RESUMO
Ovarian cancer (OC) is a common gynecological tumor with high mortality, which is difficult to control its progression with conventional treatments and is prone to recurrence. Recent studies have identified OC as an immunogenic tumor that can be recognized by the host immune system. Immunotherapy for OC is being evaluated, but approaches such as immune checkpoint inhibitors have limited efficacy, adoptive cell therapy is an alternative therapy, in which CAR(chimeric antigen receptor)-T therapy has been applied to the clinical treatment of hematological malignancies. In addition, CAR-NK and CAR-macrophage (CAR-M) have also shown great potential in the treatment of solid tumors. Here, we discuss recent advances in preclinical and clinical studies of CAR-T for OC treatment, introduce the efforts made by researchers to modify the structure of CAR in order to achieve effective OC immunotherapy, as well as the research status of CAR-NK and CAR-M, and highlight emerging therapeutic opportunities that can be utilized to improve the survival of patients with OC using CAR-based adoptive cell therapy.
Assuntos
Imunoterapia Adotiva , Neoplasias Ovarianas , Receptores de Antígenos Quiméricos , Humanos , Feminino , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/imunologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Receptores de Antígenos Quiméricos/imunologia , AnimaisRESUMO
Adoptive cell therapies involve infusing engineered immune cells into cancer patients to recognize and eliminate tumor cells. Adoptive cell therapy, as a form of living drug, has undergone explosive growth over the past decade. The recognition of tumor antigens by the T-cell receptor (TCR) is one of the natural mechanisms that the immune system used to eliminate tumor cells. TCR-T cell therapy, which involves introducing exogenous TCRs into patients' T cells, is a novel cell therapy strategy. TCR-T cell therapy can target the entire proteome of cancer cells. Engineering T cells with exogenous TCRs to help patients combat cancer has achieved success in clinical trials, particularly in treating solid tumors. In this review, we examine the progress of TCR-T cell therapy over the past five years. This includes the discovery of new tumor antigens, protein engineering techniques for TCR, reprogramming strategies for TCR-T cell therapy, clinical studies on TCR-T cell therapy, and the advancement of TCR-T cell therapy in China. We also propose several potential directions for the future development of TCR-T cell therapy.
Assuntos
Antígenos de Neoplasias , Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos de Linfócitos T , Linfócitos T , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Antígenos de Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Engenharia de Proteínas/métodosRESUMO
Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.
Assuntos
Neoplasias Hematológicas , Imunoterapia Adotiva , Terapia de Alvo Molecular , Microambiente Tumoral , Humanos , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/tratamento farmacológico , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Terapia de Alvo Molecular/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Terapia Combinada/métodos , Receptores de Antígenos Quiméricos/imunologia , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , AnimaisAssuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/tendências , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Linfócitos T/transplanteAssuntos
Custos de Cuidados de Saúde , Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/economia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Índia , Neoplasias/economia , Neoplasias/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Equidade em Saúde/economia , Equidade em Saúde/tendências , Custos de Cuidados de Saúde/tendênciasRESUMO
Engineering a patient's own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer.
Assuntos
Envelhecimento , Doenças Autoimunes , Fibrose , Cardiopatias , Imunoterapia Adotiva , Infecções , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Doenças Autoimunes/terapia , Infecções/terapia , Fibrose/terapia , Envelhecimento/patologia , Cardiopatias/terapiaRESUMO
Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has recently been added to the armamentarium in the battle against B-cell acute lymphoblastic leukemia (B-ALL). In this review, we discuss the trials that led to US Food and Drug Administration approval of CAR T-cell therapies in patients with B-ALL. We evaluate the evolving role of allogeneic hematopoietic stem cell transplant in the CAR T-cell era and discuss lessons learned from the first steps with CAR T-cell therapy in ALL. Upcoming innovations in CAR technology, including combined and alternative targets and off-the-shelf allogeneic CAR T-cell strategies are presented. Finally, we envision the role that CAR T cells could take in the management of adult patients with B-ALL in the near future.
Assuntos
Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores de Antígenos Quiméricos , Humanos , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva/história , Imunoterapia Adotiva/tendências , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfócitos T/imunologiaRESUMO
The remarkable clinical activity of chimeric antigen receptor (CAR) therapies in B cell and plasma cell malignancies has validated the use of this therapeutic class for liquid cancers, but resistance and limited access remain as barriers to broader application. Here we review the immunobiology and design principles of current prototype CARs and present emerging platforms that are anticipated to drive future clinical advances. The field is witnessing a rapid expansion of next-generation CAR immune cell technologies designed to enhance efficacy, safety and access. Substantial progress has been made in augmenting immune cell fitness, activating endogenous immunity, arming cells to resist suppression via the tumour microenvironment and developing approaches to modulate antigen density thresholds. Increasingly sophisticated multispecific, logic-gated and regulatable CARs display the potential to overcome resistance and increase safety. Early signs of progress with stealth, virus-free and in vivo gene delivery platforms provide potential paths for reduced costs and increased access of cell therapies in the future. The continuing clinical success of CAR T cells in liquid cancers is driving the development of increasingly sophisticated immune cell therapies that are poised to translate to treatments for solid cancers and non-malignant diseases in the coming years.
