Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia
6-10% of patients with AML encounter mutations in IDH1 which is a metabolic enzyme catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate. Those patients with IDH1 mutations have been associated with an adverse prognosis and relapse after standard therapy. In this study, Gail J. Roboz et al. observed that Ivosidenib (IDH1 inhibitor) monotherapy resulted in a promising response rate and significant clinical benefits in patients with newly diagnosed AML who were ineligible for standard therapy (chemotherapy) based on advanced age and/or comorbidities.
Blood, 13 February (2020)
Specific stimulation of T lymphocytes with erythropoietin for adoptive immunotherapy
In adoptive T-cell immunotherapy, expansion and persistence of the infused cells determine the clinical efficacy. Several factors can influence proliferation and the lifespan of infused T cells, such as erythropoietin (Epo). N. Vinanica et al. showed that expression of mutant Epo receptors on T cells can convert Epo into a growth factor for T cells, supporting their expansion and enhancing their antitumor activity. However, the effect of Epo can be abolished with ruxolitinib (JAK inhibitor), which allows tuning for adoptive T-cell number in vivo.
Blood, 27 February (2020)
Omeprazole inhibits IgE-mediated mast cell activation and allergic inflammation induced by ingested allergen in mice
Omeprazole, a proton pump inhibitor, reduces esophageal mast cells and inflammation in patients with eosinophilic esophagitis. However, its effect on mast cell function has not yet been depicted. C. Kanagaratham et al. demonstrated that murine and human mast cells treated with Omeprazole exhibited diminished IgE-mediated mast cell degranulation, and releases cytokines and histamine in response to allergens. Phosphorylation of protein kinases and an inhibition of calcium flux into the cytosol were also observed after Omeprazole treatment. Overall, this study has established that Omeprazole can interfere with pathways involved in mast cell differentiation and activation, as well as in allergic inflammation.
The Journal of Allergy and Clinical Immunology, 16 March (2020)
Vaccine against peanut allergy based on engineered virus-like particles displaying single major peanut allergens
Peanut allergy frequently and widely affects our society. Current treatment by oral immunotherapy is effective, but time consuming and potentially dangerous for a patient with severe peanut allergy. This preclinical study aims to test vaccine candidates for peanut allergy. The vaccines are based on plant Cucumber mosaic virus-derived VLPs coupled either to roasted peanut extract or to one of the main allergens (Ara h1 or Ara h 2). Vaccination against a single allergen was sufficient to create protection against the whole peanut extract by inducing specific IgG antibodies, diminishing local reaction, and reducing eosinophil and mast cell infiltration of the gastrointestinal tract.
The Journal of Allergy and Clinical Immunology, 1 April (2020)
A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance
Decline in the discovery of new antibiotics coupled with an increase in antibiotic resistance is a known concern. Therefore, finding an antibiotic killing both gram-positive and -negative bacteria through 2 independent mechanisms with low resistance frequencies would be a promising approach to target bacteria. SCH-79797 and Irresistin-16 are 2 potential compounds which impact bacterial membrane integrity and inhibit folate biosynthesis. To improve efficacy, James K. Martin II et al. designed a derivative based on SCH-79797, Irrestin-16, which showed increased potency and was efficient against Neisseria gonorrhoeae.
Cell, 25 June (2020)
BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner
The antituberculosis vaccine, Bacillus Calmette-Guérin (BCG) induces the innate immune memory against heterologous infections. However, the immune status after BCG vaccination is not known. After investigating the impact of BCG vaccination on systemic inflammation in a cohort of 303 healthy volunteers, BCG vaccination seemed to enhance cytokine production capacity, but dampen systemic inflammation. This reduction in inflammation after BCG vaccination was much stronger in men than in women. This study shows that understanding the vaccines ability to induce trained immunity and to affect systemic inflammation, as well as its working in different sexes may help optimize vaccine efficacy.
The Journal of Clinical Investigation, 21 July (2020)
Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity
T-cell-mediated immunity is suppressed by the programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) pathway. Currently, monospecific antibodies against either PD-1 or PD-L1 are used in the clinics. Here, M. Malabunga, H. Kotandies et al. show that co-targeting PD-1 and PD-L1 with a bispecific antibody could provide enhanced antitumor activity in preclinical studies.
Cancer Immunology Research, 27 July (2020)
Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus
Daratumumab is a monoclonal antibody targeting CD38 found on the surface of plasma cells. It is an approved treatment for multiple myeloma where it depletes plasma cells. Systemic Lupus Erythematosus is an autoimmune disease in which autoantibodies are secreted by plasma cells which attacks its own tissues, eventually leading to widespread inflammation. This study reports the cases of 2 patients refractory to previous immunosuppressive and B-cell-directed therapies who received Daratumumab as treatment. Daratumumab significantly reduced autoreactive plasma cells, interferon type I and modulated effector T-cell responses associated with chronic inflammation. All these effects were associated with an amelioration of disease manifestation.
The New England Journal of Medicine, 17 September (2020)
Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients
Combining radiation and immunotherapy has shown promising response rates and prolonged survival, due to enhanced human antitumor immunity. Here, J. Chow et al. have evaluated the impact of radiation within the tumor microenvironment, including intratumoral T cells in renal cell carcinoma patients. It seems that radiation promotes the peripheral expansion of tumor-resident T cell clones. Data from this study shows the dynamics of tumor-enriched clone expansion and contraction following radiation. Radiotherapy remodels intratumoral T cell responses, offering a rationale for combination strategies to improve patient outcome.
PNAS, 22 September (2020)
Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis
Eosinophilic Gastritis and Duodenitis are chronic inflammatory diseases characterized by gastrointestinal symptoms and eosinophilic infiltration of the gastrointestinal tract. Siglec-8 is an inhibitory receptor expressed mainly on mature eosinophils and mast cells. An anti-Siglec-8 antibody (AK002) used in this phase 2 trial with eosinophilic gastritis and/or duodenitis patients depleted eosinophils in gastrointestinal tissues and inhibited mast-cell activity, making it a potential therapeutic candidate for eosinophilic gastritis and duodenitis, as well as for other allergic and inflammatory conditions. Phase 2/3 trials involving patients with eosinophilic esophagitis are currently in progress.
