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1.
Nat Cancer ; 2(1): 18-33, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121890

RESUMO

Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2- parental tumor. These results provide a strong rationale for the clinical development of ISACs.


Assuntos
Imunoterapia , Neoplasias , Imunidade Adaptativa , Animais , Antígenos de Neoplasias , Imunoterapia/métodos , Camundongos , Neoplasias/tratamento farmacológico , Microambiente Tumoral
2.
Cancer Discov ; 10(1): 40-53, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732494

RESUMO

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor A2A de Adenosina/química , Terapia de Salvação , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma de Células Renais/patologia , Feminino , Seguimentos , Furanos/administração & dosagem , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptor A2A de Adenosina/metabolismo , Taxa de Sobrevida
3.
Arch Phys Med Rehabil ; 90(12): 1977-82, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19969157

RESUMO

UNLABELLED: Chan DK, Lonsdale C, Ho PY, Yung PS, Chan KM. Patient motivation and adherence to postsurgery rehabilitation exercise recommendations: the influence of physiotherapists' autonomy-supportive behaviors. OBJECTIVE: To investigate the impact of physiotherapists' autonomy-supportive behaviors on patients' motivation and rehabilitation adherence after anterior cruciate ligament (ACL) reconstruction surgery. DESIGN: Retrospective study. SETTING: Outpatient orthopedic clinic of a university medical center. PARTICIPANTS: Postsurgery ACL reconstruction patients (N=115; minimum postsurgery interval, 6mo; mean +/- SD postsurgery interval, 1.77+/-0.8y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Questionnaires measuring autonomy support from physiotherapists (Health Care Climate Questionnaire), treatment motivation (Treatment Self-Regulation Questionnaire), and rehabilitation adherence (adapted from the Sport Injury Rehabilitation Adherence Scale and the Patient Self-Report Scales of Their Home-Based Rehabilitation Adherence). RESULTS: Structural equation modeling analyses revealed that patients' treatment motivation mediated the relationship between physiotherapists' autonomy-supportive behaviors and rehabilitation adherence. Autonomy-supportive behavior positively predicted autonomous treatment motivation (beta=.22, P<.05). Rehabilitation adherence (R(2)=.28) was predicted positively by autonomous motivation (beta=.64, P<.05) and negatively predicted by controlled motivation (beta=-.28, P<.05). CONCLUSIONS: These preliminary findings are promising and provide an empirical basis for further research to test the efficacy of autonomy support training designed to increase patients' rehabilitation adherence.


Assuntos
Traumatismos do Joelho/reabilitação , Motivação , Cooperação do Paciente , Cuidados Pós-Operatórios , Autonomia Profissional , Adulto , Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior , Feminino , Humanos , Traumatismos do Joelho/cirurgia , Masculino , Modalidades de Fisioterapia , Relações Profissional-Paciente , Estudos Retrospectivos , Inquéritos e Questionários
4.
Cancer Immunol Res ; 6(10): 1136-1149, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30131376

RESUMO

Adenosine signaling through A2A receptors (A2AR) expressed on immune cells suppresses antitumor immunity. CPI-444 is a potent, selective, oral A2AR antagonist. Blockade of A2AR with CPI-444 restored T-cell signaling, IL2, and IFNγ production that were suppressed by adenosine analogues in vitro CPI-444 treatment led to dose-dependent inhibition of tumor growth in multiple syngeneic mouse tumor models. Concentrations of extracellular adenosine in the tumor microenvironment, measured using microdialysis, were approximately 100-150 nmol/L and were higher than corresponding subcutaneous tissue. Combining CPI-444 with anti-PD-L1 or anti-CTLA-4 treatment eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti-PD-L1 or anti-CTLA-4 monotherapy. Tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. CD8+ T-cell depletion abrogated the efficacy of CPI-444 with and without anti-PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. The antitumor efficacy of CPI-444 with and without anti-PD-L1 was associated with increased T-cell activation, a compensatory increase in CD73 expression, and induction of a Th1 gene expression signature consistent with immune activation. These results suggest a broad role for adenosine-mediated immunosuppression in tumors and justify the further evaluation of CPI-444 as a therapeutic agent in patients with solid tumors. Cancer Immunol Res; 6(10); 1136-49. ©2018 AACR.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias do Colo/tratamento farmacológico , Furanos/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Furanos/farmacologia , Humanos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , Pirimidinas/farmacologia , Linfócitos T/efeitos dos fármacos
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