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1.
Cancer Discov ; 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33811048

RESUMO

Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies. SIGNIFICANCE: Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies.

2.
J Transl Med ; 19(1): 142, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827575

RESUMO

The Great Debate session at the 2020 Melanoma Bridge virtual congress (December 3rd-5th, Italy) featured counterpoint views from experts on five specific controversial issues in melanoma. The debates considered whether or not innate immunity is important in the response to cancer and immunotherapy, how useful are the revised American Joint Committee on Cancer (AJCC) classification for the staging of patients, the use of sentinel node biopsy for staging patients, the use of triplet combination of targeted therapy plus immunotherapy versus combined immunotherapy, and the respective benefits of neoadjuvant versus adjuvant therapy. As is usual with Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their own personal opinion.

3.
Cancer Med ; 10(7): 2293-2299, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33686688

RESUMO

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies are a standard treatment for metastatic melanoma patients. However, the understanding of the efficacy of anti-PD-1 for acral melanoma (AM) and mucosal melanoma (MM) is limited as these subtypes are relatively rare compared to cutaneous melanoma (CM). METHODS: This single institution, retrospective cohort study included patients with advanced AM and MM who underwent anti-PD-1 therapy for metastatic melanoma between 2012 and 2018. Objective responses were determined using the investigator-assessed Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method. A Cox regression analysis was performed to identify the factors associated with survival outcomes. RESULTS: Ninety-seven patients were identified, 38 (39%) with AM and 59 (61%) with MM. The objective response rates (ORRs) were 21.0% and 15.2% in patients with AM and MM, respectively. The median PFS and OS were 3.6 and 25.7 months for AM patients, and 3.0 and 20.1 months for MM patients, respectively. Elevated serum lactate dehydrogenase (LDH) (AM: hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06-0.87; p = 0.03, MM: HR, 0.20; 95% CI, 0.08-0.53; p = 0.001) was significantly associated with shorter OS for both subtypes. CONCLUSIONS: The ORR, PFS, and OS with anti-PD-1 therapy were poor in patients with AM and MM compared to those previously reported clinical trials for nonacral CM. High serum LDH was associated with significantly shorter OS.

4.
Nat Med ; 27(2): 301-309, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33558722

RESUMO

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.


Assuntos
Melanoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/efeitos adversos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Adulto Jovem
5.
Clin Cancer Res ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414132

RESUMO

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike - prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for melanoma patients and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome and offer recommendations for the best path forward.

6.
Nat Biomed Eng ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398132

RESUMO

A large proportion of patients with cancer are unresponsive to treatment with immune checkpoint blockade and other immunotherapies. Here, we report a mathematical model of the time course of tumour responses to immune checkpoint inhibitors. The model takes into account intrinsic tumour growth rates, the rates of immune activation and of tumour-immune cell interactions, and the efficacy of immune-mediated tumour killing. For 124 patients, four cancer types and two immunotherapy agents, the model reliably described the immune responses and final tumour burden across all different cancers and drug combinations examined. In validation cohorts from four clinical trials of checkpoint inhibitors (with a total of 177 patients), the model accurately stratified the patients according to reduced or increased long-term tumour burden. We also provide model-derived quantitative measures of treatment sensitivity for specific drug-cancer combinations. The model can be used to predict responses to therapy and to quantify specific drug-cancer sensitivities in individual patients.

7.
Nat Med ; 26(10): 1557-1563, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33020648

RESUMO

Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients' outcomes1,2. We report on the efficacy, safety and biomarker analysis from the single-arm safety run-in (part 1; n = 9) and biomarker (part 2; n = 27) cohorts of the randomized, placebo-controlled, phase 3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n = 36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part 1, the recommended phase 3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400 mg of spartalizumab every 4 weeks plus 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. Part 2 characterized changes in PD-L1 levels and CD8+ cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3 months). Spartalizumab plus dabrafenib and trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade ≥3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, and 17% permanently discontinued all three study drugs due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T cell-inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety and on-treatment biomarker modulations associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified.

8.
Cancer Med ; 9(22): 8650-8661, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33016647

RESUMO

Elevated serum lactate dehydrogenase (sLDH) is associated with poor clinical outcomes in patients with stage IV metastatic melanoma (MM). It is currently unknown if sLDH elevation correlates with distinct molecular, metabolic, or immune features of melanoma metastases. The identification of such features may identify rational therapeutic strategies for patients with elevated sLDH. Thus, we obtained sLDH levels for melanoma patients with metastases who had undergone molecular and/or immune profiling. Our analysis of multi-omics data from independent cohorts of melanoma metastases showed that elevated sLDH was not significantly associated with differences in immune cell infiltrate, point mutations, DNA copy number variations, promoter methylation, RNA expression, or protein expression in melanoma metastases. The only significant association observed for elevated sLDH was with the number of metastatic sites of disease. Our data support that sLDH correlates with disease burden, but not specific molecular or immunological phenotypes, in metastatic melanoma.

11.
J Immunother Cancer ; 8(2)2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32843491

RESUMO

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report.

12.
J Immunother Cancer ; 8(1)2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32238470

RESUMO

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce-consisting of experts in cancer immunotherapy from academia, industry, and government-to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.

13.
Clin Cancer Res ; 26(9): 2083-2084, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32139404

RESUMO

Obtaining blood and cerebrospinal fluid is generally less invasive than standard tumor biopsy, and are increasingly used to develop surrogate biomarkers. Leptomeningeal disease, a devastating complication of cancer, represents a unique opportunity for using liquid biopsies for diagnosis, treatment, and to elucidate underlying mechanisms of resistance to therapy.See related article by Smalley et al., p. 2163.