The New England Journal of Medicine, 22 October (2020)
TOLLIP deficiency is associated with increased resistance to Legionella pneumophila pneumonia
Legionella pneumophila (Lp) is a flagellated, intracellular bacterium that can cause Legionnaires’ disease. Toll-Interacting Protein (TOLLIP) regulates many innate immune processes and dampens MyD88-dependent signaling, which could influence susceptibility to LD. After aerosol Lp infection, Tollip−/− mice showed significantly fewer bacterial colony-forming unit. They also increased cytokine responses from BAL fluid; there, macrophages suppressed intracellular Lp replication in a flagellin-independent manner. Altogther, these results could represent a novel understanding of Legionella pneumophila infection and permit the development of novel immunomodulatory therapies.
Mucosal Immunology (August 2019)
Progranulin deficiency confers resistance to autoimmune encephalomyelitis in mice
Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing, pathogen removal, and autoimmunity. Patients with multiple sclerosis (MS) have high levels of circulating progranulin. When depleted pharmacologically in mice, subjects develop MS-like experimental autoimmune encephalomyelitis (EAE). However, progranulin-deficient mice (Grn−/−) were resistant to EAE. Data revealed a loss of MHC-II-positive antigen-presenting cells in Grn−/− mice as well as a reduction in the number of CD8+ and CD4+ T-cells. Hence, results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.
Cellular and Molecular Immunology (August 2019)
PD-1hi CD8+ resident memory T cells balance immunity and fibrotic sequelae
CD8+ tissue-resident memory T (TRM) cells provide frontline immunity in mucosal tissues, although the mechanism leading to their maintenance, heterogeneity, and pathological behavior is mostly unknown. Using influenza virus (IAV) as a model, Wang et al. have examined the ability of CD8+ T cells recognizing two epitopes of IAV. They found that NP366–374-specific TRM cells express higher levels of PD1 and become more exhausted-like when compared with PA224–233-specific TRM, allowing reactivation upon reinfection. Ultimately, maintaining the cells in this statement prevented inflammation-induced lung fibrosis
Science Immunology (June 2019)
Low-dose interleukin-2 therapy in refractory systemic lupus erythematosus: an investigator-initiated, single-centre phase 1 and 2a clinical trial
Acquired deficiency of interleukin-2 (IL-2) and related defects in regulatory T cell homeostasis were shown to play a role in the pathogenesis of systemic lupus erythematosus. Patients with lupus were supplemented using low-dose recombinant human IL-2 (aldesleukin) four cycles of 5 days followed by a 9–16 days rest. Interestingly, 100% of patients saw their proportion of CD25hi-expressing cells among circulating CD3 + CD4 + FOXP3 + CD127lo regulatory T cells increase after treatment. Therefore, IL-2 treatment resulted in a preferential proliferation of regulatory T cells that retained suppressive capacity.
Lancet Rheumatology (September 2019)
Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target
Malaria still kills nearly 500,000 people per year and infects more than 200 million individuals globally. PfCLK3 plays a key role in RNA splicing of the pathogen. By screening a library of nearly 30,000 compounds, the authors identified a probe molecule that selectively inhibited PfCLK3 and killed blood-stage P. falciparum. Because of the high degree of homology between orthologs of CLK3 in other Plasmodium species, the approach was shown to also affect P. vivax and P. berghei as well as killing the blood stages of P. berghei and P. knowlesi. Therefore, CLK3 could be a prophylactic, curative, and transmission-blocking potential target against malaria.
Science (August 2019)
Oncolytic Viruses Engineered to Enforce Leptin Expression Reprogram Tumor-Infiltrating T Cell Metabolism and Promote Tumor Clearance
Oncolytic viruses’ immunotherapy might be the solution to overcome the failure to recruit T cells to the tumors when treating with single-agent immunotherapies. Rivadeneira et al. demonstrate that engineered oncolytic viruses expressing a metabolic modulator such as adipokine leptin are improving T cell metabolic functions in the tumor microenvironment, leading to a better antitumor response. Leptin expressing oncolytic viruses do not only lyse tumor cells, but also have the capacity to remodel the tumor immune microenvironment by promoting the infiltration of new T cells and thus allowing for a better therapeutic response. This study is a proof of concept that metabolic modulators can be delivered by oncolytic viruses directly to the tumor microenvironment to promote metabolic reprogramming of tumor-infiltrating lymphocytes.
Immunity (August 2019)
PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance
Only a subset of patients is responding to anti-PD-1 and PD-L1 antibodies. To overcome such resistance, strategies using anti-PD-1 or anti-PD-L1 antibodies in combination with immune-activating agents, such as vaccines, are being developed. Here, the authors report a new mechanism of resistance to anti-PD-1 therapy. They showed that the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade under unprimed or suboptimally primed CD8+ T cell conditions induced a dysfunctional PD-1+Cd38hi phenotype, rending mice resistant to further anti-PD-1 therapy. However, this induction of dysfunctional CD8+ T cells by these tumors could be reversed if mice were optimally primed at the time of tumor implantation. Therefore, PD-1+ CD28hi CD8+ cells can serve as a predictive and therapeutic biomarker for anti-PD-1 treatment.
Nature Immunology (September 2019)
Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell–Mediated Inflammation and Immunosuppression
Immune-checkpoint protein V-domain immunoglobulin suppressor of T-cell activation (VISTA) has a role in regulating TLR signaling in myeloid cells and controlling myeloid cell-mediated inflammation and immunosuppression. Production of proinflammatory mediators are increased and T cell-suppressive functions are decreased when VISTA is blocked. VISTA could be a critical immune-checkpoint protein in myeloid cell.
