RESUMO
Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
Assuntos
Antígenos CD5 , Imunoterapia Adotiva , Linfócitos T , Animais , Imunoterapia Adotiva/métodos , Antígenos CD5/imunologia , Camundongos , Humanos , Linfócitos T/imunologia , Linfócitos T/transplante , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Linhagem Celular Tumoral , Sistemas CRISPR-Cas , FemininoRESUMO
Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor microenvironment. With this rapid clinical and scientific progress, the field of cancer immunotherapy is currently at a critical inflection point, with potential for exponential growth over the next decade. Recognizing this, the Society for Immunotherapy of Cancer convened a diverse group of experts in cancer immunotherapy representing academia, the pharmaceutical and biotechnology industries, patient advocacy, and the regulatory community to identify current opportunities and challenges with the goal of prioritizing areas with the highest potential for clinical impact. The consensus group identified seven high-priority areas of current opportunity for the field: mechanisms of antitumor activity and toxicity; mechanisms of drug resistance; biomarkers and biospecimens; unique aspects of novel therapeutics; host and environmental interactions; premalignant immunity, immune interception, and immunoprevention; and clinical trial design, endpoints, and conduct. Additionally, potential roadblocks to progress were discussed, and several topics were identified as cross-cutting tools for optimization, each with potential to impact multiple scientific priority areas. These cross-cutting tools include preclinical models, data curation and sharing, biopsies and biospecimens, diversification of funding sources, definitions and standards, and patient engagement. Finally, three key guiding principles were identified that will both optimize and maximize progress in the field. These include engaging the patient community; cultivating diversity, equity, inclusion, and accessibility; and leveraging the power of artificial intelligence to accelerate progress. Here, we present the outcomes of these discussions as a strategic vision to galvanize the field for the next decade of exponential progress in cancer immunotherapy.
Assuntos
Imunoterapia , Neoplasias , Humanos , Imunoterapia/métodos , Neoplasias/terapia , Neoplasias/imunologia , Sociedades MédicasRESUMO
Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment for hematological malignancies, but its adaptation to solid tumors is impeded by multiple challenges, particularly T cell dysfunction and exhaustion. The heterogeneity and inhospitableness of the solid tumor microenvironment (TME) contribute to diminished CAR T cell efficacy exhibited by reduced cytotoxicity, proliferation, cytokine secretion, and the upregulation of inhibitory receptors, similar to the phenotype of tumor-infiltrating lymphocytes (TILs). In this review, we highlight recent advances in T cell therapy for solid tumors, particularly brain cancer. Innovative strategies, including locoregional delivery and 'armoring' CAR T cells with cytokines such as interleukin (IL)-18, are under investigation to improve efficacy and safety. We also highlight emerging issues with toxicity management of CAR T cell adverse events. This review discusses the obstacles associated with CAR T cell therapy in the context of solid tumors and outlines current and future strategies to overcome these challenges.
Assuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Linfócitos T , Microambiente Tumoral , Humanos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Animais , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Anti-CD19 CAR T cells were among the last decade's scientific breakthroughs, achieving remarkable remissions in patients with B cell leukemias and lymphomas. Now, the engineered cell therapies are traversing disease indications into autoimmunity and resolving disease symptoms in patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis.1.