Assuntos
Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Linfócitos T , Humanos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Baseada em Transplante de Células e Tecidos/tendências , Terapia Genética/métodos , Terapia Genética/tendências , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/normas , Imunoterapia Adotiva/tendências , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Linfócitos T/imunologia , Microambiente Tumoral , Linfócitos B/patologiaRESUMO
Neuro-endocrine prostate cancer (NEPC) accounts for about 20% of lethal metastatic castration-resistant prostate cancer (CRPC). NEPC has the most aggressive biologic behavior of all prostate cancers and is associated with poor patient outcome. Effective treatment for NEPC is not available because NEPC exhibit distinct cell-surface expression profiles compared to other types of prostate cancer. Recently, the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (known as CEA or CD66e) was suggested to be a specific surface protein marker for NEPC. Therefore, we identified a new, fully-human anti-CEACAM5 monoclonal antibody, 1G9, which bound to the most proximal membrane domains, A3 and B3, of CEACAM5 with high affinity and specificity. It shows no off-target binding to other CEACAM family members, membrane distal domains of CEACAM5, or 5800 human membrane proteins. IgG1 1G9 exhibited CEACAM5-specific ADCC activity toward CEACAM5-positive prostate cancer cells in vitro and in vivo. Chimeric antigen receptor T cells (CAR-T) based on scFv 1G9 induced specific and strong antitumor activity in a mouse model of prostate cancer. Our results suggest that IgG1 and CAR-T cells based on 1G9 are promising candidate therapeutics for CEACAM5-positive NEPC and other cancers.
Assuntos
Antígeno Carcinoembrionário/genética , Tumores Neuroendócrinos/terapia , Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias da Próstata/terapia , Receptores de Antígenos Quiméricos/imunologia , Animais , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/imunologia , Antígeno Carcinoembrionário/imunologia , Antígeno Carcinoembrionário/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoglobulina G/imunologia , Imunoterapia Adotiva/tendências , Masculino , Camundongos , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Próstata/patologia , Próstata/cirurgia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
Chimeric Antigen Receptor T (CAR-T) cells are currently approved for B cell malignancies only, in children and adults. Despite a lack of robust evidence to approve such cellular immunotherapy for pediatric solid tumors, there is a growing interest for this approach in the treatment of pediatric brain tumors. Following the identification of tumor antigens as targets, the first clinical trials demonstrated some degree of clinical and biological responses to CAR-T cells for such tumor types. Additionaly, several preclinical studies have recently identified new attractive targets and antigen combination strategies, along with a superior tumor trafficking following locoregional administration. We review here the preclinical and clinical knowledge at the basis of the current clinical development of CAR-T cells for pediatric brain tumors.
Assuntos
Neoplasias Encefálicas/terapia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Antígenos de Neoplasias/imunologia , Barreira Hematoencefálica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Criança , Ensaios Clínicos como Assunto , Humanos , Memória Imunológica , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/tendências , Linfócitos T/imunologia , Microambiente Tumoral/imunologiaRESUMO
CAR-T cells originate from two different approaches, cellular immunotherapy based on tumor immunosurveillance by T lymphocytes, combined with molecular engineering of bispecific antibodies and antibody fragments. The latter makes it possible to retarget immune effector cytotoxic cells (such as NK cells and T lymphocytes) to tumor cells through the binding to tumor-associated antigens. We present herein the history of bispecific antibodies, highlighting how such antibodies played a major role in CAR-T cell development. We will first evoke how antibody engineering led to the construction of various bispecific formats, in particular using the single chain Fv fragment (scFv) which has been used as the initial building block to generate chimeric bi-, tri- or multifunctional molecules. We will also describe how bispecific antibodies, either full IgG or as scFv or F(ab')2 format, directed against Fcγ receptors or CD3É and against tumor-associated antigens, induce a potent anti-tumor cytotoxicity following the recruitment and activation of immune effector cells, including CD3+ T lymphocytes. These anti-tumor effects have been translated into the clinics, especially to treat malignant hemopathies. At last, recently generated bispecific CAR-T cells suggest that the embrace between cell therapy and bispecific antibodies is not over and that we are yet to witness further discoveries enabling these cells to be even more efficient.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Imunoterapia Adotiva/tendências , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/transplante , Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Ensaios Clínicos como Assunto , Previsões , Engenharia Genética , Humanos , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de IgG/imunologiaRESUMO
CAR-T cells have recently made a stunning entry on the arena of immunotherapy of B-cell lymphomas. This new treatment approach represents the culmination of 30 years of efforts to understand the role of T cells in the antitumor response. However, this technology is still in its infancy and suffers from a number of limitations. Many areas for improvement, based in particular on the possibilities of additional genetic manipulations of CAR-T cells, aim at reducing their toxicity, increasing their persistence in vivo, preventing the risk of tumor escape, recruiting other immune effectors, or extending their application to other cancers. Further studies of the dynamic interaction between the patient and these live drugs will allow elucidating the mechanisms determining the antitumor response in this context and thus developing more efficiently the future CAR-T cells.