Cancer immunology Research (September 2019)
Overexpression of B7-H3 as an opportunity for targeted therapy in head and neck cancers
Current treatments for head and neck cancers (HNCs) such as surgery, radiotherapy, chemotherapy or combined therapy are aggressive and costly. B7-H3 expression is upregulated in various cancers like hypopharyngeal carcinoma and oral cancer. The correlation of B7-H3 expression in HNCs with clinicopathological variables was investigated and the efficacy of anti-B7-H3xCD3 biAbs was assessed. Anti-B7-H3xCD3 biAbs suppress the growth of tumors in mouse xenografts and prolonged the survival of the mice. Therefore, by having a frequently overexpressed B7-H3 in HNCs, B7-H3 might be a promising therapeutic target for biAb therapy.
American Journal of Translational Research (August 2019)
Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis
Immunotherapy is an important treatment for cancer and has shown to be beneficial pertaining to the survival of patients in different cancer types. Immune checkpoint inhibitors (ICI) can cause increased T-cell activation and effective antitumor immune responses. However, this treatment is also associated with serious immune-related adverse effects. One of the most common toxicities is ICI-associated colitis. It has been demonstrated that ICI-associated colitis significantly changes gut microbiota. Wang and colleagues treated two ICI-associated colitis patients with fecal microbiota transplantation (FMT). Their results suggest that FMT might be a novel treatment for ICI-associated colitis, since both cases showed significant and rapid improvement.
Nature, 12 November (2018)
Therapeutic treatment of Zika virus infection using a brain-penetrating antiviral peptide
Zika virus is a mosquito-borne virus that can cause neurodegenerative diseases. Jackman and colleagues developed an antiviral peptide able to cross the blood-brain barrier, which might work also in other mosquito-borne viruses than Zika. The therapeutic treatment was tested in mice and reduced mortality, viral loads and clinical symptoms, it lowered neuroinflammation, neurodegeneration and brain damage.
Nature, 22 October (2018)
Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis
Ibrutinib is a small molecule Bruton tyrosine kinase (Bkt) inhibitor and is approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia among others. However, aspergillosis is often observed following treatment with this drug. Bkt is critical for endosomal signaling during murine macrophage phagocytosis of Aspergillus fumigatus. Bercusson et al. show that Ibrutinib is a potent inhibitor of both NFAT and NF-kB responses in human macrophage Bkt phosphorylation. An Bkt depletion impairs these responses in human macrophages to A. fumigatus, which results in impaired neutrophil recruitment. This mechanism may increase the susceptibility of invasive aspergillosis in patients treated with Ibrutinib.
Blood, 1 November (2018)
Antibiotics induce sustained dysregulation of intestinal T cell immunity by perturbing macrophage homeostasis
Antibiotics are a common treatment for bacterial infections, however they not only act on the bacteria themselves. Scott and colleagues investigated the effect of antibiotics on the immune system in mouse models. They showed that intestinal macrophages become hyperresponsive to bacterial stimulation after treatment with antibiotics, and produce an excess of inflammatory cytokines. This excess of cytokines polarizes CD4+ T cells to become TH1 cells. Subsequently, these mice were more susceptible for infections that require other types of effector T-cells, like TH17 and TH2 cells. Administration of the short chain fatty acid burytate restored the hyper responsiveness of intestinal macrophages and prevented the switch to TH1 cells.
Science translational medicine, 24 October (2018)
Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma
Peripheral T-cell lymphomas (PTCLs) can result from malignant transformation of mature T-cells or natural killer cells. PTLCs deriving from T follicular helper cells like angio-immunoblastic T-cell lymphoma (AITL) appear to be frequent. Patients with AITL have a poor prognosis with a median overall survival of 6 months. Currently there are three approved drugs on the market; Pralatrexate, Romidepsin and Belinostat, all showing only limited beneficial effects in PTCLs. Genetic mutations regulating cysteine methylations and hydroxymethylations, causing changes in DNA methylation levels were found frequently in AITL patients (TET2, DNMTA3A and IDH2 in 80%, 25% and 25% respectively). Treatment with hypomethylating agents, like 5-azacytidine and decitabine, might be effective in these diseases. Lemonnier and colleagues treated patients with 5-azacyticine for 7 days every 28 days. The treatment was well tolerated, 75% of the patients showed a response. This might be a breakthrough in treatment of AITL patients.
Blood, 22 November (2018)
Imatinib stimulates prostaglandin E2 and attenuates cytokine release via EP4 receptor activation
Imatinib is an effective treatment for different forms of leukemia with a constitutively active protein kinase BCR-ABL. Besides the treatment for leukemias, Imatinib also was shown to have a beneficial effect in rheumatoid arthritis and asthma. Bärnthaler et al. were interested in the effect of Imatinib on prostanoid synthesis, especially prostaglandin E2 (PGE2). PGE2 inhibits immune responses via EP4 activation by inducing cytokine and chemokine expression and promoting a shift of TH1 to a TH2 response. They showed that Imatinib causes an increase in PGE2 in vitro and in vivo. The effects of Imatinib are downregulation of inflammatory cytokines, decreased inflammatory cell infiltration and less edema formation.
The Journal of Allergy and Clinical Immunology, 15 October (2018)
New application for an old drug
Despite the fact that several therapies have been approved for relapsing multiple sclerosis, only two therapies are currently used for the treatment of progressive multiple sclerosis. A recent report by Fox R.J. et al. on a phase II clinical trial identifies Ibudilast, a small molecule used in Asian countries for the treatment of asthma and stroke, as a possible alternative to treat patients with progressive multiple sclerosis. In a randomized study, over a period of 96 weeks, the patients treated with Ibudilast exhibited slower progression of brain atrophy compared to placebo, corresponding to approximately 2.5ml less brain-tissue loss. New trials are still required to confirm the effects of Ibudilast in slowing brain atrophy, however this initial report suggests it could be a promising alternative to treat patients suffering from progressive multiple sclerosis.
