Immunotherapy advances最新文献

Objectives: Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab.

Methods: Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed.

Results: Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9.

Conclusion: Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.

Cell therapy is an innovative approach that permits numerous possibilities in the field of cancer treatment. CAR-T cells have been successfully used in patients with hematologic relapsed/refractory. However, the need for autologous sources for T cells is still a major drawback. CAR-NK cells have emerged as a promising resource using allogeneic cells that could be established as an off-the-shelf treatment. NK cells can be obtained from various sources, such as peripheral blood (PB), bone marrow, umbilical cord blood (CB), and induced pluripotent stem cells (iPSC), as well as cell lines. Genetic engineering of NK cells to express different CAR constructs for hematological cancers and solid tumors has shown promising preclinical results and they are currently being explored in multiple clinical trials. Several strategies have been employed to improve CAR-NK-cell expansion and cytotoxicity efficiency. In this article, we review the latest achievements and progress made in the field of CAR-NK-cell therapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several advanced malignancies leading to durable remission in a subset of patients. Their rapidly expanding use has led to an increased frequency of immune-related adverse events (irAEs). The pathogenesis of irAEs is poorly understood but may involve aberrant activation of T cells leading to inflammatory cytokine release or production of pathogenic antibodies leading to organ damage. Severe irAEs can be extremely debilitating and, in some cases, life threatening. IrAEs may not always be corticosteroid responsive or may require excessively high, often toxic, corticosteroid doses. Therapeutic plasma exchange (PLEX) is a treatment modality that has shown promising results for the management of certain severe irAEs, including irAEs that are not mentioned in current treatment guidelines. PLEX may attenuate ongoing irAEs and prevent delayed irAEs by accelerating clearance of the ICI, or by acutely removing pathogenic antibodies, cytokines, and chemokines. Here, we summarize examples from the literature in which PLEX was successfully used for the treatment of irAEs. We posit that timing may be a critical factor and that earlier utilization of PLEX for life-threatening irAEs may result in more favorable outcomes. In individuals at high risk for irAEs, the availability of PLEX as a potential therapeutic mitigation strategy may encourage life-saving ICI use or rechallenge. Future research will be critical to better define which indications are most amenable to PLEX, particularly to establish the optimal place in the sequence of irAE therapies and to assess the ramifications of ICI removal on cancer outcomes.

Hepatocellular carcinoma is a significant global health challenge with steadily increasing incidence in the East Asia region. While both Hepatitis C and B virus infections account for the majority of HCC cases, the advent of potent antivirals against HCV infection has biased the aetiology towards chronic HBV infection that at the moment remains without an effective cure. For this reason, HBV-HCC remains a persistent global problem. Treatment options for intermediate to advanced stages of HBV-HCC remain limited, hence novel therapeutic strategies are required to fulfil this medical need. Following the considerable success of adoptive T-cell immunotherapy against B-cell malignancies, it is conceivable to envision whether the same could be achieved against HBV-HCC. In this review, we describe the development of T-cell therapy strategies for HBV-HCC and discuss the safety and the efficacy of the strategies in terms of the direct killing of tumour cells and the other alterations possibly induced by the action of the T cells.

Despite three decades of research to its name and increasing interest in immunotherapies that target it, LAG-3 remains an elusive co-inhibitory receptor in comparison to the well-established PD-1 and CTLA-4. As such, LAG-3 targeting therapies have yet to achieve the clinical success of therapies targeting other checkpoints. This could, in part, be attributed to the many unanswered questions that remain regarding LAG-3 biology. Of these, we address: (i) the function of the many LAG-3-ligand interactions, (ii) the hurdles that remain to acquire a high-resolution structure of LAG-3, (iii) the under-studied LAG-3 signal transduction mechanism, (iv) the elusive soluble form of LAG-3, (v) the implications of the lack of (significant) phenotype of LAG-3 knockout mice, (vi) the reports of LAG-3 expression on the epithelium, and (vii) the conflicting reports of LAG-3 expression (and potential contributions to pathology) in the brain. These mysteries which surround LAG-3 highlight how the ever-evolving study of its biology continues to reveal ever-increasing complexity in its role as an immune receptor. Importantly, answering the questions which shroud LAG-3 in mystery will allow the maximum therapeutic benefit of LAG-3 targeting immunotherapies in cancer, autoimmunity and beyond.

Objectives: We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia.

Methods: We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses.

Results: Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A.

Conclusion: Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.

Oral tolerance is a physiological phenomenon described more than a century ago as a suppressive immune response to antigens that gain access to the body by the oral route. It is a robust and long-lasting event with local and systemic effects in which the generation of mucosally induced regulatory T cells (iTreg) plays an essential role. The idea of using oral tolerance to inhibit autoimmune and allergic diseases by oral administration of target antigens was an important development that was successfully tested in 1980s. Since then, several studies have shown that feeding specific antigens can be used to prevent and control chronic inflammatory diseases in both animal models and clinically. Therefore, oral tolerance can be classified as an antigen-specific form of oral immunotherapy (OIT). In the light of novel findings on mechanisms, sites of induction and factors affecting oral tolerance, this review will focus on specific characteristics of oral tolerance induction and how they impact in its therapeutic application.

We are at a critical stage in the COVID-19 pandemic where vaccinations are being rolled out globally, in a race against time to get ahead of the SARS-CoV-2 coronavirus and the emergence of more highly transmissible variants. A range of vaccines have been created and received either emergency approval or full licensure. To attain the upper hand, maximum vaccine synthesis, deployment, and uptake as rapidly as possible is essential. However, vaccine uptake, particularly in younger adults is dropping, at least in part fuelled by reports of rare complications associated with specific vaccines. This review considers how vaccination with adenovirus vector-based vaccines against the SARS-CoV-2 coronavirus might cause rare cases of thrombosis and thrombocytopenia in some recipients. A thorough understanding of the underlying cellular and molecular mechanisms that mediate this syndrome may help to identify methods to prevent these very rare, but serious side effects. This will also help facilitate the identification of those at highest risk from these outcomes, so that we can work towards a stratified approach to vaccine deployment to mitigate these risks.

Cancer immunotherapies have significantly improved patient survival and treatment options in recent years. Nonetheless, the success of immunotherapy is limited to certain cancer types and specific subgroups of patients, making the development of new therapeutic approaches a topic of ongoing research. Chimeric antigen receptor (CAR) cells are engineered immune cells that are programmed to specifically eliminate cancer cells. Ideally, a CAR recognizes antigens that are restricted to tumor cells to avoid off-target effects. NKG2D is an activating immunoreceptor and an important player in anti-tumor immunity due to its ability to recognize tumor cells and initiate an anti-tumor immune response. Ligands for NKG2D are expressed on malignant or stressed cells and typically absent from healthy tissue, making it a promising CAR candidate. Here, we provide a summary of past and ongoing NKG2D-based CAR clinical trials and comment on potential pitfalls.