Assuntos
Imunoterapia Adotiva/tendências , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Engenharia Celular , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Injeções Intravenosas , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/administração & dosagem , Linfócitos T/imunologia , Evasão Tumoral/imunologiaRESUMO
Despite recent therapeutic advances, multiple myeloma remains an incurable disease and the therapeutic options currently available are insufficient in refractory patients. Chimeric antigen receptor (CAR)-expressing T cells are an innovative form of adoptive cell therapy in which T cells are reprogrammed to induce an anti-tumor response. Following the successful use of CAR-T cells in the treatment of other B-cell malignancies, CAR-T-based strategies which target the B cell maturation antigen (BCMA) on the surface of tumor plasma cell are now being used in MM patients. Idecabtagene vicleucel (ide-cel), an anti-BCMA CAR-T which has shown impressive efficacy in heavily pretreated patients, is now approved by both the FDA and EMA and is available in France through a temporary use authorization (ATU) status. However, relapses seem inevitable and strategies to delay the time to progression are being investigated. These include strategies to improve the functional persistence of CAR-T in vivo by enriching for a T memory profile and reducing their immunogenicity. In addition, since changes in BCMA expression may decrease the activity of CAR-T cells in tumor plasma cells, approaches to minimize this escape are also being studied. Finally, antigens other than BCMA on the surface of plasma cells could constitute new targets of interest for recognition by CAR-T cells. The development of CAR-T-based therapies in myeloma could lead to multiple therapeutic innovations and holds promise for eventual prolonged remissions or even cure.
Assuntos
Antígeno de Maturação de Linfócitos B/imunologia , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Antineoplásicos Imunológicos/uso terapêutico , Antígeno de Maturação de Linfócitos B/metabolismo , Membrana Celular/imunologia , Progressão da Doença , Humanos , Imunoterapia Adotiva/tendências , Células T de Memória/imunologia , Mieloma Múltiplo/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Linfócitos T/imunologia , Evasão TumoralRESUMO
Cancer immunotherapy is becoming more important in the clinical setting, especially for cancers resistant to conventional chemotherapy, including targeted therapy. Chimeric antigen receptor (CAR)-T cell therapy, which uses patient's autologous T cells, combined with engineered T cell receptors, has shown remarkable results, with five US Food and Drug Administration (FDA) approvals to date. CAR-T cells have been very effective in hematologic malignancies, such as diffuse large B cell lymphoma (DLBCL), B cell acute lymphoblastic leukemia (B-ALL), and multiple myeloma (MM); however, its effectiveness in treating solid tumors has not been evaluated clearly. Therefore, many studies and clinical investigations are emerging to improve the CAR-T cell efficacy in solid tumors. The novel therapeutic approaches include modifying CARs in multiple ways or developing a combination therapy with immune checkpoint inhibitors and chemotherapies. In this review, we focus on the challenges and recent advancements in CAR-T cell therapy for solid tumors.
Assuntos
Imunoterapia Adotiva/tendências , Imunoterapia/tendências , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/imunologia , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/terapia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/imunologiaAssuntos
Alergia e Imunologia/tendências , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Imunoterapia/tendências , Oncologia/tendências , Animais , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Difusão de Inovações , Previsões , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/tendências , Microambiente Tumoral/imunologiaRESUMO
Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.
Assuntos
Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Receptores de Antígenos Quiméricos/uso terapêutico , HumanosRESUMO
Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.
Assuntos
Antígenos CD19/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/administração & dosagem , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Adolescente , Adulto , Antígenos CD19/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/tendências , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/tendências , Lactente , Masculino , Pediatria , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Adulto JovemRESUMO
Chimeric antigen receptor (CAR) transduced T cells have significantly improved cancer immunotherapy. Similarly, engineering regulatory T cells (Treg) with specific receptors to endow specificity and increase efficacy of Tregs holds great promise for therapy of a variety of adverse immune responses. In this review, we focus on our approaches using retroviral transduction of specific T-cell receptors, single chain variable fragments (scFv) or antigen in models of monogenic diseases, autoimmunity and allergy. The advantages of each of these for different targets diseases are discussed as well as their potential for clinical translation.