The New England Journal of Medicine, August 30 (2018)
Efgartigimod: an alternative treatment for autoimmune diseases
Autoimmune diseases are caused by a failure that renders the immune system incapable to distinguish between self- and non-self-antigens. In several autoimmune disorders autoreactive immunoglobulins (i.e. IgG) play a key role in the disease pathology. Current strategies to treat these diseases include IgG replacement therapy (IVIg), immunoadsorption or plasmapheresis. However, the adverse effects and high costs of such strategies make the search for new treatment tools attractive. In a recent publication, Ulrichts P. et al. explore the use of efgartigimod, a human IgG1-derived Fc fragment with increased affinity for FcRn, to reduce the serum IgG levels in cynomolgus monkeys and healthy human volunteers. The inhibition of FcRn by efgartigimod was shown to induce a fast, specific and long lasting reduction of IgG serum levels, making it an interesting alternative for the elimination of pathogenic IgGs.
The Journal of Clinical Investigation, July 24 (2018)
Targeting IL-4 receptor to treat uncontrolled asthma
Nearly 20% of the asthma patients suffer from uncontrolled, moderate-to-severe disease. These patients have increased risk of illness and reduced lung function. Asthma is characterized by elevated levels of type 2 inflammation, with secretion of cytokines such as interleukin-5 (IL-5), IL-4 and IL-13. In a recent phase III clinical trial Castro M. et al. use the monoclonal antibody Dupilumab, which binds to the a subunit of the IL-4 receptor, blocking IL-4 and IL-13 signaling, to treat patients diagnosed with persistent asthma. In the trial, the patients that were treated with Dupilumab had lower rate of severe asthma exacerbations, no loss of lung function and reduced biomarkers of type 2 inflammation like serum IgE. No severe adverse effects were observed.
The New England Journal of Medicine, June 28 (2018)
Killing two birds with one stone
One of the most effective treatments to relieve severe pain is the use of opioids. They mediate their functions by activation of the mu opioid peptide (MOP) receptor. Unfortunately, MOP activation generates a variety of adverse effects (e.g. respiratory problems, hyperalgesia and addiction); therefore, new pain relieving strategies are needed. To this end, Ding H. et al. have developed a novel bifunctional agonist that targets MOP receptor and another opioid receptor subtype, the nociceptin/orphanin FQ peptide (NOP) receptor. The new agonist called AT-121, showed potent analgesic effects in non-human primates with no reinforcing impact or physical dependence and did not cause opioid-induced hyperalgesia. These results suggest that AT-121 could be used as a pain-killer treatment, but more research is required to pave the way to routine clinical use.
Science Translational Medicine, August 29 (2018)
Inhibiting tyrosine kinases in psoriasis
Psoriasis is a chronic immune disorder for which the etiology is not fully understood, but several cytokines (e.g. IL-12, IL-23 and interferons among others) play a key role in the uncontrolled proliferation of epidermal keratinocytes. Tyrosine kinase 2 (TYK2) is a mediator of the intracellular signaling pathways related to the cytokine storm observed in psoriasis, which makes it an attractive target for treatment of the disease. A recent phase II clinical trial by Papp K. et al. reports that the oral administration of the TYK2 inhibitor BMS-986165 has a beneficial effect in patients with psoriasis. The administration of BMS-986165 resulted in a greater clearing of psoriasis lesions during the 12-weeks period of the trial.
The New England Journal of Medicine, October 4 (2018)
Antibodies to reduce the HIV viral reservoir
Viral rebound in HIV infected patients that stop antiretroviral therapy (ART) is caused fundamentally by the viral reservoir in CD4+ T cells. While many efforts are currently made to find a cure for HIV there is no evidence that these strategies target the viral reservoir. To explore this possibility Borducchi E.N. et al. evaluated the capacity of the neutralizing antibody PGT121 and vesatolimod (GS-9620), a TLR7 agonist, to target the viral reservoir in rhesus monkeys after ART. The combination of the neutralizing antibody with stimulation of the innate immune system delayed the viral rebound with undetectable viral loads, suggesting a mechanism involving NK cell and monocyte-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) of the infected CD4+ T cells. Further investigation needs to be done to test this hypothesis in human subjects.
Nature, October 03 (2018)
Gut targeting to fight HIV
Gastrointestinal (GI) tract homing CD4+ T cells that express the a4b7 integrin are viral targets that contribute to HIV pathogenesis. Given their importance, anti-a4b7 therapy has been considered for treatment of HIV, however only studies in primates were previously done. A recent study by Uzzan et al. reports the possibility to target HIV infected CD4+ T cells with vedolizumab (VDZ), an anti-α4β7 antibody, currently used for the treatment of ulcerative colitis and Crohn’s disease. The patients involved in the study showed reduced naïve CD4+ T cells and a decrease in activated CD4+ T cells in the terminal ileum. No serious adverse effects were observed in the involved patients. These results provide a rationale for future studies involving a4b7 targeting in HIV infections.
Science Translational Medicine, October 03 (2018)
Alternative treatment for relapsed and refractory CLL/SLL
Chronic lymphocytic leukemia (CLL) is a common lymphoproliferative disorder in adults. Chemotherapy and anti-CD20 antibodies have long been the therapeutic options utilized. However, due to the development of resistance or intolerance to current therapeutic methods, new treatment strategies are needed. A phase III study by Flinn I.W. et al. explores the possibility to use duvelisib, a dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and –γ, as a treatment option for patients with relapsed and refractory CLL/small lymphocytic lymphoma (SLL). The overall response rate as well as the lymph node response rate was higher in the duvelisib treated group when compared to ofatumumab (anti-CD20 antibody). In parallel, the patients involved in the study showed a reduction in the serum levels of chemokines and cytokines associated with malignant B cells. These results support the use of duvesilib as a potential treatment for patients with relapsed CLL/SLL.