14.
Clin Cancer Res ; 26(8): 1886-1895, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32015020

RESUMO

PURPOSE: There is a need for sensitive, reproducible biomarkers for patients with stage III melanoma to guide clinical decision making. Circulating tumor cells (CTCs) can be detected in patients with melanoma; however, there are limited data regarding their significance in stage III disease. The aim of this study was to determine whether CTCs are associated with early relapse in stage III melanoma. EXPERIMENTAL DESIGN: We prospectively assessed CTCs at first presentation in clinic (baseline) for 243 patients with stage III melanoma. CTCs were measured using the CellSearch System. Relapse-free survival (RFS) was compared between patients with one or more baseline CTC versus those with no CTCs. Log-rank test and Cox regression analysis were applied to establish associations of CTCs with RFS. RESULTS: At least one baseline CTC was identified in 90 of 243 (37%) patients. Forty-five (19%), 67 (28%), 118 (49%), and 13 (5%) patients were stage IIIA, IIIB, IIIC, or IIID, respectively. CTC detection was not associated with substage, or primary tumor characteristics. Multivariable analysis demonstrated that the detection of ≥1 baseline CTC was significantly associated with decreased 6-month RFS [log-rank, P < 0.0001; HR, 3.62, 95% confidence interval (CI), 1.78-7.36; P < 0.0001] and 54-month RFS (log-rank, P = 0.01; HR, 1.69; 95% CI, 1.13-2.54; P = 0.01). CONCLUSIONS: ≥1 CTC was independently associated with melanoma relapse, suggesting that CTC assessment may be useful to identify patients at risk for relapse who could derive benefit from adjuvant therapy.

15.
Nature ; 577(7791): 549-555, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942075

RESUMO

Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.


Assuntos
Linfócitos B/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Estruturas Linfoides Terciárias/imunologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Células Clonais/citologia , Células Clonais/imunologia , Células Clonais/metabolismo , Células Dendríticas Foliculares/citologia , Células Dendríticas Foliculares/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Memória Imunológica/imunologia , Espectrometria de Massas , Melanoma/patologia , Melanoma/cirurgia , Metástase Neoplásica/genética , Fenótipo , Prognóstico , RNA-Seq , Receptores Imunológicos/imunologia , Análise de Célula Única , Linfócitos T/citologia , Linfócitos T/imunologia , Transcriptoma
16.
Nature ; 577(7791): 556-560, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942077

RESUMO

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.


Assuntos
Linfócitos B/imunologia , Imunoterapia , Sarcoma/tratamento farmacológico , Sarcoma/imunologia , Estruturas Linfoides Terciárias/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Células Dendríticas Foliculares/imunologia , Humanos , Mutação , Fenótipo , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Reprodutibilidade dos Testes , Sarcoma/classificação , Sarcoma/patologia , Taxa de Sobrevida , Microambiente Tumoral
17.
Clin Cancer Res ; 26(6): 1258-1266, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31900276

RESUMO

PURPOSE: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. PATIENTS AND METHODS: Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response. RESULTS: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS). CONCLUSIONS: We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.

18.
Cancer Chemother Pharmacol ; 84(6): 1289-1301, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31549216

RESUMO

PURPOSE: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. METHODS: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1-7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard "3 + 3" design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC-MS/MS and AAS during cycles 1 and 2. RESULTS: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1-16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. CONCLUSION: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Benzimidazóis/toxicidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/toxicidade , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Carboplatina/toxicidade , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Paclitaxel/farmacocinética , Paclitaxel/toxicidade , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Resultado do Tratamento
19.
Clin Cancer Res ; 25(21): 6406-6416, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371342

RESUMO

PURPOSE: OX40 agonist-based combinations are emerging as a novel avenue to improve the effectiveness of cancer immunotherapy. To better guide its clinical development, we characterized the role of the OX40 pathway in tumor-reactive immune cells. We also evaluated combining OX40 agonists with targeted therapy to combat resistance to cancer immunotherapy.Experimental Design: We utilized patient-derived tumor-infiltrating lymphocytes (TILs) and multiple preclinical models to determine the direct effect of anti-OX40 agonistic antibodies on tumor-reactive CD8+ T cells. We also evaluated the antitumor activity of an anti-OX40 antibody plus PI3Kß inhibition in a transgenic murine melanoma model (Braf mutant, PTEN null), which spontaneously develops immunotherapy-resistant melanomas. RESULTS: We observed elevated expression of OX40 in tumor-reactive CD8+ TILs upon encountering tumors; activation of OX40 signaling enhanced their cytotoxic function. OX40 agonist antibody improved the antitumor activity of CD8+ T cells and the generation of tumor-specific T-cell memory in vivo. Furthermore, combining anti-OX40 with GSK2636771, a PI3Kß-selective inhibitor, delayed tumor growth and extended the survival of mice with PTEN-null melanomas. This combination treatment did not increase the number of TILs, but it instead significantly enhanced proliferation of CD8+ TILs and elevated the serum levels of CCL4, CXCL10, and IFNγ, which are mainly produced by memory and/or effector T cells. CONCLUSIONS: These results highlight a critical role of OX40 activation in potentiating the effector function of tumor-reactive CD8+ T cells and suggest further evaluation of OX40 agonist-based combinations in patients with immune-resistant tumors.


Assuntos
Anticorpos Anti-Idiotípicos/farmacologia , Melanoma/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Receptores OX40/imunologia , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Receptores OX40/antagonistas & inibidores
20.
Lancet Oncol ; 20(7): e378-e389, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31267972

RESUMO

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.


Assuntos
Melanoma/terapia , Terapia Neoadjuvante , Ensaios Clínicos como Assunto , Humanos , Melanoma/secundário , Seleção de Pacientes
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