reclassifying SLONM+MGUS as SLONM with Monoclonal Gammopathy of Clinical (Neurological) Significance (SLONM+MGCS). Disclosures No relevant conflicts of interest to declare.

Circulating CXCR5\u2212PD-1hi peripheral T helper cells are associated with progression to type 1 diabetes

Aims/hypothesisType 1 diabetes is preceded by a period of asymptomatic autoimmunity characterised by positivity for islet autoantibodies. Therefore, T helper cell responses that induce B cell activation are likely to play a critical role in the disease process. Here, we aimed to evaluate the role of a recently described subset, C-X-C motif chemokine receptor type 5-negative, programmed cell death protein 1-positive (CXCR5−PD-1hi) peripheral T helper (Tph) cells, in human type 1 diabetes.MethodsThe phenotype of blood CXCR5−PD-1hi CD4+ T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5−PD-1hi T cells were analysed in a cohort of 44 children with newly diagnosed type 1 diabetes, 40 autoantibody-positive (AAb+) at-risk children and 84 autoantibody-negative healthy control children, and the findings were replicated in a separate cohort of 15 children with newly diagnosed type 1 diabetes and 15 healthy control children.ResultsCirculating CXCR5−PD-1hi Tph cells share several features associated with B cell helper function with circulating CXCR5+PD-1hi follicular T helper (Tfh) cells. Moreover, the frequency of circulating Tph cells was increased in children with newly diagnosed type 1 diabetes, especially in those who are positive for multiple autoantibodies. Importantly, circulating Tph cells were also increased in autoantibody-positive at-risk children who later progressed to type 1 diabetes.Conclusions/interpretationOur results demonstrate that circulating CXCR5−PD-1hi Tph cells are associated with progression to clinical type 1 diabetes. Consequently, Tph cells could have potential both as a biomarker of disease progression and as a target for immunotherapy in type 1 diabetes.

Analysis of the relationship between ratio N/L and survival in lung cancer patients treated with immunotherapy.

e14247 Background: The neutrophil-lymphocyte (N / L) ratio is a marker of general immune response in different stress situations, having shown a relationship between the quotient and the evolution of patients treated with immunotherapy (IT), emphasizing the importance of inflammation in these patients. Methods: In order to evaluate this relationship in a context of usual clinical practice, we performed a retrospective review of patients with pulmonary neoplasia who received IT treatment in the first line or successive, between November 2015 and December 2018, excluding those who received treatment within of clinical trial. Data were collected from the clinical history of each patient, with special attention to baseline neutrophil and lymphocyte numbers, objective response to therapy by criteria iRECIST 1.1 after 3 months of treatment and overall survival (OS) defined from the beginning of treatment until death by progression of the disease. Results: 92 patients (29 women and 63 men) with a median age of 64 years (44-79) were analyzed. 15 (16,3%) patients (p) received immunotherapy as first line treatment, 65.2% (60 p) received it as 2nd line and 18,5% (17 p) as 3rd or succesive lines. The average number of cycles received was 14 (1-52). Regarding the type of IT, 54 p (58,7%) received treatment with Nivolumab, 33 patients (36%) with Pembrolizumab and 5 patients (5.3%) were treated with Atezolizumab. Two stretches of baseline N / L ratios ≤5 (low) and > 5 (high) were defined. Low ratio N / L (≤5) was identified in 62p (67.4%) of the patients treated with IT and high ratio N/L ( > 5) in 30p (32,6%). Of the 62 patients with a low ratio: 41p (66.1%) had some type of response or stabilization of their disease, 13 patients (21%) had progression and 8 patients (12.9%) received less than three months of treatment, 6 patients for PS deterioration and the other 2 patients continue with the treatment and are pending reevaluation. Among the 30 patients with high N / L quotient: 7p (23.3%) presented response or stabilization of the disease, 23 patients (76,7%) presented progression or treatment was interrupted due to deterioration of the ECOG. The average survival in the group with a low N / L ratio (≤5) was 213 weeks compared to the group with a high N / L ratio ( > 5) 144 weeks (p < 0.05). Conclusions: The N / L ratio has been identified in some studies as an adverse prognostic factor in patients treated with IT. Our data from the usual clinical practice support this theory. If these findings are confirmed in future studies, it could be used as a response biomarker for better patient selection.

