RESUMO
BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.
Assuntos
Linfoma não Hodgkin , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Humanos , Anticorpos , Antígenos CD19 , Epitopos/metabolismo , Imunoterapia Adotiva/efeitos adversos , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/metabolismo , Recidiva Local de Neoplasia/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidoresRESUMO
The PD-1/PD-L1 pathway is a key immune checkpoint that regulates T cell activation. There is strong rationale to develop PD-1 agonists as therapeutics against autoimmunity, but progress in this area has been limited. Here, we generated T cell receptor (TCR) targeting, PD-1 agonist bispecifics called ImmTAAI molecules that mimic the ability of PD-L1 to facilitate the colocalization of PD-1 with the TCR complex at the target cell-T cell interface. PD-1 agonist ImmTAAI molecules specifically bound to target cells and were highly effective in activating the PD-1 receptor on interacting T cells to achieve immune suppression. Potent PD-1 antibody ImmTAAI molecules closely mimicked the mechanism of action of endogenously expressed PD-L1 in their localization to the target cell-T cell interface, inhibition of proximal TCR signaling events, and suppression of T cell function. At picomolar concentrations, these bispecifics suppressed cytokine production and inhibited CD8+ T cell-mediated cytotoxicity in vitro. Crucially, in soluble form, the PD-1 ImmTAAI molecules were inactive and, hence, could avoid systemic immunosuppression. This study outlines a promising new route to generate more effective, potent, tissue-targeted PD-1 agonists that can inhibit T cell function locally with the potential to treat autoimmune and chronic inflammatory diseases of high unmet need.
Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , HumanosRESUMO
Activation of T cells by agonistic peptide-MHC can be inhibited by antagonistic ones. However, the exact mechanism remains elusive. We used Jurkat cells expressing two different TCRs and tested whether stimulation of the endogenous TCR by agonistic anti-Vß8 antibodies can be modulated by ligand-binding to the second, optogenetic TCR. The latter TCR uses phytochrome B tetramers (PhyBt) as ligand, the binding half-life of which can be altered by light. We show that this half-life determined whether the PhyBt acted as a second agonist (long half-life), an antagonist (short half-life) or did not have any influence (very short half-life) on calcium influx. A mathematical model of this cross-antagonism shows that a mechanism based on an inhibitory signal generated by early recruitment of a phosphatase and an activating signal by later recruitment of a kinase explains the data.
Assuntos
Optogenética , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Anticorpos/metabolismo , Membrana Celular/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Meia-Vida , Humanos , Células Jurkat , Ligantes , Modelos Biológicos , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
BACKGROUND: Oncolytic virotherapy with vaccinia virus (VV) can lead to effective anti-tumor immunity by turning "cold" tumors into "hot" tumors. However, its therapeutic potential is affected by the tumor's local immunosuppressive tumor microenvironment (TME). Therefore, it is necessary to explore the use of immune checkpoint inhibitors to arm oncolytic VVs to enhance their anti-tumor efficacy. METHODS: A novel recombinant oncolytic VV, VV-α-TIGIT, which encoded a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT) was generated by homologous recombination with a shuttle plasmid. The anti-tumor efficacy of the VV-α-TIGIT was investigated in several subcutaneous and ascites tumor models. FINDINGS: The functional α-TIGIT was sufficiently produced and secreted by tumor cells infected with VV-α-TIGIT, which effectively replicated in tumor cells leading to significant oncolysis. Intratumoral injection of VV-α-TIGIT improved anti-tumor efficacy in several murine subcutaneous tumor models compared to VV-Control (without α-TIGIT insertion). Intraperitoneal injection of VV-α-TIGIT achieved approximately 70% of complete tumor regression in an ascites tumor model. At the same time, treatment with VV-α-TIGIT significantly increased the recruitment and activation of T cells in TME. Moreover, the in vivo anti-tumor activity of VV-α-TIGIT was largely dependent on CD8+ T cell-mediated immunity. Finally, the tumor-bearing mice cured of VV-α-TIGIT treatment resisted rechallenge with the same tumor cells, suggesting a long-term persistence of tumor-specific immunological memory. INTERPRETATION: The recombinant oncolytic virus VV-α-TIGIT successfully combines the advantages of oncolytic virotherapy and intratumorally expression of immune checkpoint inhibitor against TIGIT. This novel strategy can provide information on the optimal design of novel antibody-armed oncolytic viruses for cancer immunotherapy. FUNDING: This work was supported by the National Natural Science Foundation of China (81773255, 81472820, and 81700037), the Science and Technology Innovation Foundation of Nanjing University (14913414), and the Natural Science Foundation of Jiangsu Province of China (BK20171098).
