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1.
Cancer Immunol Res ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833270

RESUMO

Allogeneic chimeric antigen receptor (CAR)-expressing T cells offer many advantages over autologous therapies, but their benefits are curtailed by graft-versus-host disease (GvHD) and elimination by recipient immune cells. Moreover, just as with autologous therapies, allogeneic CAR T cells are susceptible to activation-induced cell death (AICD) caused by chronic antigen exposure (CAE). Granzyme B (GzmB) and Fas/FasL-initiated, caspase-mediated apoptosis are key mechanisms of T-cell death caused by T/NK cell-mediated allorejection or CAE. We explored a protective strategy of engineering CAR T cells to overexpress variants of the GzmB-specific serine protease inhibitor, SerpinB9 (SB9), to improve allogeneic T-cell persistence and antitumor efficacy. We showed that the overexpression of an SB9 variant with broadened caspase specificity, SB9(CAS), not only significantly reduced rejection of allogeneic CAR T cells, but also increased their resistance to AICD and enabled them to thrive better under CAE, thus improving allogeneic T-cell persistence and antitumor activity in vitro and in vivo. In addition, while SB9(CAS)-overexpression improved the efficacy of allogeneic CAR T-cell therapy by conferring protection to cell death, we did not observe any autonomous growth and the engineered CAR T cells were still susceptible to an inducible suicide switch. Hence, SB9(CAS)-overexpression is a promising strategy that can strengthen current development of cell therapies, broadening their applications to address unmet medical needs.

2.
Blood Adv ; 5(20): 4112-4124, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34432872

RESUMO

Myelodysplastic syndrome (MDS) is a hematological malignancy characterized by blood cytopenias and predisposition to acute myeloid leukemia (AML). Therapies for MDS are lacking, particularly those that have an impact in the early stages of disease. We developed a model of MDS in zebrafish with knockout of Rps14, the primary mediator of the anemia associated with del(5q) MDS. These mutant animals display dose- and age-dependent abnormalities in hematopoiesis, culminating in bone marrow failure with dysplastic features. We used Rps14 knockdown to undertake an in vivo small-molecule screening, to identify compounds that ameliorate the MDS phenotype, and we identified imiquimod, an agonist of Toll-like receptor-7 (TLR7) and TLR8. Imiquimod alleviates anemia by promoting hematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation and Myd88. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature, indicating cross talk via TLR7 between proinflammatory pathways endogenous to Rps14 loss and the NF-κB pathway. Finally, in highly purified human bone marrow samples from anemic patients, imiquimod led to an increase in erythroid output from myeloerythroid progenitors and common myeloid progenitors. Our findings have both specific implications for the development of targeted therapeutics for del(5q) MDS and wider significance identifying a potential role for TLR7 ligation in modifying anemia.


Assuntos
Síndromes Mielodisplásicas , Peixe-Zebra , Animais , Hematopoese , Humanos , Síndromes Mielodisplásicas/genética , Transdução de Sinais , Receptor 7 Toll-Like/genética
3.
Commun Biol ; 4(1): 368, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33742099

RESUMO

High expression levels of human epidermal growth factor receptor 2 (HER2) have been associated with poor prognosis in patients with pancreatic adenocarcinoma (PDAC). However, HER2-targeting immunotherapies have been unsuccessful to date. Here we increase the breadth, potency, and duration of anti-PDAC HER2-specific CAR T-cell (HER2.CART) activity with an oncolytic adeno-immunotherapy that produces cytokine, immune checkpoint blockade, and a safety switch (CAdTrio). Combination treatment with CAdTrio and HER2.CARTs cured tumors in two PDAC xenograft models and produced durable tumor responses in humanized mice. Modifications to the tumor immune microenvironment contributed to the antitumor activity of our combination immunotherapy, as intratumoral CAdTrio treatment induced chemotaxis to enable HER2.CART migration to the tumor site. Using an advanced PDAC model in humanized mice, we found that local CAdTrio treatment of primary tumor stimulated systemic host immune responses that repolarized distant tumor microenvironments, improving HER2.CART anti-tumor activity. Overall, our data demonstrate that CAdTrio and HER2.CARTs provide complementary activities to eradicate metastatic PDAC and may represent a promising co-operative therapy for PDAC patients.


