Immunomedicine最新文献

The genetically engineered chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable clinical efficacy in the treatment of hematological malignancies. Nonetheless, it is difficult to harvest adequate autologous T cells to manufacture potent CAR-T cell products in patients with high tumor burden and prior tumor-reductive treatment. Here we reported a relapsed/refractory acute lymphoblastic leukemia patient with high leukemia burden and central nervous system (CNS) involvement. The patient responded to donor-derived HLA-matched allogeneic CAR-T treatment, with the achievement of quick complete remission. And for the first time, we revealed the development of a cerebral CRS in situ after allogeneic CAR-T therapy.

Acute myeloid leukemia (AML) is one of the lethal hematological malignancies with high relapse rates and poor prognosis. Since chimeric antigen receptor cellular therapy has exhibited remarkable therapeutic outcomes in B-cell malignancies, many studies have attempted to translate this success to other malignancies, including AML. Herein we review current achievements of chimeric antigen receptor-based cell therapy in AML preclinical studies and clinical trials with potential AML-associated cell markers. Furthermore, we discuss future prospects of chimeric antigen receptor-based cell therapy options for patients with AML.

Despite the emergence of new strategies in recent years, multiple myeloma (MM) is still an incurable disease with poor outcome. As a new treatment, chimeric antigen receptor (CAR-) T cell therapy brought exciting news to patients with relapsed or refractory MM. B-cell maturation antigen (BCMA) is ubiquitously expressed on the surface of myeloma cells and is considered an “ideal” target of CAR-T cell. BCMA-targeted CAR-T cell therapies achieved remarkable efficacy in relapsed or refractory MM patients in several clinical trials. However, some patients had no response or relapsed after BCMA targeted CAR-T cell therapy. Myeloma cells also express other surface markers which might be used as targets for CAR-T cell therapy. Encouragingly, CAR-T cells targeting these non-BCMA markers are being tested in clinical trials or under preclinical investigation, already showing some promising results. In this review, we summarized and provided an update of these advances.

Tumor-derived exosomes (TEXs) are a class of extracellular vesicles which play an important role in the tumor microenvironment. These vesicles have multiple biological functions including promotion of cancer progression and reduction of anti-tumor immunity. Recently, interaction between TEXs and immune cells are of great interest in cell-based immunotherapy. Here, we review the effects of TEXs on the survival and functions of T cell subsets, as well as their clinical applications. Unraveling the immunoregulatory function of exosomes allows a better understanding of the molecular and cellular basis for cancer immunotherapy.

The balance of activating and inhibitory signals from the low affinity Fc gamma receptors modulates immune responses triggered by IgG antibody-immune complexes. In homeostasis, this leads to antigen clearance, while in autoimmune diseases to unwanted immune response. Besides the activating receptors FcɣRIIa, FcɣRIIIa, and the inhibitory FcɣRIIb receptor, a third activating receptor, FcɣRIIc, was shown to be expressed on several immune cell types, however, only in the presence of a functional FCGR2C-ORF allele. FcɣRIIc expression is associated with autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus or systemic sclerosis. Thus, the determination of the functional FCGR2C gene resulting in protein expression on immune cells becomes highly relevant, particularly in the context of unwanted immune responses through inadvertent FcɣRIIc activation by molecules targeting stimulation of the inhibitory receptor FcɣRIIb, currently pursued by several pharmaceutical companies. The high degree of homology within the FCGR2/3 gene cluster complicates development of an accurate method for identification of FcɣRIIc expression. Here we describe a comprehensive approach to characterize genetic status of the FCGR2C gene locus consisting of cDNA sequencing, SNaPshot genotyping and low-coverage next-generation sequencing. This might enable Mendelian randomization hypothesis testing across autoimmune diseases to personalize therapies and enhance treatment outcomes.

May 19, 2021

Vaccination targeting infectious pathogens has profoundly impacted public health and has led to the eradication of diseases that have plagued human history. The development of therapeutic vaccines for cancer has been pursued over many years in effort to harness the selectivity and potency of the immune system with the promise of greater efficacy and safety than standard cytotoxic therapy. The unique potency of immune therapy was highlighted by the observation that allogeneic hematopoietic stem cell transplantation is uniquely curative for a subset of patients with hematologic malignancies due to the graft versus tumor effect mediated by alloreactive lymphocytes.¹ Vaccine platforms were developed in an effort to elicit tumor specific immune responses to target established malignancy and provide immunologic memory to prevent recurrence. Initial studies focused on the introduction of tumor associated antigens as peptides, proteins or whole tumor cells, or lysate most commonly in the setting of advanced disease.² While clinical trials demonstrated immunologic responses and anecdotal disease regression, therapeutic efficacy was not clearly seen and several randomized trials did not show benefit over standard therapy.³ As such, vaccination was often viewed as an unrealized promise subsequently displaced by other therapeutic strategies.

