Abstract
Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. The ongoing ...development of immunotherapy has shown significant promise in many fields, including that of gliomas. Genetic studies have revealed that greater than 70% of DIPG cases harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). We have previously identified novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation. Accordingly, we have implemented a clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine, combined with the tetanus toxoid (TT) peptide, emulsified in Montanide. The TLR3 agonist, Poly-ICLC, was given concurrently to improve therapeutic effects of the vaccine. Our objective is to characterize vaccine-induced H3.3K27M-specific T cells from peripheral blood at several time points of the study through the evaluation of a large number of analytes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. The specificity of the H3.3K27M-specific dextramer was validated through significant binding to H3.3K27M TCR-transduced CD8 T cells and lack of non-specific binding. Subsequently, patient-derived PBMC samples were analyzed using this methodology, revealing a time course-dependent, progressive expansion of CD45RA+ effector memory cells with an inverse downregulation of CD45RO+ in H3.3K27M-specific CD8 T cells. Additionally, progressive upregulation of HLA-DR was observed in several myeloid-derived populations through the course of the trial. Future plans include the longitudinal quantification of IFN-γ and TNF-α expression as a response to the H3.3K27M peptide vaccine at each time point. The development of this methodology may greatly aid in the comprehensive evaluation of immunotherapeutic outcomes on the cellular basis.
Abstract
INTRODUCTION: Pediatric Adamantinomatous Craniopharyngioma (ACP) is well known for its association with poor quality of life in young patients. Biologically guided therapies are currently ...unavailable. We and others have shown that the ACP tumor microenvironment is infiltrated with immune cells and that ACP cyst fluid (CF) is enriched with cytokines. To identify potential targeted therapies, we seek to understand the response of normal human T-lymphocytes to ACP cyst fluid. METHODS: Cyst fluid was collected intraoperatively from pediatric ACP patients. Human T- cells enriched from PBMC fractions of healthy donors were activated by CD3/CD28/CD2 co-stimulation and cultured in IL-2 supplemented conditioned media containing either ACP CF at 10% or no cyst fluid for 24 hours, after which cells were placed in fresh media. After 48 hours, the supernatants were collected for IL-6 ELISA and the cells were immunolabelled for flow cytometry. RESULTS: CF treated T-cells demonstrated decreased IL-6 secretion compared to control media treated T-cells (124.8±10.9 pg/mL vs 231.25±30.6 pg/mL; P=0.04). The proportion of Helper T-cells double positive for CD25 and CD137 (CD4+CD25+CD137+) was decreased with CF treatment (61.0% ± 3.6 vs 72.5%± 0.2; P=0.04). The proportion of Cytotoxic T-cells double positive for CD25 and CD137 (CD8+CD25+CD137+) was also decreased with CF treatment (21.0% ± 0.1 vs 36.3% ± 1.1; P=0.003). CONCLUSION: This study characterizes the response of T-cells under the influence of ACP cyst fluid. The cytokine milieu of ACP cyst fluid appears to have immunomodulatory effects on activated T-cells. The decrease in IL-6 secretion and markers of T-cell activation may indicate an immunosuppressive environment, thus supporting the paradigm for compromised tumor immunosurveillance in pediatric ACP. Further studies to characterize immune cells and their extensive cytokine secretory profile in response to ACP cyst fluid, in order to more completely understand ACP immunopathology, are underway.
Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1+ classical dendritic cells (cDC1), thereby ...limiting antitumor immunity in mammary carcinomas. We found that increased CXCL9 expression by splenic cDC1s upon TIM-3 blockade required type I interferons and extracellular DNA. Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting. TIM-3 blockade increased uptake of extracellular DNA by cDC1 through an endocytic process that resulted in cytoplasmic localization. DNA uptake and efficacy of TIM-3 blockade required DNA binding by HMGB1, while galectin-9-induced cell surface clustering of TIM-3 was necessary for its suppressive function. Human peripheral blood cDC1s also took up extracellular DNA upon TIM-3 blockade. Thus, TIM-3 regulates endocytosis of extracellular DNA and activation of the cytoplasmic DNA sensing cGAS-STING pathway in cDC1s, with implications for understanding the mechanisms underlying TIM-3 immunotherapy.
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•TIM-3 blockade promotes endocytosis of extracellular DNA by dendritic cells•DNA uptake and CXCL9 expression by dendritic cells is HMGB1 dependent•Galectin-9 regulates TIM-3 cell surface clustering and inhibitory function•Antitumor efficacy of TIM-3 mAb and paclitaxel is dependent upon cGAS and STING
Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. de Mingo Pulido et al. provide insight into the underlying mechanisms by revealing that TIM-3 suppresses HMGB1-dependent endocytosis of extracellular DNA and the subsequent activation of the cGAS-STING pathway in intra-tumoral dendritic cells.