Blood, October 04 (2018)
From brain to breath: Neuropeptide NMU worsens allergic lung inflammation
Type 2 innate lymphoid cells (ILC2s) are important players in the maintenance of mucosal homeostasis under normal physiological conditions, while they function as initiators of inflammation in the context of allergic asthma. The regulation of ILC2s under healthy and diseased conditions are however poorly understood. Wallrapp and colleagues demonstrate that the neuropeptide receptor Nmur1 was upregulated in lung infiltrating ILC2s in an allergic asthma mouse model and that the ligand peptide NMU worsened allergic responses. This work describes a novel interplay between players in neurological and immunological pathways in allergic asthma.
Nature, September 21 (2017)
Anti-Dengue antibodies effective against Zika: Two birds with one stone?
A study by Fernandez et al. showed that human monoclonal antibodies against the E-dimer epitope of the Dengue virus is effective against infection with the Zika virus in a preclinical mouse model. These findings potentially opens up the possibility of the development of a therapy to combat both diseases in humans.
Nature Immunology, September 25 (2017)
Preventing HIV’s sweet escape: Glycans aid the development of broadly neutralizing antibodies
Andrabi and coworkers describe the recognition of sialic-acid containing glycans on HIV envelopes by broadly neutralizing antibodies. This recognition served as an “anchor” for the antibodies and aided maturation, development and ultimately resulted in an improved immune response in vitro. Glycan interactions should therefore be taken into consideration when developing new vaccination strategies.
Immunity, September 19 (2017)
Antibodies against adult asthma
Findings of a phase 2 clinical trial reported that adults suffering from uncontrolled asthma, who have been receiving beta-agonists and glucocorticoids to no avail, experienced less exacerbations in a one-year period when receiving tezepelumab in combination with standard treatment when compared to the placebo group. Tezepelumab, a human monoclonal antibody against epithelial-cell–derived cytokine thymic stromal lymphopoietin (TSLP), is therefore a promising treatment for a subset of asthma patients who respond poorly to current strategies.
The New England Journal of Medicine, September 7 (2017)
Getting to the heart of matter: Overfed macrophages regulates PD-L1 and T cells in coronary disease
Coronary artery disease (CAD) patients are at risk of increased reactivation of latent herpes zoster infections, which cause shingles. However, the mechanism is not well elucidated. Watanabe et al. describes that under nutrient rich conditions CAD macrophages, via accumulated pyruvate, upregulate checkpoint inhibitor PD-L1, while inhibiting T cell immunity. CAD patients may benefit from metabolite-based immunotherapy in future.
The Journal of Clinical Investigations, July (2017)
Twice as nice: Bispecific T cell–redirecting antibodies effective against numerous solid tumors
Ishiguro and colleagues describe the development of a bispecific T cell–redirecting antibody (TRAB) recognizing CD3, a T-cell marker, and glypican 3, an antigen commonly found on solid tumors. The newly constructed TRAB was found to be an effective immunotherapy against different cancer models in mice and well tolerated in cynomolgus monkeys. The proposed TRAB therapy therefore shows promise for clinical applications in humans.
Science Translation Medicine, October 4 (2017)
CD8+ T Cell Responses restricted by MHC class II exist in human HIV Infection: a role in infection control?
Ranasinghe and colleagues report about the capacity of CD8+ T cells to elicit a HLA class II restricted CD8+ T cells immune response in chronic human HIV infection. These results challenge the paradigm concerning CD8+ T cells recognition and restriction, and may play a key role in the development of future T cell based vaccine and immunotherapy of viral infections.
Immunity, October 18 (2016)
Antimalarial treatment doesn’t affect cancer’s immune answer
Antimalarial treatment as well as inhibitors of apoptosis have shown no impact on the efficiency of the adaptive immune system to produce an anti-tumor response. These data suggest that the combination of these treatments with anti-tumor therapies is possible, and might become useful in various clinical contexts.
Journal of clinical investigations, October 24 (2016)
Romosozumab treatment beneficially affects osteoporosis.
In this large-scaled study, the beneficial effects of the monoclonal antibody to sclerostin (so-called Romosozumab) on osteoporosis in postmenopausal woman was tested over a period of 2 years. The data showed a beneficial effect of the treatment over the placebo group, with a diminished number of vertebral fractures after 12 and 24 months.
The New-England Journal of Medicine, October 10 (2016).
Pembrolizumab treatment in NSCLC patients: a phase 3 trial results.
In this open-label, phase 3 trial, the effects of the Pembrolizumab, a monoclonal antibody against PD-1, was assessed on advanced untreated NSCLC patients. The results not only showed an ameliorated survival rate, but also a diminished number of adverse events compared to platinum-based chemotherapy.
The New-England Journal of Medicine, October 9 (2016).
Venetoclax resistance in activated CLL cells can be overcome by Kinase inhibitors.
Venetoclax is a promising treatment developed against chronic lymphocytic leukemia (CLL) that inhibits Bcl2 and helps to induce apoptosis. However, resistance to the treatment was reported. In this study, Opperman et al. developed a model of culture which mimic microenvironment of tumors, and therefore increased pertinence of the answer observed from cancer cells under treatments. Their approach permitted the discovery of a drug combination that overcomes CLL resistance to Venetoclax, and increased the knowledge about the impact of the microenvironment on treatment response.
Blood, September 19 (2016).
Replication-defective virus vaccine: positive outcomes in human!
Wang and colleagues modified a human cytomegalovirus (HCMV) so that its replication machinery would be defective and therefore could be used as vaccination tool to enhance the immunogenicity of the treatment. The results of their study show an important and safe immune answer to the treatment. Thus, the utilization of such replication-defective virus in vaccines is proven possible and might open a wide field of possibilities in order to create a new generation of treatments against viruses.
Science translational medicine, October 26 (2016).
Vaccination by bolus dose: old fashioned?
Since its discovery, vaccine has been administrated at once, injecting abolus dose in the organism. As a natural infection is usually from a longer duration with a different pattern of presence of the antigen, an assay was developed to mimic this more natural kinetics over a 1-2 weeks’ vaccination process during germinal center induction. The resulting enhanced GC B-cell differentiation and antigen-specific antibody production may influence the posology of vaccines in the nearest future.