Assuntos
Imunoterapia Adotiva , Lúpus Eritematoso Sistêmico , Neoplasias , Humanos , Autoimunidade/imunologia , Lúpus Eritematoso Sistêmico/terapia , Linfócitos T , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/uso terapêuticoRESUMO
The advent of chimeric antigen receptor (CAR) T cell therapy has resulted in unprecedented long-term clearance of relapse/refractory hematological malignancies in both pediatric and adult patients. However, severe toxicities, such as cytokine release syndrome and neurotoxicity, associated with CAR T cells affect therapeutic utility; and treatment efficacies for solid tumors are still not impressive. As a result, engineering strategies that modify other immune cell types, especially natural killer (NK) cells have arisen. Owing to both CAR-dependent and CAR-independent (innate immune-mediated) antitumor killing capacity, major histocompatibility complex-independent cytotoxicity, reduced risk of alloreactivity and lack of major CAR T cell toxicities, CAR NK cells constitute one of the promising next-generation CAR immune cells that are also amenable as 'off-the-shelf' therapeutics. In this Review, we compare CAR T and CAR NK cell therapies, with particular focus on immunological synapses, engineering strategies and challenges.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Criança , Células Matadoras Naturais , Imunoterapia Adotiva/métodos , Terapia Baseada em Transplante de Células e TecidosRESUMO
The lack of antibodies with sufficient cancer selectivity is currently limiting the treatment of solid tumors by immunotherapies. Most current immunotherapeutic targets are tumor-associated antigens that are also found in healthy tissues and often do not display sufficient cancer selectivity to be used as targets for potent antibody-based immunotherapeutic treatments, such as chimeric antigen receptor (CAR) T cells. Many solid tumors, however, display aberrant glycosylation that results in expression of tumor-associated carbohydrate antigens that are distinct from healthy tissues. Targeting aberrantly glycosylated glycopeptide epitopes within existing or novel glycoprotein targets may provide the cancer selectivity needed for immunotherapy of solid tumors. However, to date only a few such glycopeptide epitopes have been targeted. Here, we used O-glycoproteomics data from multiple cell lines to identify a glycopeptide epitope in CD44v6, a cancer-associated CD44 isoform, and developed a cancer-specific mAb, 4C8, through a glycopeptide immunization strategy. 4C8 selectively binds to Tn-glycosylated CD44v6 in a site-specific manner with low nanomolar affinity. 4C8 was shown to be highly cancer specific by IHC of sections from multiple healthy and cancerous tissues. 4C8 CAR T cells demonstrated target-specific cytotoxicity in vitro and significant tumor regression and increased survival in vivo. Importantly, 4C8 CAR T cells were able to selectively kill target cells in a mixed organotypic skin cancer model having abundant CD44v6 expression without affecting healthy keratinocytes, indicating tolerability and safety.
Assuntos
Anticorpos Monoclonais , Neoplasias , Humanos , Anticorpos Monoclonais/farmacologia , Neoplasias/patologia , Glicoproteínas , Epitopos , GlicopeptídeosRESUMO
A challenge when targeting T-cell lymphoma with chimeric antigen receptor (CAR) T-cell therapy is that target antigens are often shared between T cells and tumor cells, resulting in fratricide between CAR T cells and on-target cytotoxicity on normal T cells. CC chemokine receptor 4 (CCR4) is highly expressed in many mature T-cell malignancies, such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL), and has a unique expression profile in normal T cells. CCR4 is predominantly expressed by type-2 and type-17 helper T cells (Th2 and Th17) and regulatory T cells (Treg), but it is rarely expressed by other T helper (Th) subsets and CD8+ cells. Although fratricide in CAR T cells is generally thought to be detrimental to anticancer functions, in this study, we demonstrated that anti-CCR4 CAR T cells specifically depleted Th2 and Tregs, while sparing CD8+ and Th1 T cells. Moreover, fratricide increased the percentage of CAR+ T cells in the final product. CCR4-CAR T cells were characterized by high transduction efficiency, robust T-cell expansion, and rapid fratricidal depletion of CCR4-positive T cells during CAR transduction and expansion. Furthermore, mogamulizumab-based CCR4-CAR T cells induced superior antitumor efficacy and long-term remission in mice engrafted with human T-cell lymphoma cells. In summary, CCR4-depleted anti-CCR4 CAR T cells are enriched in Th1 and CD8+ T cells and exhibit high antitumor efficacy against CCR4-expressing T-cell malignancies.
Assuntos
Linfoma Cutâneo de Células T , Linfoma de Células T Periférico , Linfoma de Células T , Neoplasias Cutâneas , Adulto , Humanos , Animais , Camundongos , Receptores CCR4/metabolismo , Linfócitos T ReguladoresRESUMO
Therapeutic modalities that engage the immune system to recognize and eliminate cancer, known as cancer immunotherapy, has emerged as a distinct pillar of cancer therapy. Among the most promising treatment approaches are therapeutic vaccines, immune checkpoint blockade, bispecific T-cell engagers (BiTEs) and adoptive cell therapies. These approaches share a common mechanism of action, which is elicitation of a T-cell-based immune response, either endogenous or engineered, against tumor antigens, but interactions between the innate immune system, particularly antigen-presenting cells, and immune effectors also underlie the efficacy of cancer immunotherapies and approaches engaging these cells are also under development. To view this SnapShot, open or download the PDF.
