Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients ...respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
Mechanisms of Resistance to PD-1 and PD-L1 Blockade Nowicki, Theodore S; Hu-Lieskovan, Siwen; Ribas, Antoni
The cancer journal (Sudbury, Mass.),
2018 Jan/Feb, 2018-1-00, 20180101, Letnik:
24, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Cancer immunotherapy utilizing blockade of the PD-1/PD-L1 checkpoint has revolutionized the treatment of a wide variety of malignancies, leading to durable therapeutic responses not typically seen ...with traditional cytotoxic anticancer agents. However, these therapies are ineffective in a significant percentage of patients, and some initial responders eventually develop resistance to these therapies with relapsed disease. The mechanisms leading to both primary and acquired resistance to PD-1/PD-L1 inhibition are varied and can be both multifactorial and overlapping in an individual patient. As the mechanisms of resistance to PD-1/PD-L1 blockade continue to be further characterized, new strategies are being developed to prevent or reverse resistance to therapy, leading to improved patient outcomes.
The combination of inhibitors to BRAF and MEK improved response rates and progression-free survival among patients with metastatic melanoma. Some toxicity was increased, but the incidence of second ...skin cancers was drastically reduced by the combination therapy.
Approximately 50% of metastatic cutaneous melanomas harbor a
BRAF
V600 mutation, resulting in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.
1
,
2
These discoveries led to the development of agents that specifically target this driver mutation. The BRAF inhibitor vemurafenib (Zelboraf, Genentech) was approved worldwide on the basis of results from a phase 3 trial showing improved progression-free survival and overall survival, as compared with chemotherapy alone; the relative reduction in the risk of death was 63% and in the risk of disease progression was 74%.
3
Similar results were also reported for another BRAF inhibitor, dabrafenib,
4
which has also . . .
The genetic, functional or compositional heterogeneity of healthy and diseased tissues presents major challenges in drug discovery and development. Such heterogeneity hinders the design of accurate ...disease models and can confound the interpretation of biomarker levels and of patient responses to specific therapies. The complex nature of virtually all tissues has motivated the development of tools for single-cell genomic, transcriptomic and multiplex proteomic analyses. Here, we review these tools and assess their advantages and limitations. Emerging applications of single cell analysis tools in drug discovery and development, particularly in the field of oncology, are discussed.
Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. ...During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years - and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma.
In a comparison of tumors from patients with melanoma who benefitted from blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) with tumors from patients who did not benefit, tumor neoantigens were ...detected that were strongly associated with a response.
Immune checkpoint blockade has led to durable antitumor effects in patients with metastatic melanoma, non–small-cell lung cancer, and other tumor types, but the factors determining whether a patient will have a response remain elusive.
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,
2
The fully human monoclonal antibodies ipilimumab and tremelimumab block cytotoxic T-lymphocyte antigen 4 (CTLA-4), resulting in T-cell activation. Some studies have established correlations between outcomes with ipilimumab and peripheral-blood lymphocyte count, markers of T-cell activation,
3
an “inflammatory” microenvironment,
4
,
5
and maintenance of high-frequency T-cell receptor clonotypes.
6
The relationship among the genomic landscape of the tumor, the mutational load, and the benefit from treatment remains obscure. . . .
The independent mechanisms of action and largely nonoverlapping toxicity profiles of vemurafenib and ipilimumab made it logical to test them together in a study of patients with melanoma. An ...unexpected level of hepatic toxicity caused the early termination of the study.
To the Editor:
There has been great interest in testing combination therapy with the BRAF inhibitor vemurafenib and the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)–blocking antibody ipilimumab, currently the only two agents approved for the treatment of advanced melanoma on the basis of improved overall survival.
1
Vemurafenib and ipilimumab have different mechanisms of action, and preclinical studies have suggested that BRAF inhibitors may enhance immune-cell function and antigen presentation.
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–
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The only clinically significant overlapping toxic effects for these agents are in skin and liver, which rarely limit their use in patients. Therefore, ample rationale exists to investigate combined therapy with . . .
The "cancer immunogram" Blank, Christian U.; Haanen, John B.; Ribas, Antoni ...
Science (American Association for the Advancement of Science),
05/2016, Letnik:
352, Številka:
6286
Journal Article
Recenzirano
Visualizing the state of cancer–immune system interactions may spur personalized therapy
The impact of cancer immunotherapy on clinical cancer care is growing rapidly. However, different ...immunotherapies remedy distinct problems in cancer–immune system interactions. What would be the most effective therapy for an individual patient? Here, a framework is proposed for describing the different interactions between cancer and the immune system in individual cases, with the aim to focus biomarker research and to help guide treatment choice.
In long-term follow-up of more than 500 patients with melanoma containing a
BRAF
V600E or V600K mutation, a combination of dabrafenib plus trametinib was associated with progression-free survival in ...19% of the patients and overall survival in 34% at 5 years. A complete response to dabrafenib plus trametinib was the strongest predictor of long-term survival.
In a multinational, randomized study, pembrolizumab produced significantly improved progression-free and overall survival and less high-grade toxicity than did ipilimumab in patients with metastatic ...melanoma.
Two therapeutic strategies have improved survival for patients with advanced melanoma in recent years: immunotherapy with checkpoint inhibitors and targeted therapies blocking BRAF and MEK.
1
BRAF and MEK inhibitors are indicated for the approximately 40 to 50% of patients with
BRAF
V600 mutations,
1
whereas immunotherapies are effective independently of
BRAF
mutational status.
2
Ipilimumab, which blocks cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), a coinhibitory molecule of the immune system,
3
,
4
is approved for treating advanced melanoma on the basis of its survival benefit.
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,
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However, grade 3 or 4 adverse events, mostly immune-related,
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are observed in 23% of patients.
5
,
6
When activated . . .
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