Cancer immunotherapy holds great potential to battle cancer by exerting a durable immunity effect. However, this process might be limited by various constraints existing in the tumor microenvironment ...(TME), such as the lack of available neoantigen, insufficient T cells from the naive repertoire, or immunosuppressive networks in which immunogenic tissue is protected from immune attacks. Certain chemotherapeutic drugs could elicit immune-potentiating effects by either inducing immunogenicity or relieving tumor-induced immunosuppression. Some also leave tumors directly susceptible to cytotoxic T cell attacks. Mounting evidence accumulated from preclinical and clinical studies suggests that these two treatment modalities might be mutually reinforcing as an effective “chemo-immunotherapy” strategy. Herein, we reviewed the latest advances in cancer immunotherapy and related mechanisms involved in chemotherapeutic-mediated immune activation. The emerging combination strategies and synergistic effects in response to chemo-immunotherapy are highlighted. We also discuss the challenges and critical considerations in its future development.
•This review presents the latest advances and mechanisms involved in chemo-immunotherapy.•This review proposes a design strategy with emerging strategies, including cascade-, spatial- and co-delivery pattern.•Challenges and future perspectives of integrating the combination of immuno-chemo therapies are highlighted.
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•Acute hepatitis resulting from treatment of metastatic cancer with immune checkpoint inhibitors is rare.•Immune-mediated hepatitis diagnosis requires exclusion of all causes of ...hepatitis.•Liver histology is paramount for the diagnosis and severity evaluation of liver damage.•Management should be based on biological and histological severity of liver injury.•Immune-mediated hepatitis does not require the systematic use of corticosteroids.
Immunotherapy for metastatic cancer can be complicated by the onset of hepatic immune-related adverse events (IRAEs). This study compared hepatic IRAEs associated with anti-programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs).
Among 536 patients treated with anti-PD-1/PD-L1 or CTLA-4 immunotherapies, 19 (3.5%) were referred to the liver unit for grade ≥3 hepatitis. Of these patients, nine had received anti-PD-1/PD-L1 and seven had received anti-CTLA-4 mAbs, in monotherapy or in combination with anti-PD-1. Liver investigations were undertaken in these 16 patients, including viral assays, autoimmune tests and liver biopsy, histological review, and immunostaining of liver specimens.
In the 16 patients included in this study, median age was 63 (range 33-84) years, and nine (56%) were female. Time between therapy initiation and hepatitis was five (range, 1–49) weeks and median number of immunotherapy injections was two (range, 1–36). No patients developed hepatic failure. Histology related to anti-CTLA-4 mAbs demonstrated granulomatous hepatitis including fibrin ring granulomas and central vein endotheliitis. Histology related to anti-PD-1/PD-L1 mAbs was characterised by lobular hepatitis. The management of hepatic IRAEs was tailored according to the severity of both the biology and histology of liver injury: six patients improved spontaneously; seven received oral corticosteroids at 0.5–1 mg/kg/day; two were maintained on 0.2 mg/kg/day corticosteroids; and one patient required pulses and 2.5 mg/kg/day of corticosteroids, and the addition of a second immunosuppressive drug. In three patients, immunotherapy was reintroduced without recurrence of liver dysfunction.
Acute hepatitis resulting from immunotherapy for metastatic cancer is rare (3.5%) and, in most cases, not severe. Histological assessment can distinguish between anti-PD-1/PD-L1 and anti-CTLA-4 mAb toxicity. The severity of liver injury is helpful for tailoring patient management, which does not require systematic corticosteroid administration.
Immunotherapy for metastatic cancer can be complicated by immune-related adverse events in the liver. In patients receiving immunotherapy for metastatic cancer who develop immune-mediated hepatitis, liver biopsy is helpful for the diagnosis and evaluation of the severity of liver injury. This study demonstrates the need for patient-oriented management, which could eventually avoid unnecessary systemic corticosteroid treatment.
Immunologic control of malignancy has long been recognized as an important determinant of disease progression. Recent advances in immunology have led to the focus on several mechanisms that can be ...targeted to achieve tumor suppression. In particular, checkpoint inhibition has evolved in less than a decade to become one of the most important strategies in cancer therapy, with a meaningful improvement in patient survival. Six agents have been approved for clinical use to date and many more are in the industry pipeline. The spectrum of malignancies responsive to immunotherapy ranges from advanced melanoma, for which the first immune checkpoint inhibitor ipilimumab was approved, to Hodgkin lymphoma, non–small cell lung cancer, renal cell carcinoma, and others. Notwithstanding its clinical benefits, checkpoint inhibition carries a risk for significant off-target toxicity stemming from the immune system activation. In this review, we discuss general principles of checkpoint inhibition, mechanisms of toxicity, and kidney complications of the treatment and propose diagnostic and treatment strategies when kidney injury occurs.