Assuntos
Vacinas Anticâncer , Neoplasias , Humanos , Imunoterapia , Neoplasias/terapia , Linfócitos T , Vacinas Anticâncer/uso terapêuticoRESUMO
ABSTRACT: Genetically engineered chimeric antigen receptor (CAR) T-cell therapy leverages the ability of the immune system to eliminate tumors and redirects cytotoxic functions toward cells expressing specified tumor-restricted antigens. Although 6 CAR T-cell therapies have received Food and Drug Administration (FDA) approval for the treatment of many hematological malignancies, limitations involving T cell-intrinsic, T cell-extrinsic, and therapeutic factors remain in the treatment of both liquid and solid tumors. Chimeric antigen receptor design, signals from the tumor microenvironment, tumor antigen escape mechanisms, and systemic inflammatory consequences of CAR T-cell infusion all influence the efficacy and feasibility of CAR T-cell therapy in different malignancies. Here, we review the core structure of the CAR, the evolution of different CAR generations, CAR T-cell therapy limitations, and current strategies being investigated to overcome the T cell-intrinsic, T cell-independent, and therapeutic barriers to successful CAR T-cell therapy.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfócitos T , Receptores de Antígenos Quiméricos/genética , Neoplasias/terapia , Antígenos de Neoplasias , Microambiente Tumoral , Terapia Baseada em Transplante de Células e Tecidos , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy and safety remain. Investigators have begun to enhance CAR-T cells with the expression of accessory molecules to address these challenges. Current systems rely on constitutive transgene expression or multiple viral vectors, resulting in unregulated response and product heterogeneity. Here, we develop a genetic platform that combines autonomous antigen-induced production of an accessory molecule with constitutive CAR expression in a single lentiviral vector called Uni-Vect. The broad therapeutic application of Uni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improves efficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcription factors that modulate T cell biology. Uni-Vect is also implemented as a platform to characterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundation for a more clinically actionable next-generation cellular immunotherapy.
Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T , Humanos , Imunoterapia Adotiva/métodos , Linfócitos T , Vetores Genéticos/genética , Citocinas/metabolismoRESUMO
The myeloma surface proteome (surfaceome) determines tumor interaction with the microenvironment and serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to define the myeloma surfaceome at baseline, in drug resistance, and in response to acute drug treatment. We provide a scoring system for surface antigens and identify CCR10 as a promising target in this disease expressed widely on malignant plasma cells. We engineer proof-of-principle chimeric antigen receptor (CAR) T-cells targeting CCR10 using its natural ligand CCL27. In myeloma models we identify proteins that could serve as markers of resistance to bortezomib and lenalidomide, including CD53, CD10, EVI2B, and CD33. We find that acute lenalidomide treatment increases activity of MUC1-targeting CAR-T cells through antigen upregulation. Finally, we develop a miniaturized surface proteomic protocol for profiling primary plasma cell samples with low inputs. These approaches and datasets may contribute to the biological, therapeutic, and diagnostic understanding of myeloma.
Assuntos
Mieloma Múltiplo , Resistência a Medicamentos , Humanos , Imunoterapia/métodos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Proteômica , Microambiente TumoralRESUMO
Despite tremendous success against hematological malignancies, the performance of chimeric Ag receptor T cells against solid tumors remains poor. In such settings, the lack of success of this groundbreaking immunotherapy is in part mediated by ligand engagement of immune checkpoint molecules on the surface of T cells in the tumor microenvironment. Although CTLA-4 and programmed death-1 (PD-1) are well-established checkpoints that inhibit T cell activity, the engagement of glycans and glycan-binding proteins are a growing area of interest due to their immunomodulatory effects. This review discusses exemplary strategies to neutralize checkpoint molecules through an in-depth overview of genetic engineering approaches aimed at overcoming the inhibitory programmed death ligand-1 (PD-L1)/PD-1 axis in T cell therapies and summarizes current knowledge on glycoimmune interactions that mediate T cell immunosuppression.