The efficacy of cancer immunotherapy has been recently transformed with the enhanced understanding of the immunoregulatory aspects of the tumor microenvironment.^{4, 5} The role of negative costimulatory signaling as a mediator of T cell exhaustion led to the development of checkpoint blockade as effective therapy for diverse malignancies, particularly when characterized by high mutational burden and the presence of tumor specific neoepitopes. In addition, CAR T cell therapy involving the ex vivo generation of effector cells with high levels of costimulatory molecule expression have received FDA approval for treatment of patients with lymphoma, acute lymphocytic leukemia, and multiple myeloma demonstrating a profound impact on a subset of patients with advanced disease. In this context, vaccine design has similarly evolved to incorporate this increased understanding of the complex interface between tumor cells and the immune environment to augment therapeutic efficacy, identify the optimal settings of intervention, and develop combinatorial approaches.

A critical factor for vaccine design is the identification of antigenic targets that are selectively expressed by malignant cells and potentially recognized by the T cell repertoire.⁶ These have included aberrantly expressed oncogenic proteins, tissue specific markers, and antigens characteristically expressed in fetal development that are upregulated in the setting of malignancy.⁷ While selection of

Generation of immunity against cancer through vaccination has long been an elusive goal for tumor immunologists. Putative candidates for vaccination targets include oncofetal antigens, viral antigens, neoantigens, and differentiation antigens. The first attempts at cancer vaccination used injections of whole autologous tumor cells. However, these unmodified tumor cells did not engender a robust immune response. Subsequent efforts were focused at enhancing the immunogenicity of whole autologous tumor cell vaccines through genetic modification, often through virally mediated transduction of genes encoding immunostimulatory molecules. Of many immunostimulatory cytokines evaluated in the context of gene-modified tumor cell vaccines, granulocyte–macrophage colony-stimulating factor (GM-CSF) emerged as the most potent in generating protective antitumor immunity. Vaccination using irradiated, GM-CSF producing tumor cells (GVAX) consistently induced antitumor immunity across several experimental tumor models. The term GVAX can connote GM-CSF secreting cell vaccines prepared with different vectors as well as vector targets including autologous tumor cells, allogeneic tumor cell lines, and bystander third party tumor cells lines. GVAX has been evaluated against solid tumors, hematologic malignancies, and in the context of hematopoietic stem cell transplantation. GVAX has been extensively studied in clinical trials, both alone and in conjunction with lymphodepleting chemotherapy, immune checkpoint inhibitors, and other vaccines.

Tumor cells present antigen in the context of negative costimulation and immunosuppressive factors, resulting in the inhibition of T cell activation and immune tolerance. Dendritic cells (DCs) are a complex network of antigen presenting cells that play a critical role in maintaining the equilibrium between immune activation directed against pathogens and tolerance necessary to prevent damage mediated by autoreactive T cell clones. DCs uniquely induce primary immune responses through the constitutive and enhanced expression of positive costimulatory molecules and inflammatory cytokines necessary for T cell activation. In this context, the design of a cancer vaccine is based on the effective presentation tumor associated antigens to evoke an antigen specific activated T cell response, and importantly, immune memory. As such, DCs have played a major role in the development of cancer vaccine therapy as critical mediators of antigen presentation reversing a major component of tumor mediated immune suppression. DC based vaccines have involved the loading of individual tumor associated antigens or the use of whole tumor cells and have demonstrated potent induction of tumor specific immunity. The correlation of immune response with clinical outcome and integration of DC vaccines with other immune based therapy is currently being explored.

The development of cancer vaccines is based on the premise that tumor cells are potentially targetable by host immunity through the effective presentation of tumor-associated antigens to reactive T-cell populations. Vaccine efficacy may be limited by the functional properties of effector cells including the lack of high-affinity T cells to target self-antigens. In contrast, neoantigens arise from tumor-specific mutational events that generate epitopes that are potentially seen as foreign by host immunity. As such, neoantigen-targeted vaccination provides a high level of tumor specificity, promotes greater T-cell effector function, and minimizes off-target toxicities. Next-generation sequencing and high-throughput computational algorithms have allowed for the identification of neoantigens in solid tumor and hematologic malignancies. Vaccine generation involves the screening of potential epitopes based on HLA restriction and reactivity by the T-cell repertoire. Early phase studies have demonstrated feasibility of vaccine production and resultant potent immunologic responses. The clinical impact of neoantigen vaccination and its incorporation into combinatorial immunotherapeutic strategies is currently being explored.