In recent years, the role of cancer immunotherapy has become increasingly important compared to traditional cancer treatments, including surgery, chemotherapy and radiotherapy. Of note, the clinical ...successes of immune checkpoint blockade, such as PD-1 and CTLA-4, represent a landmark event in cancer immunotherapy development. Therefore, further exploration of how immune checkpoints are regulated in the tumor microenvironment will provide key insights into checkpoint blockade therapy. In this review, we discuss in details about the regulation of immune checkpoints mediated by immune cells, oncolytic viruses, epigenetics, and gut microbiota and mutual regulation by co-expressed checkpoints. Finally, predictions are made for future personalized cancer immunotherapy based on different checkpoint modulations.
Hepatocellular carcinoma (HCC) arises on the background of chronic liver disease. Despite the development of effective anti-viral therapeutics HCC is continuing to rise, in part driven by the ...epidemic of non-alcoholic fatty liver disease. Many patients present with advanced disease out with the criteria for transplant, resection or even locoregional therapy. Currently available therapeutics for HCC are effective in a small minority of individuals. However, there has been a major global interest in immunotherapies for cancer and although HCC has lagged behind other cancers, great opportunities now exist for treating HCC with newer and more sophisticated agents. Whilst checkpoint inhibitors are at the forefront of this revolution, other therapeutics such as inhibitory cytokine blockade, oncolytic viruses, adoptive cellular therapies and vaccines are emerging. Broadly these may be categorized as either boosting existing immune response or stimulating de novo immune response. Although some of these agents have shown promising results as monotherapy in early phase trials it may well be that their future role will be as combination therapy, either in combination with one another or in combination with treatment modalities such as locoregional therapy. Together these agents are likely to generate new and exciting opportunities for treating HCC, which are summarized in this review.
Peanut sublingual immunotherapy (SLIT) for 1 year has been shown to induce modest clinical desensitization in allergic children. Studies of oral immunotherapy, epicutaneous immunotherapy, and SLIT ...have suggested additional benefit with extended treatment.
We sought to investigate the safety, clinical effectiveness, and immunologic changes with long-term SLIT in children with peanut allergy.
Children with peanut allergy aged 1 to 11 years underwent extended maintenance SLIT with 2 mg/d peanut protein for up to 5 years. Subjects with peanut skin test wheals of less than 5 mm and peanut-specific IgE levels of less than 15 kU/L were allowed to discontinue therapy early. Desensitization was assessed through a double-blind, placebo-controlled food challenge (DBPCFC) with up to 5000 mg of peanut protein after completion of SLIT dosing. Sustained unresponsiveness was further assessed by using identical DBPCFCs after 2 to 4 weeks without peanut exposure.
Thirty-seven of 48 subjects completed 3 to 5 years of peanut SLIT, with 67% (32/48) successfully consuming 750 mg or more during DBPCFCs. Furthermore, 25% (12/48) passed the 5000-mg DBPCFC without clinical symptoms, with 10 of these 12 demonstrating sustained unresponsiveness after 2 to 4 weeks. Side effects were reported with 4.8% of doses, with transient oropharyngeal itching reported most commonly. Side effects requiring antihistamine treatment were uncommon (0.21%), and no epinephrine was administered. Peanut skin test wheals, peanut-specific IgE levels, and basophil activation decreased significantly, and peanut-specific IgG4 levels increased significantly after peanut SLIT.
Extended-therapy peanut SLIT provided clinically meaningful desensitization in the majority of children with peanut allergy that was balanced with ease of administration and a favorable safety profile.
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In the last decade, there has been great advancement in manipulating the immune system or the cells of the immune system to bring about effective therapies. While harnessing the ...immune system against cancer is not a new concept, successful reprograming with T cells with chimeric antigen receptor (CAR) forming CAR-T cell therapy has revolutionized the treatment landscape for patients with refractory, high-grade B cell malignancies. The journey from proof-of-concept to FDA-approved commercial CAR-T products has taken almost 3 decades and untold amount of efforts, resources and manpower. With the success of CD19 CAR adoptive cellular immunotherapy leading the charge, CARs targeting various malignancies are in various stages of active development, racing towards regulatory approval, and raising hopes of further breakthroughs in cancer treatment options. In this review we will highlight recent clinical developments of the B cell maturation antigen (BCMA) CAR-T therapy for multiple myeloma (MM) to showcase how innovative CAR designs, coupled with careful selection of tumor-associated antigens, used in combination with other therapeutic agents, could help overcome some of the current limitations experienced in CAR-T immunotherapy. More patients could benefit from novel upfront cell therapy trials, that when combined with the current established induction regimens could have the potential to recondition and alter tumor environments, help restore somnolent anti-tumor immunity, and induce more effective and durable remissions.
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