PNAS, October 3 (2016).
Innate and adaptive immune response collaboration to treat cancer.
Most of immune treatments of cancer have shown a large variety of limitations, resulting in a modest antitumor efficacy when used individually. By combining treatments such as tumor-antigen-specific antibody, anti PD-1 and amphiphile–vaccine, the outcome on the eradication of cancer in mice was promising. Despite the complexity of defining optimal dosing levels and schedules for each component, the possibilities of treatment using several combinations of agents are limitless and promising.
Nature Medicine, October 24 (2016)
Adoptive T Cell-Transfer in the Treatment of B Cell Malignancies
Ramos CAand colleagues report about the generation of chimeric antigen receptors (CARs), which are specific for the κ-light chain of the B cell receptor. CAR T cells therefore only target κ-light chain expressing B cells, which are characteristic for various B cell malignancies. The published phase-I study indicated feasibility and the potential of such CAR T cells to lead to complete clinical responses.
Journal of Clinical Investigation, June 6 (2016)
A STING into the Cancer’s Heart
Stimulator of interferon genes, short STING, plays central roles in detecting misplaced DNA. Emily Curran and colleagues activated the STING pathway, using the antagonist DMXAA, in case of acute myeloid leukemia (AML) in mouse models. The team observed pronounced induction of interferons and finally a significant increase in the overall survival in two different mouse models of AML, rendering STING to a promising pharmacological target.
Cell Reports,June 14 (2016)
Sepsis = False Alarm?
If bacteria enter the blood stream, a life-threatening condition called sepsis, characterized by a massive immune response and cell death, can occur. For decades, the reasons for these events have remained obscure. Vanaja S and colleagues now identified outer membrane vesicles (OMVs), produced by bacteria, which deliver lipopolysaccharides (LPS) to the cytosol of host cells. In the cytosol, the released LPS is sensed by caspase-11, which activates cascades leading to inflammation and cell death – a reaction which only should take place, when the bacteria it-self is in the intracellular compartment. Targeting OMV-pathways might therefore be reasonable therapeutic or preventative approaches.
Cell, May 19 (2016)
In 2014, the outbreak of Ebola in various African countries was declared as a public health emergency of international concern. Selidji Agnandji and colleagues recently tested a vaccine-approach using replicating-competent stomatitis viruses, which express an Ebola-virus glycoprotein. While no serious side effects were reported in a cohort of 158 volunteers, further analysis revealed promising immune responses even after a single dose, rendering the vaccine to an interesting candidate for future studies.
New England Journal of Medicine,April 28 (2016)
RNAi: A Potential Antibiotics-Substitution Approach
For decades, antibiotics have been the gold standard in fighting bacterial infections. Due to emerging resistances, novel treatment approaches are needed more than ever. Manoj Puthia and colleagues report about effective fighting of bacterial infections by boosting the innate immune system. Targeting the transfection factor interferon regulatory factor 7 (IRF-7), protected mice against infections. RNAi-based inhibition of IRF-7 could be a valuable approach to treat bacterial infections without the use of classical antibiotics.
Science Translational Medicine, April 27 (2016)
Treatment-Possibilities for Inflammatory Conditions!
Neutrophils are major effector cells in acute inflammatory responses. During apoptosis or necrosis, dying neutrophils release a variety of antimicrobial peptides, including the human neutrophil peptide 1 (HNP1). Matthew Brook and colleagues show, that HNP1 effectively inhibits protein translation in macrophages, thereby limiting inflammatory responses. Taking advantage of this newly gained knowledge, future peptide-based therapeutic could act as an anti-inflammatory drug.
Proceedings of the National Academy of Science, April 19 (2016)
Disulfiram to activate dormant-HIV
Advances in HIV research have provided us with powerful antiretroviral drugs to eradicate HIV from the blood. However the virus can still be in a dormant state elsewhere and re-emerge should the patient stop taking the drugs. Julian Elliot et al. conducted a clinical trial with the well-known anti-alcohol drug disulfiram and observed how this drug also flushes out dormant HIV in infected people. Disulfiram may be suited for future studies in combination with a second drug to activate latent HIV and then eliminate it over a finite period.
The Lancet HIV, November 17 (2015)
Relevance of gut microbiota for cancer immunotherapy
The presence of certain gut microbes might be responsible for a more effective cancer immunotherapy. Vetizou et al. have explored the role of the gut microbiota by implanting melanoma tumors on mice with different commensal bacteria. The researchers found that tumors grew less aggressively and even responded better to an anti-PD-L1 immunotherapy on some mice than others. The difference was linked to the presence of certain Bifidobacterium species in the GI tract of mice responding positively against cancer tumors. To prove the latter, a cocktail of Bifidobacterium species was then added to the other mice and indeed, the anti-tumor response was stronger. These interesting results might not be directly extrapolated to humans, but might help us understand why different cancer immunotherapies vary among patients.
Science, November 5 (2015)
Targeting HIV-infected cells by DARTs
The strategy to eliminating HIV consists of a “kick and kill” tactic by activating latent HIV expression and then immune-mediated elimination. Focusing on the latter, Sloan et al. designed Dual-Affinity Re-Targeting (DART) molecules that target both killer T cells and HIV-infected cells containing viral envelope protein (Env). These engineered molecules induce killing of the HIV-infected cells and reduce the levels of HIV expression in blood cells from HIV patients on antiretroviral therapy, pointing towards efficient DART-mediated killing of HIV reservoir cells. Next steps to prove the DART efficacy will need to be performed in vivo; however, this study shows the potential of these molecules for HIV therapy.