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/transplante , Antígeno CTLA-4/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Galectina 1/imunologia , Galectina 3/imunologia , Galectinas/imunologia , Humanos , Imunomodulação/imunologia , Ativação Linfocitária/imunologia , Neoplasias/imunologia , Polissacarídeos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologiaRESUMO
T-cell therapies have made significant improvements in cancer treatment over the last decade. One cellular therapy utilizing T-cells involves the use of a chimeric MHC-independent antigen-recognition receptor, typically referred to as a chimeric antigen receptor (CAR). CAR molecules, while mostly limited to the recognition of antigens on the surface of tumor cells, can also be utilized to exploit the diverse repertoire of macromolecules targetable by antibodies, which are incorporated into the CAR design. Leaning into this expansion of target macromolecules will enhance the diversity of antigens T-cells can target and may improve the tumor-specificity of CAR T-cell therapy. This review explores the types of macromolecules targetable by T-cells through endogenous and synthetic antigen-specific receptors.
Assuntos
Antígenos/metabolismo , Imunidade Celular , Substâncias Macromoleculares/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Animais , Humanos , Polissacarídeos/metabolismo , RNA/metabolismoRESUMO
Activating RAS missense mutations are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here we employ a multi-omics approach to characterize HLA class I-restricted mKRAS epitopes. We provide proteomic evidence of mKRAS epitope processing and presentation by high prevalence HLA class I alleles. Select epitopes are immunogenic enabling mKRAS-specific TCRαß isolation. TCR transfer to primary CD8+ T cells confers cytotoxicity against mKRAS tumor cell lines independent of histologic origin, and the kinetics of lytic activity correlates with mKRAS peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8+ T cells leads to tumor eradication in a xenograft model of metastatic lung cancer. This study validates mKRAS peptides as bona fide epitopes facilitating the development of immune therapies targeting this oncoprotein.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinogênese/imunologia , Epitopos de Linfócito T/imunologia , Neoplasias Pulmonares/imunologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Transferência Adotiva , Alelos , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Peptídeos/genética , Peptídeos/imunologia , Proteômica , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Coevolutionary adaptation between humans and helminths has developed a finely tuned balance between host immunity and chronic parasitism due to immunoregulation. Given that these reciprocal forces drive selection, experimental models of helminth infection are ideally suited for discovering how host protective immune responses adapt to the unique tissue niches inhabited by these large metazoan parasites. This review highlights the key discoveries in the immunology of helminth infection made over the last decade, from innate lymphoid cells to the emerging importance of neuroimmune connections. A particular emphasis is placed on the emerging areas within helminth immunology where the most growth is possible, including the advent of genetic manipulation of parasites to study immunology and the use of engineered T cells for therapeutic options. Lastly,we cover the status of human challenge trials with helminths as treatment for autoimmune disease, which taken together, stand to keep the study of parasitic worms at the forefront of immunology for years to come.
Assuntos
Helmintíase , Helmintos , Parasitos , Animais , Interações Hospedeiro-Parasita , Humanos , Imunidade Inata , Linfócitos , Linfócitos TRESUMO
CD19-specific CAR-T cell therapies are the gold standard of adoptive cellular immunotherapy for hematopoietic malignancies. In Science Translational Medicine, Park et al. develop an oncolytic vaccinia virus that introduces truncated CD19 expression in solid tumors, which are then eradicated by CD19-specific CAR-T cells in immunodeficient and immunocompetent mouse models.
Assuntos
Neoplasias , Vírus Oncolíticos , Animais , Antígenos CD19 , Imunoterapia , Imunoterapia Adotiva , Camundongos , Neoplasias/terapia , Linfócitos T/imunologiaRESUMO
CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) T cells or bispecific T cell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with T cell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.
Assuntos
Barreira Hematoencefálica/metabolismo , Células Epiteliais/metabolismo , Imunoterapia Adotiva/efeitos adversos , Animais , Anticorpos Biespecíficos/imunologia , Antígenos CD19/imunologia , Linfócitos B/imunologia , Barreira Hematoencefálica/imunologia , Encéfalo/imunologia , Encéfalo/metabolismo , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Músculo Liso Vascular/metabolismo , Neoplasias , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Análise de Célula Única/métodos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We stand against racism and discrimination in cancer research in the U.S. By sharing the stories of scientists from different ethnicities, identities, and national origins, we want to promote change through mentoring, active participation, and policy changes and to inspire the next generation of cancer researchers: we make better science together.