Assuntos
Adenoviridae/patogenicidade , Carcinoma Ductal Pancreático/terapia , Imunoterapia Adotiva , Terapia Viral Oncolítica , Vírus Oncolíticos/patogenicidade , Neoplasias Pancreáticas/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Antígeno B7-H1/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/virologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Interleucina-12/genética , Masculino , Metástase Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/virologia , Receptor ErbB-2/genética , Receptores de Antígenos Quiméricos/genética , Anticorpos de Cadeia Única/genética , Anticorpos de Cadeia Única/imunologia , Linfócitos T/imunologia , Carga Tumoral , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Mol Ther ; 28(5): 1251-1262, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32145203

RESUMO

No single cancer immunotherapy will likely defeat all evasion mechanisms of solid tumors, including plasticity of tumor antigen expression and active immune suppression by the tumor environment. In this study, we increase the breadth, potency, and duration of anti-tumor activity of chimeric antigen receptor (CAR) T cells using an oncolytic virus (OV) that produces cytokine, checkpoint blockade, and a bispecific tumor-targeted T cell engager (BiTE) molecule. First, we constructed a BiTE molecule specific for CD44 variant 6 (CD44v6), since CD44v6 is widely expressed on tumor but not normal tissue, and a CD44v6 antibody has been safely administered to cancer patients. We then incorporated this BiTE sequence into an oncolytic-helper binary adenovirus (CAdDuo) encoding an immunostimulatory cytokine (interleukin [IL]-12) and an immune checkpoint blocker (PD-L1Ab) to form CAdTrio. CD44v6 BiTE from CAdTrio enabled HER2-specific CAR T cells to kill multiple CD44v6+ cancer cell lines and to produce more rapid and sustained disease control of orthotopic HER2+ and HER2-/- CD44v6+ tumors than any component alone. Thus, the combination of CAdTrio with HER2.CAR T cells ensures dual targeting of two tumor antigens by engagement of distinct classes of receptor (CAR and native T cell receptor [TCR]), and significantly improves tumor control and survival.


Assuntos
Adenoviridae/metabolismo , Anticorpos Biespecíficos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Interleucina-12/uso terapêutico , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/metabolismo , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Feminino , Humanos , Receptores de Hialuronatos/imunologia , Receptores de Hialuronatos/metabolismo , Inibidores de Checkpoint Imunológico/metabolismo , Interleucina-12/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/metabolismo , Neoplasias/patologia , Células PC-3 , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Immunol Immunother ; 67(11): 1753-1765, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30167862

RESUMO

Epithelial ovarian cancer (EOC) is the most lethal of all gynecological malignancies in the UK. Recent evidence has shown that there is potential for immunotherapies to be successful in treating this cancer. We have previously shown the effective application of combinations of traditional chemotherapy and CAR (chimeric antigen receptor) T cell immunotherapy in in vitro and in vivo models of EOC. Platinum-based chemotherapy synergizes with ErbB-targeted CAR T cells (named T4), significantly reducing tumor burden in mice. Here, we show that paclitaxel synergizes with T4 as well, and look into the mechanisms behind the effectiveness of chemo-immunotherapy in our system. Impairment of caspase activity using pan-caspase inhibitor Z-VAD reveals this chemotherapy-induced apoptotic pathway as an essential factor in driving synergy. Mannose-6-phosphate receptor-mediated autophagy and the arrest of cell cycle in G2/M are also shown to be induced by chemotherapy and significantly contributing to the synergy. Increased expression of PD-1 on T4 CAR T cells occurred when these were in culture with ovarian tumor cells; on the other hand, EOC cell lines showed increased PD-L1 expression following chemotherapy treatment. These findings provided a rationale to look into testing PD-1 blockade in combination with paclitaxel and T4 immunotherapy. Combination of these three agents in mice resulted in significant reduction of tumor burden, compared to each treatment alone. In conclusion, the mechanism driving synergy in chemo-immunotherapy of EOC is multifactorial. A deeper understanding of such process is needed to better design combination therapies and carefully stratify patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Autofagia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sinergismo Farmacológico , Imunoterapia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário , Combinação de Medicamentos , Feminino , Humanos , Camundongos , Camundongos SCID , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas
6.
EMBO Rep ; 19(8)2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29907679

RESUMO

In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 in vitro and in vivo We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL-dependent oncogenic signalling.


Assuntos
Moléculas de Adesão Celular/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Benzocicloeptenos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Galinhas , Colesterol/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Tubas Uterinas/patologia , Feminino , Proteínas Ligadas por GPI/metabolismo , Inativação Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Invasividade Neoplásica , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Resultado do Tratamento , Triazóis/farmacologia , Receptor Tirosina Quinase Axl
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