PLOS Pathogens,Nov 5 (2015)
Universal flu vaccination
Seasonal flu vaccines are usually based on a prediction of the strains likely to dominate that year. Therefore, protection is limited to a match between the strains in the vaccine and the circulating virus. By adding an adjuvant to stimulate both innate and adaptive immunity, Brendon Chua and colleagues have improved the effectiveness of an influenza A vaccine in mice. The TLR2 agonist-based lipopeptide adjuvant, R4Pam2Cys, is a synthetic lipopeptide that mimics a component of the bacterial membrane and is therefore capable of triggering antigen-independent immunity. This adjuvant-boosted vaccine would therefore cross-protect against different strains and could also protect against flu strains from other species.
mBio, October 27(2015)
Nanocarrier to carry new hope to battle brain cancer
Gliobastoma multiforme (GBM), a type of brain cancer, is known for being inoperable and resistant to therapies. One of the main problems for its successful therapy relies on the prevention of local accessibility of therapeutic drugs by the blood brain barrier. Recently, Ting Xu et al. developed a special nanocarrier formed from amphiphilic peptides and polymers, called 3HM. The novel nanocarriers have been found to successfully cross the blood brain barrier and accumulate inside GBM tumors in rats. This finding will open the possibility of treating GBM via intravenous drug administration rather than common invasive methods.
Journal of Controlled Release,Sept 27 (2015)
Glutamine analogue reverses cerebral malaria
Cerebral malaria is a fatal complication of infection with Plasmodium falciparum and there are currently no treatments available. Gordon et al. have recently reported the potential of targeting glutamine metabolism to arrest the disease. The authors infected mice with Plasmodium berghei ANKA to induce experimental cerebral malaria and then treated them with a glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON), which blocks glutamine transport and inhibits glutaminase. Indeed, DON treatment prevented the development of neurological signs of disease: it restored the blood-brain barrier integrity and reduced cerebral swelling. This study identifies DON as a promising candidate for treating cerebral malaria.
Proceedings of the National Academy of Sciences, August 26 (2015)
Syndecan-4 as a novel target for allergic inflammation
Polte and colleagues found that Syndecan-4 has a critical role in triggering asthma. Syndecan-4, a transmembrane heparin sulfate proteoglycan, is expressed on antigen presenting cells and plays a crucial role in allowing their migration to lymph nodes to initiate an immune response. Using Syndecan-4 deficient mice or an anti-Syndecan-4 antibody the researchers showed that blocking this molecule reduced asthma phenotypes. These findings indicate that this molecule might be a novel target for therapeutic intervention in allergic inflammatory diseases.
Nature Communications,July 13 (2015)
Modified T cells to fight cancer
Obenaus et al. created transgenic mice that are able to produce human T cell receptors directed against specific tumor cells. Specifically, the researchers isolated human T cell receptors that recognize a target antigen called MAGE-A1. This antigen is expressed on the surface of malignant tumor cells of some cancer types like multiple myeloma; but not on healthy cells. After some successful trials on mice and human cells in vitro, the scientists are now planning an initial clinical trial by adding the T cell with the modified T cell receptors targeting MAGE-A1 into multiple myeloma patients. Approval for this clinical trial may pave the way towards more effective immunotherapies against cancer.
Nature Biotechnology,March 16 (2015)
Nanovectors as “swiss-army-knifes” in cancer treatment
Mathew Hembury et al. developed a nanoparticle, which combines therapeutic and diagnostic functionalities. The gold-silica nanoparticles are highly biocompatible, emerge photonic and magnetic properties, which are beneficial for imaging-based diagnostics and that combine chemotherapy with photothermal therapy. Tested in a mouse model of colorectal cancer, the nanoparticles not only allowed a precise surveillance of the cancer but also decreased the tumor burden significantly.
Proceedings of the National Academy of Science, Feb 4 (2015)
New biomarkers for HIV
If patients with advanced HIV suffer from a co-infection with tuberculosis, the antiretroviral therapy during antibiotic treatment of tuberculosis is risky and can lead to to tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) or even death soon after the initiation of therapy. Shruti Ramivohan et al. performed a cohort study in Botswana with over 200 patients. They identified several biomarkers markers, including GM-CSF and Eotaxin, which substantially differ between patients encountering early mortality or tuberculosis-associated IRIS. The newly discovered biomarkers could help distinguishing the two groups before the start of antiretroviral treatment and would provide valuable indications for the subsequent treatment strategies.
The Lancet Infectious Disease, Feb 9 (2015)
Treating diabetes by boosting T cells in the fat tissue
FoxP3+ regulatory T (Treg) cells play important roles in tissue homeostasis. The lack of Treg cells is associated with severe autoimmune diseases. Treg cells within adipose tissue prevent obesity-associated inflammation, latter of which can lead to diabetes type 2. A recent study by Ajithkumar Vasanthakuma et al. associates the homeostatic function of Treg cells within adipose tissue not only with the prevention of inflammatory reactions but also with sustained insulin sensitivity. Interestingly, IL-33 was found to boost the Treg cell population within the adipose tissue, thereby efficiently preventing the development of diabetes type 2.
Nature Immunology, Jan 19 (2015)
IgG antibodies against microbial attachment sites
While the anti-protein binding properties of IgG antibodies have been extensively investigated in the last decades, little is known about the anti-carbohydrate binding properties of IgG. Christoph Schneider et al. investigated the potential of IVIG (pooled IgG) to bind to carbohydrates on a glycan array involving 610 immobilized glycans. A surprisingly universal carbohydrate-binding repertoire and a structure-relationship in terms of immunogenicity was found, which might be exploited for the design of glycovaccines. Furthermore, the study revealed the potential of IgG to interact with host attachment sites of viruses, bacteria and bacterial toxins. Such specific anti-attachment site antibodies might be used in the context of so-called anti-adhesion therapy.
Science Translational Medicine, Jan 7 (2015)
Monoclonal antibodies and other peptide-based therapeutics are of great importance for the treatment of many diseases. However, the high molecular weight and the peptide structure relate the use of many peptide based therapeutics to several limitations such as allergic reactions, poor tissue penetration or a lack of oral bioavailability. Patrick J McEnaney et al. now report the development of novel synthetic molecules with the targeting and effector-cell-activating functions of an antibody, while being less than 5% of its molecular weight. These so-called SyAMs (synthetic antibody mimics) easily penetrate tissue, are selective, bind only to activating Fc receptors and avoid the deposition of complement in the tissue. SyAMs display a promising tool in fighting a variety of cell- or virus-based diseases.