Assuntos
Anticorpos Monoclonais/genética , Vetores Genéticos/genética , Imunoterapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Vaccinia virus/genética , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ordem dos Genes , Engenharia Genética , Vetores Genéticos/administração & dosagem , Humanos , Memória Imunológica , Imunofenotipagem , Masculino , Camundongos , Vírus Oncolíticos/imunologia , Domínios e Motivos de Interação entre Proteínas/genética , Domínios e Motivos de Interação entre Proteínas/imunologia , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Linfócitos T/metabolismo , Transgenes , Resultado do Tratamento , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Proinflammatory cytokines released from the pancreatic islet immune cell infiltrate in type 1 diabetes (T1D) cause insulinopenia as a result of severe beta cell loss due to apoptosis. Diabetes prevention strategies targeting different cytokines with antibodies in combination with a T cell antibody, anti-TCR, have been assessed for therapy success in the LEW.1AR1-iddm (IDDM) rat, an animal model of human T1D. Immediately after diabetes manifestation, antibody combination therapies were initiated over 5 days with anti-TNF-α (tumour necrosis factor), anti-IL-1ß (interleukin), or anti-IFN-γ (interferon) together with anti-TCR for the reversal of the diabetic metabolic state in the IDDM rat. Anti-TCR alone showed only a very limited therapy success with respect to a reduction of immune cell infiltration and beta cell mass regeneration. Anti-TCR combinations with anti-IL-1ß or anti-IFN-γ were also not able to abolish the increased beta cell apoptosis rate and the activated immune cell infiltrate leading to a permanent beta cell loss. In contrast, all anti-TCR combinations with anti-TNF-α provided sustained therapy success over 60 to 360 days. The triple combination of anti-TCR with anti-TNF-α plus anti-IL-1ß was most effective in regaining sustained normoglycaemia with an intact islet structure in a completely infiltration-free pancreas and with a normal beta cell mass. Besides the triple combination, the double antibody combination of anti-TCR with anti-TNF-α proved to be the most suited therapy for reversal of the T1D metabolic state due to effective beta cell regeneration in an infiltration free pancreas. KEY MESSAGES: Anti-TCR is a cornerstone in combination therapy for autoimmune diabetes reversal. The combination of anti-TCR with anti-TNF-α was most effective in reversing islet immune cell infiltration. Anti-TCR combined with anti-IL-1ß was not effective in this respect. The combination of anti-TCR with anti-TNF-α showed a sustained effect over 1 year.
Assuntos
Anticorpos Monoclonais/farmacologia , Citocinas/antagonistas & inibidores , Diabetes Mellitus Tipo 1/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Diabetes Mellitus Tipo 1/etiologia , Gerenciamento Clínico , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ratos , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Linfócitos T/metabolismoAssuntos
Anti-Inflamatórios/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Cadeias alfa de HLA-DR/genética , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Proteínas Recombinantes/farmacologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Antígenos de Diferenciação de Linfócitos B/metabolismo , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Glicoproteína Mielina-Oligodendrócito/genética , Pandemias , Pneumonia Viral/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , SARS-CoV-2RESUMO
CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes.
Assuntos
Antígenos/imunologia , Antígenos CD5/metabolismo , Diferenciação Celular/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Reguladores/fisiologia , Animais , Antígenos CD5/genética , Diferenciação Celular/genética , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/genética , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
Adoptive immunotherapy can induce sustained therapeutic effects in some cancers. Antitumor T-cell grafts are often individually prepared in vitro from autologous T cells, which requires an intensive workload and increased costs. The quality of the generated T cells can also be variable, which affects the therapy's antitumor efficacy and toxicity. Standardized production of antitumor T-cell grafts from third-party donors will enable widespread use of this modality if allogeneic T-cell responses are effectively controlled. Here, we generated HLA class I, HLA class II, and T-cell receptor (TCR) triple-knockout (tKO) T cells by simultaneous knockout of the B2M, CIITA, and TRAC genes through Cas9/sgRNA ribonucleoprotein electroporation. Although HLA-deficient T cells were targeted by natural killer cells, they persisted better than HLA-sufficient T cells in the presence of allogeneic peripheral blood mononuclear cells (PBMC) in immunodeficient mice. When transduced with a CD19 chimeric antigen receptor (CAR) and stimulated by tumor cells, tKO CAR-T cells persisted better when cultured with allogeneic PBMCs compared with TRAC and B2M double-knockout T cells. The CD19 tKO CAR-T cells did not induce graft-versus-host disease but retained antitumor responses. These results demonstrated the benefit of HLA class I, HLA class II, and TCR deletion in enabling allogeneic-sourced T cells to be used for off-the-shelf adoptive immunotherapy.