A future for CD3 antibodies in immunotherapy of type 1 diabetes.

A future for CD3 antibodies in immunotherapy of type 1 diabetes.

Advances in immunotherapy of type I diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting 3 million individuals in the U.S. The pathogenesis of T1DM is driven by immune-mediated destruction of pancreatic β cells, the source of glucose regulator insulin. While T1DM can be successfully managed with insulin replacement therapy, approaches that can modify the underlying immuno-pathology of β cell destruction has been long sought after. Immunotherapy can attenuate T cell responses against β cell antigens. Given the detailed cellular and molecular definitions of T1DM immune responses, rational immunomodulation can be and have been developed in mouse models, and in some instances, tested in humans. The possibility of identifying individuals who are predisposed to T1DM through genotyping lend to the possibility of preventive vaccines. While much has been accomplished in delineating the mechanisms of immunotherapies, some of which are being tested in humans, long-term preservation of β cells and insulin independency has not been achieved. In this regard, the drug delivery field has much to offer in maximizing the benefits of immune modulators by optimizing spatiotemporal presentation of antigens and costimulatory signals. In this review, we attempt to capture the current state of T1DM immunotherapy by highlighting representative studies.

Immunotherapy for type 1 diabetes: what’s in the pipeline?

Immunotherapy for type 1 diabetes: what’s in the pipeline?

Anti-IL-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes

Immunotherapy for type 1 diabetes (T1D) has previously focused on suppressing the autoimmune response against pancreatic beta cells to preserve endogenous insulin production and regulate glucose levels. With increased attention toward combination therapy strategies, studies indicate the multifunctional cytokine interleukin-21 (IL-21) may be a suitable target as an immuno-modulatory arm, while glucagon-like peptide-1 receptor (GLP-1R) agonists may be appropriate as a beta cell protective arm in combination therapy for T1D. We report here that treatment with anti-IL-21 monoclonal antibody delays diabetes onset in the spontaneous non-obese diabetic (NOD) and NOD.scid adoptive transfer models, while its effect in reversing recent-onset hyperglycemia is limited. However, the combination of anti-IL-21 plus the GLP-1R agonist liraglutide is effective in reversing established disease compared to either monotherapy in both the NOD and rat insulin promotor-lymphocytic choriomeningitis virus glycoprotein (RIP-LCMV-GP) models of autoimmune diabetes. Enhanced efficacy is particularly evident in severely hyperglycemic mice, with return to normoglycemia remaining stable for the majority of mice even after therapy is withdrawn. Importantly, increased beta cell proliferation does not appear to be the predominant mechanism. In conclusion, combination therapy with anti-IL-21 and liraglutide is able to consistently reverse disease in mouse models of T1D. The observed effects rival the most effective experimental disease-modifying treatments tested in preclinical studies.

Immunotherapy for Type 1 Diabetes: Why Do Current Protocols Not Halt the Underlying Disease Process?

T cell-directed immunosuppression only transiently delays the loss of β cell function in recent-onset type 1 diabetes. We argue here that the underlying disease process is carried by innate immune reactivity. Inducing a non-polarized functional state of local innate immunity will support regulatory Tcell development and β cell proliferation.

Impact of disease heterogeneity on treatment efficacy of immunotherapy in Type 1 diabetes: different shades of gray.

Type 1 diabetes results from selective destruction of insulin-producing pancreatic β-cells by a progressive autoimmune process. Type 1 diabetes proves very heterogeneous in pathology, disease progression and efficacy of therapeutic intervention. Indeed, several immunotherapies that appear ineffective for the entire treated patient population in fact look promising in subgroups of patients. It therefore seems inconceivable that one standard therapy will provide the golden bullet of disease intervention. Instead, personalized medicine may improve immune intervention efficacy rates. We discuss the effect of disease heterogeneity on treatment outcome of immunotherapies, identifying apparent gaps in our understanding of treatment efficacy in subgroups of Type 1 diabetic patients as well as identifying future opportunities for immunotherapy.