Additional Immunomodulatory Agents Research Articles

A Question of Tolerance-Antigen-Specific Immunotherapy for Type 1 Diabetes.

Antigen-specific immunotherapy (ASI) is a long sought-after goal for type 1 diabetes (T1D), with the potential of greater long-term safety than non-specific immunotherapy. We review the most recent advances in identification of target islet epitopes, delivery platforms and the ongoing challenges. It is now recognised that human proinsulin contains a hotspot of epitopes targeted in people with T1D. Beta-cell neoantigens are also under investigation as ASI target epitopes. Consideration of the predicted HLA-specificity of the target antigen for subject selection is now being incorporated into trial design. Cell-free ASI approaches delivering antigen with or without additional immunomodulatory agents can induce antigen-specific regulatory T cell responses, including in patients and many novel nanoparticle-based platforms are under development. ASI for T1D is rapidly advancing with a number of modalities currently being trialled in patients and many more under development in preclinical models.

Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME)

BackgroundThe efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and -low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors.MethodsDomatinostat was evaluated in PD-1 blockade-insensitive CTL-low (CT26) and CTL-high (C38) syngeneic models alone and in combination with different immune-inhibitory and -stimulatory approaches. Effects on the immunophenotype were assessed via flow cytometry and RNA-seq analyses. The changes in RNA-seq-based immune signatures determined in a murine setting were investigated in patient samples from the first-dose cohort of the SENSITIZE trial (NCT03278665) evaluating domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/nonresponding to PD-1 blockade.ResultsDomatinostat increased the expression of antigen-presenting machinery (APM) genes and MHC class I and II molecules, along with CTL infiltration, in tumors of both immune phenotypes. In combination with PD-(L)1 blockade, domatinostat augmented antitumor effects substantially above the effects of single-agent therapies, displaying greater benefit in tumors with pre-existing CTLs. In this setting, the combination of domatinostat with agonistic anti-4-1BB or both PD-1 and LAG3 blockade further increased the antitumor efficacy.In CTL-low tumors, domatinostat enhanced the expression of genes known to reinforce immune responses against tumors. Specifically, domatinostat increased the expression of Ifng and genes associated with responses to pembrolizumab and nivolumab.Clinically, these findings were confirmed in patients with advanced melanoma treated with domatinostat for 14 days, who demonstrated elevated expression of APM and MHC genes, the IFNG gene, and the IFN-γ and pembrolizumab response signatures in individual tumor samples.ConclusionIn summary, these data suggest a promising potential of domatinostat in combination with immunotherapy to improve the outcome of refractory cancer patients.

An Adult Case of Fisher Syndrome Subsequent to Mycoplasma pneumoniae Infection

Reported herein is an adult case of Fisher syndrome (FS) that occurred as a complication during the course of community-acquired pneumonia caused by Mycoplasma pneumoniae. A 38-yr-old man who had been treated with antibiotics for serologically proven M. pneumoniae pneumonia presented with a sudden onset of diplopia, ataxic gait, and areflexia. A thorough evaluation including brain imaging, cerebrospinal fluid examination, a nerve conduction study, and detection of serum anti-ganglioside GQ1b antibody titers led to the diagnosis of FS. Antibiotic treatment of the underlying M. pneumoniae pneumonia was maintained without additional immunomodulatory agents. A complete and spontaneous resolution of neurologic abnormalities was observed within 1 month, accompanied by resolution of lung lesions.

Juvenile dermatomyositis: recognition and treatment.

Juvenile dermatomyositis (JDM) is a multisystem disease characterized by acute and chronic lymphocytic inflammation of the skeletal muscle and skin. The disease is marked early in its course by the presence of a vasculopathy or vasculitis, and later by the development of calcinosis. Research has focused on the epidemiology, etiology, and pathogenesis of the disease with, until more recently, limited therapeutic interventions. This article highlights treatment regimens, both traditional and more recent interventions. Traditional treatment for JDM includes high dose corticosteroid treatment with additional agents used in resistant disease or children with unwarranted adverse effects. Traditional therapy begins with daily oral corticosteroids, with intravenous corticosteroids utilized in severe disease; however, recent data suggests that short-term use of intravenous corticosteroids will allow a short-term improvement in strength, with no long-term change in outcome. More recent investigations suggest that early intervention with additional immunomodulatory agents will allow for a faster recovery, with less medication and disease sequelae. Use of methotrexate as an agent early in the disease course is becoming common place. Methotrexate, in conjunction with oral corticosteroids, allows a rapid improvement in symptoms, and allows for a more rapid reduction in corticosteroid dose. Methotrexate is considered as a steroid sparing agent, whether oral or intravenous corticosteroids are used. Additional immunomodulatory agents include the use of cyclosporine with or without methotrexate. Intravenous immunoglobulin has been reported to have benefit in resistant disease. There are exciting new agents which have great potential in treating JDM. Many of these agents are termed biologics and are being tested in adult myositis and juvenile arthritis. These include tumor necrosis factor (TNF)-alpha inhibitors, such as a chimeric monoclonal antibody to TNF-alpha, and a recombinant soluble human TNF receptor (p75)-Fc fusion protein. Many other new biological agents are also being tested in myositis.