Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade

BackgroundCD8+ tissue-resident memory T (TRM) cells, marked by CD103 (ITGAE) expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy.MethodsHere, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1)).ResultsITGAE was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ TRM cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion.ConclusionsOur analyses indeed demonstrate that the presence of CD103+ CD8+ TRM cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response.

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Appropriate endpoints for superficial bladder cancer clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.1987.5.12.2004 ◽

1987 ◽

Vol 5 (12) ◽

pp. 2004-2008 ◽

Cited By ~ 24

Author(s):

L A Kalish ◽

M B Garnick ◽

J P Richie

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Clinical Outcome ◽

Superficial Bladder Cancer ◽

Invasive Disease ◽

Actual Data ◽

Cancer Clinical Trials ◽

Data Sets ◽

End Points

Many protocols for treatment of superficial bladder cancer include periodic cystoscopic examinations with resection of visible lesions. This allows pathological restaging of the disease at each examination. For example, this type of follow-up is common in clinical trials evaluating intravesical therapies. In such trials, clinical outcome is typically summarized using end-points that measure failure to control superficial disease. Alternative endpoints measuring failure to prevent progression to invasive disease are often ignored. In this report, the rationale for ignoring the invasive disease endpoints is given and flaws in the rationale are described. Evidence from actual data sets support the view that superficial disease endpoints may not be appropriate surrogates for invasive disease endpoints. It is recommended that time to invasive disease should be considered a major endpoint when designing and analyzing trials in superficial bladder cancer.

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Bladder cancer clinical trials

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2005.05.005 ◽

2005 ◽

Vol 23 (4) ◽

pp. 275-279 ◽

Cited By ~ 26

Author(s):

Seth P. Lerner

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Cancer Clinical Trials

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Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.741316 ◽

2021 ◽

Vol 8 ◽

Author(s):

Vinodh Kannappan ◽

Misha Ali ◽

Benjamin Small ◽

Gowtham Rajendran ◽

Salena Elzhenni ◽

...

Keyword(s):

Clinical Trials ◽

Cancer Cells ◽

Cancer Progression ◽

Anticancer Agents ◽

Molecular Targets ◽

Cancer Therapeutics ◽

New Drugs ◽

Cancer Clinical Trials ◽

Anticancer Efficacy ◽

Wide Range

Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

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