Assuntos
Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe I/química , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Aloenxertos , Animais , Antígenos CD19/imunologia , Sistemas CRISPR-Cas , Células Cultivadas , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Leucócitos Mononucleares , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/imunologia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3ζ- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.
Assuntos
Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos Quiméricos/química , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/efeitos dos fármacos , Engenharia Celular , Células Cultivadas , Humanos , Imunoterapia Adotiva , Células Jurkat , Ativação Linfocitária/efeitos dos fármacos , Células PC-3 , Ligação Proteica , Engenharia de Proteínas , Multimerização Proteica , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/química , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Currently, there is a multitude of CD3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. The key safety concerns with CD3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (CRS), target organ toxicity due to redirection of T-cells to normal tissues expressing the tumor-associated antigen (TAA) (off-tumor/on-target cytotoxicity), and, in some instances, neurotoxicity. Another key challenge is to arrive at a safe clinical starting dose and an efficient escalating strategy that allows patients in early dose cohorts the potential for clinical benefit in Phase 1 trials. To expand the therapeutic index and bring more treatment options to patients, there are intense efforts to overcome these challenges through improvements in molecular design, preclinical safety assessment strategies, and clinical management practices. A recent workshop at the U.S. Food and Drug Administration (FDA) with industry, academic, and regulatory agency representation was held to discuss the challenges and explore where such improvements to the development of CD3 bispecifics can be implemented. Here, the content of the presentations and the discussion that occurred during this workshop are summarized.
Assuntos
Anticorpos Biespecíficos/toxicidade , Antígenos de Neoplasias/metabolismo , Antineoplásicos/toxicidade , Complexo CD3/antagonistas & inibidores , Síndrome da Liberação de Citocina/prevenção & controle , Animais , Anticorpos Biespecíficos/administração & dosagem , Antígenos de Neoplasias/imunologia , Antineoplásicos/administração & dosagem , Complexo CD3/imunologia , Complexo CD3/metabolismo , Consenso , Conferências de Consenso como Assunto , Síndrome da Liberação de Citocina/induzido quimicamente , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais/normas , Europa (Continente) , Humanos , Japão , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Pesquisa Translacional Biomédica/normas , Estados Unidos , United States Food and Drug AdministrationRESUMO
This report addresses whether small molecules can deplete FoxP3-expressing regulatory T (T reg) cells, thereby augmenting antitumor immunity. Imatinib, a tyrosine kinase inhibitor of oncogenic BCR-ABL protein expressed by chronic myelogenous leukemia (CML) cells, possesses off-targets including LCK expressed in T cells. We showed that imatinib-treated CML patients in complete molecular remission (CMR) exhibited selective depletion of effector T reg (eT reg) cells and significant increase in effector/memory CD8+ T cells while non-CMR patients did not. Imatinib at CML-therapeutic concentrations indeed induced apoptosis specifically in eT reg cells and expanded tumor antigen-specific CD8+ T cells in vitro in healthy individuals and melanoma patients, and suppressed colon tumor growth in vivo in mice. Mechanistically, because of FoxP3-dependent much lower expression of LCK and ZAP-70 in T reg cells compared with other T cells, imatinib inhibition of LCK further reduced their TCR signal intensity, rendering them selectively susceptible to signal-deprived apoptotis. Taken together, eT reg cell depletion by imatinib is instrumental in evoking effective immune responses to various cancers.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Imunidade/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Camundongos Transgênicos , Inibidores de Proteínas Quinases/farmacologia , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Resultado do TratamentoRESUMO
Inhibitors of Bruton tyrosine kinase (BTK), a kinase downstream of BCR, display remarkable activity in a subset of mantle cell lymphoma (MCL) patients, but the drug resistance remains a considerable challenge. In this study, we demonstrate that aberrant expression of ROR1 (receptor tyrosine kinase-like orphan receptor 1), seen in a large subset of MCL, results in BCR/BTK-independent signaling and growth of MCL cells. ROR1 forms a functional complex with CD19 to persistently activate the key cell signaling pathways PI3K-AKT and MEK-ERK in the BCR/BTK-independent manner. This study demonstrates that ROR1/CD19 complex effectively substitutes for BCR-BTK signaling to promote activation and growth of MCL cells. Therefore, ROR1 expression and activation may represent a novel mechanism of resistance to inhibition of BCR/BTK signaling in MCL. Our results provide a rationale to screen MCL patients for ROR1 expression and to consider new therapies targeting ROR1 and/or CD19 or their downstream signaling pathways for MCL-expressing ROR1.
Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Linfoma de Célula do Manto/patologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/metabolismo , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/antagonistas & inibidores , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: To date, breakthrough chimeric antigen receptor (CAR) T-cell therapies, such as tisagenlecleucel, indicated for pediatric acute lymphoblastic leukemia (pALL) and diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel, indicated for DLBCL, although clinically effective, have been limited by treatment delays. Our study measured the social value of CAR T-cell therapy (CAR T) for relapsed or refractory pALL and DLBCL in the United States and quantified social value lost due to treatment delays. STUDY DESIGN: We used an economic framework for therapy valuation, measuring social value as the sum of consumer surplus and manufacturer profit. Consumer surplus is the difference between the value of health gains from a therapy and its incremental cost, while accounting for indirect costs and benefits to patients. METHODS: For 20 incident cohorts of pALL (n = 20 × 400 = 8000) and DLBCL (n = 20 × 5902 = 118,040), we quantified patient value, calculated as the value of additional quality-adjusted life-years gained with CAR T, minus the incremental cost of CAR T compared with standard of care (SOC). We calculated manufacturer profits using a range of production costs given uncertainties in the production process. Patient value and manufacturer profits were summed to obtain total social value. We measured social value lost from treatment delays, assuming that patients received the SOC while awaiting CAR T-cell treatment. RESULTS: Depending on production costs, as much as $6.5 billion and $34.8 billion in social value was generated for patients with pALL and DLBCL, respectively. However, with 1, 2, or 6 months of treatment delay (assuming $200,000 production costs), the pALL population lost 9.8%, 36.2%, and 67.3% of social value, respectively, whereas the DLBCL population lost 4.2%, 11.5%, and 46.0%, relative to no delay. CONCLUSIONS: The social value of CAR T is significantly limited by treatment delays. Efficient payment mechanisms, adequate capital, and payment policy reform are urgently needed to increase patient access and maximize the value of CAR T.
Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Tempo para o Tratamento/economia , Antígenos CD19/economia , Antígenos CD19/uso terapêutico , Produtos Biológicos , Indústria Farmacêutica/economia , Gastos em Saúde , Humanos , Imunoterapia Adotiva , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , Receptores de Antígenos de Linfócitos T/uso terapêuticoRESUMO
In addition to a role in translation, AIMP1 is secreted to affect various immune cells, such as macrophages, dendritic cells, B cells, and natural killer cells. However, the direct effects of AIMP1 on T cells have not yet been reported. In this study, we investigated whether AIMP1 could modulate T cell responses directly. Results revealed that AIMP1 significantly inhibited T cell receptor (TCR)-dependent activation and proliferation of CD4 T cells, as well as decreased TCR stimuli-induced Ca2+ influx in CD4 T cells. In addition, microscopic analysis revealed that lipid raft association in response to TCR engagement was significantly reduced in the presence of AIMP1, and the phosphorylation of PLCγ and PI3K was also down-regulated in CD4 T cells by AIMP1. Furthermore, AIMP1 specifically enhanced the differentiation of regulatory T (Treg) cells, while it had no effect on T helper type 1 (Th1), type 2 (Th2), and type 17 (Th17) cell differentiation. Collectively, these results indicate that AIMP1 affects T cells directly by down-regulating TCR signaling complex formation and inducing Treg cell differentiation in CD4 T cells.
Assuntos
Citocinas/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Microdomínios da Membrana/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Cálcio/imunologia , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/imunologia , Feminino , Regulação da Expressão Gênica , Imunofenotipagem , Transporte de Íons/efeitos dos fármacos , Microdomínios da Membrana/imunologia , Microdomínios da Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/imunologia , Fosfolipase C gama/genética , Fosfolipase C gama/imunologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologiaRESUMO
Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.