Journal of the American Chemical Society, Dec 16 (2014)
3D-Vaccine platform modulate immune cells and increase vaccine efficacy
In order to increase the efficacy of vaccines, Jaeyun Kim et al. have developed a silica-based vaccine platform, which spontaneously assembles to a scaffold, as soon as it has been administered. By the establishment of an infection-mimicking microenvironment, this biodegradable 3D scaffold has the potential to efficiently recruit and manipulate immune cells and might serve as a multifunctional vaccine modulating immune cells and provoking immune responses. As the platform can be loaded with a variety of antigens and drugs, the potential field of clinical application is enormous.
Nature Biotechnology, Dec 8 (2014)
Reversing Type 2 diabetes
Type 2 diabetes has risen steeply in the last decade, possibly as a cause of excess weight and a sedentary way of living. Suh et al have recently reported an injection of the protein FGF1 that in mice not only keeps sugar levels under control, but reverses insulin insensitivity. The mechanism of FGF1 is not fully elucidated yet but seems as a promising tool for glucose control. Human trials of FGF1 are planned in order to use this target as a therapeutic drug.
Nature, July 16 (2014)
New drug targets for memory impairment in Alzheimer’s disease
There is currently no cure for Alzheimer’s disease, which is the most common cause of dementia. Seonmi Jo et al have reported that reactive astrocytes, frequently observed in Alzheimer’s patients, produce abnormally and in high quantities the neurotransmitter GABA by the enzyme monoamine oxidase B (MAO-B) and release it though the Bestrophin-1 (Best1) channel. The released GABA then inhibits neighboring neurons and cause impairment in synaptic transmission, plasticity, and memory. By blocking MAO-B or Best1 in the brains of Alzheimer’s disease model mice, the authors successfully ameliorate damages in neuronal features. This study is therefore of great clinical relevance, as new therapeutic targets are proposed for treating Alzheimer’s disease.
Nature Medicine, June 29 (2014)
Linear ubiquitination regulates directly immunity
A new substrate of the linear ubiquitin assembly complex (LUBAC), consisting of HOIL-1, HOIP, and Sharpin has been implicated in reducing inflammation in human autoimmune and hyper-inflammatory diseases, such as rheumatoid arthritis and Type 2 diabetes. Rodgers et al have recently showed that HOIL-1L , plays an essential role in the formation of the NLRP3-ASC inflammasome signaling complex. It was found in vivo, that mice lacking HOIL-1L are completely resistant to sepsis. With these findings, the authors provide a new therapeutic strategy for reducing inflammation in disease.
The Journal of Experimental Medicine, June 23 (2014)
Including fiber in daily consumption helps protect from asthma
A recent study from Trompette et al has shown that dietary fermentable fiber content modified the intestinal microbiota. As fermentable fibers reach the intestine, they promote the outgrowth of bacteria from the Bacteroidetes phylum, which consequently ferment the fibers and transform them into short-chain fatty acids. These fatty acids then enter the bloodstream and influence the development and functionality of immune cells, which eventually trigger a weaker allergic airway inflammation. These results are clinically relevant as they support the fact that targeting diet is a crucial strategy not only for intestinal diseases but also for respiratory inflammatory diseases.
Nature Medicine, Jan 5 (2014)
Inhibition of antioxidants for blocking cancer cells
Non-small-cell lung cancers (NSCLC) is the most common type of lung cancers and are often related with poor prognosis. Adenocarcinoma is a subtype of NSCLC and is characterized by overproducing an antioxidant protein called superoxide dismutase 1 (SOD1) as a mean to escape immunologic response via reactive oxygen species. Recently, Glasauer et al reported a SOD1 pharmacological inhibitor, called ATN-224, that arrested the growth of human NSCLC cells and induced their death. Therefore, this antioxidant inhibition by ATN-224 has potential clinical applications for the treatment of patients with NSCLC.
Journal of Clinical Investigation, Jan 2 (2014)
Jumping genes linked to schizophrenia
Bundo et al reported that brains of people with schizophrenia present higher numbers of retrotransposons, or jumping genes, in comparison to healthy controls. Specifically, it was found that a retrotransposon called long interspersed nuclear element-1 was present in the brains of schizophrenia patients and in animal models of schizophrenia. Finding a specific role of what these jumping genes do in the brain is an area of current interest in research.
Neuron, Jan 2 (2014)
PKM2: Vital protein for cancer development
Jiang et al have reported that the tumor-specific pyruvate kinase M2 (PKM2) is a central player in the orderly cell division that allows cancer cells to proliferate. These findings are of significant importance for the development of new therapeutic strategies having PKM2 a pivotal role in controlling cell-cycle progression and tumorigenesis.
Molecular Cell, Dec 5 (2013)
Promising personalized vaccine for Gliobastoma multiforme tumors
Glioblastoma multiforme (GBM) tumors, are aggressive tumors invading the brain and are often resistant to standard therapies. Bloch et al recently described how patients with GBM treated with a heat-shocked protein peptide complex (HSPPC)-96 vaccination showed improved survival compared to those treated with usual therapies. The HSPPC-96 vaccine is produced individually for each patient using that patient’s own resected tumor tissue, in an effort to activate the immune system response against remaining brain tumor cells. The HSPPC-96 vaccine is currently in phase II trial and might offer a valuable immunotherapy to extend the lives of people suffering GBM.
Neuro-Oncology, Dec 12 (2013)
Next-generation antimalarial drug
In a continuous effort to eradicate malaria, different research groups have focused on targeting Plasmodium essential pathways for all life stages. McNamara et al have identified a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class involved in blocking the intracellular development of this parasite. By interacting with the ATP-binding pocket of PI(4)K, the imidazopyrazines showed a great potential for the prevention, treatment and elimination of malaria.
Nature, Dec 12 (2013)