Assuntos
Antineoplásicos/farmacologia , Carcinogênese/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , China , Estudos de Coortes , Variações do Número de Cópias de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Esôfago/patologia , Esôfago/cirurgia , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genética , Transcriptoma/genética , Sequenciamento do Exoma/métodosRESUMO
A variety of natural compounds have been shown to modulate T cell receptor (TCR) activation, including natural sesquiterpene lactones (SLs). In the present studies, we evaluated the biological activity of 11 novel semi-synthetic SLs to determine their ability to modulate TCR activation. Of these compounds, α -epoxyarglabin, cytisinyl epoxyarglabin, 1 ß ,10 α -epoxyargolide, and chloroacetate grosheimin inhibited anti-CD3-induced Ca2+ mobilization and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in Jurkat T cells. We also found that the active SLs depleted intracellular glutathione (GSH) in Jurkat T cells, supporting their reactivity towards thiol groups. Because the zeta-chain associated tyrosine kinase 70 kDa (ZAP-70) is essential for TCR signaling and contains a tandem SH2 region that is highly enriched with multiple cysteines, we performed molecular docking of natural SLs and their semi-synthetic derivatives into the ZAP-70 binding site. The docking showed that the distance between the carbon atom of the exocyclic methylene group and the sulfur atom in Cys39 of the ZAP-70 tandem SH2 module was 3.04â»5.3 Å for active compounds. Furthermore, the natural SLs and their derivatives could be differentiated by their ability to react with the Cys39 SH-group. We suggest that natural and/or semi-synthetic SLs with an α -methylene- γ -lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation.
Assuntos
Glutationa/metabolismo , Lactonas/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Sesquiterpenos/metabolismo , Proteína-Tirosina Quinase ZAP-70/metabolismo , Comunicação Celular , Humanos , Células Jurkat , Lactonas/síntese química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Sesquiterpenos/síntese química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Adoptive infusion of chimeric antigen receptor transduced T- cells (CAR-T) is a powerful tool of immunotherapy for hematological malignancies, as evidenced by recently published and unpublished clinical results. OBJECTIVE: In this report, we performed a meta-analysis to evaluate the efficacy and side effects of CAR-T on refractory and/or relapsed B-cell malignancies, including leukemia and lymphoma. METHODS: Clinical studies investigating efficacy and safety of CAR-T in acute and chronic lymphocytic leukemia and lymphoma were identified by searching PubMed and EMBASE. Outcomes of efficacy subjected to analysis were the rates of complete remission (CR) and partial remission (PR). The safety parameters were the prevalence of adverse effects including fever, hypotension, and acute renal failure. Meta analyses were performed using R software. Weighted hazard ratio (HR) with 95% confidence intervals was calculated for each outcome. Fixed or random-effects models were employed depending on the heterogeneity across the included studies. RESULTS: Nineteen published clinical studies with a total of 391 patients were included for the meta-analysis. The pooled rate of complete remission was 55% (95% CI 41%-69%); the pooled rate of partial remission was 25% (95% CI: 19%-33%). The prevalence of fever was 62% (95% CI: 41%-79%), the hypotension was 22% (95% CI: 15%-31%), and the acute renal failure was 24% (95% CI: 16%-34%). All adverse effects were manageable and no death was reported due to toxicity. CONCLUSION: CD19-targeted CAR-T is an effective modality in treating refractory B-cell malignancies including leukemia and lymphoma. However, there is still a need to develop strategies to improve the safety in its clinical use.
Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva , Linfoma de Células B/terapia , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células B/imunologia , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
PURPOSE OF REVIEW: This review describes cardiotoxicity associated with adoptive T cell therapy and immune checkpoint blockade. RECENT FINDINGS: Cardiotoxicity is a rare but potentially fatal complication associated with novel immunotherapies. Both affinity-enhanced and chimeric antigen receptor T cells have been reported to cause hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Immune checkpoint inhibitors are generally well-tolerated but have the potential to cause myocarditis, with clinical presentations ranging from asymptomatic cardiac biomarker elevation to heart failure, arrhythmia, and cardiogenic shock. Electrocardiography, cardiac biomarker measurement, and cardiac imaging are key components of the diagnostic evaluation. For suspected myocarditis, endomyocardial biopsy is recommended if the diagnosis remains unclear after initial testing. The incidence of immunotherapy-associated cardiotoxicity is likely underestimated and may increase as adoptive T cell therapy and immune checkpoint inhibitors are used in larger populations and for longer durations of therapy. Baseline and serial cardiac evaluation is recommended to facilitate early identification and treatment of cardiotoxicity.
Assuntos
Cardiotoxicidade/imunologia , Imunoterapia/efeitos adversos , Neoplasias/terapia , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/imunologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/imunologia , Humanos , Hipotensão/epidemiologia , Hipotensão/etiologia , Hipotensão/imunologia , Neoplasias/complicações , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/imunologia , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/imunologiaRESUMO
BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adolescente , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD19 , Criança , Pré-Escolar , Feminino , Humanos , Infusões Intravenosas , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Análise de Sobrevida , Adulto JovemRESUMO
Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design: TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35-55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35-55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results: TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion: TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.