PD-1 blockade in tumors with mismatch repair deficiency.

Le, Dung T.; Uram, Jennifer N.; Wang, Hao; Bartlett, Bjarne R.; Kemberling, Holly; Eyring, Aleksandra; Skora, Andrew D.; Azad, Nilofer S.; Laheru, Daniel A.; Donehower, Ross C.; Luber, Brandon; Crocenzi, Todd S.; Fisher, George A.; Duffy, Steve M; Lee, James J.; Koshiji, Minori; Eshleman, James R.; Anders, Robert A.; Vogelstein, Bert; Díaz, Luis A.

doi:10.1200/jco.2015.33.18_suppl.lba100

Cited by 587 publications

(892 citation statements)

References 26 publications

Supporting

Mentioning

838

Contrasting

Unclassified

Order By: Relevance

“…An example of this is the contrast between the strong preclinical responses to anti-CTLA-4 and anti-PD-L1 treatment in the CT26 model, derived from a murine colorectal tumor, and clinical responses in colorectal cancer in which, with the exception of patients with mismatch repair-deficient disease, limited activity with immune-checkpoint blockade has been observed to date (46).…”

Section: Discussionmentioning

confidence: 99%

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Mosely

Prime

Sainson

et al. 2017

Cancer Immunology Research

334

381

View full text Add to dashboard Cite

(word count: 239):Murine syngeneic tumor models are critical to novel immuno-based therapy development but the molecular and immunological features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly-used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We employed array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor 'inflamed' and 'non-inflamed' tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo.4

show abstract

Section: Discussionmentioning

confidence: 99%

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Mosely

Prime

Sainson

et al. 2017

Cancer Immunology Research

334

381

View full text Add to dashboard Cite

show abstract

“…Therefore, the US Food and Drug Administration approved them for treatment of patients with unresectable or metastatic melanoma and disease progression following Ipilimumab (anti-CTL4 antibody), and for B-Raf proto-oncogene, serine/ threonine kinase (BRAF) V600 mutation-positive patients with a BRAF inhibitor respectively. The improved response and prolonged survival of anti-PD-1/PD-L1 antibodies were also supported by other trials for patients with metastatic non-small cell lung cancer (NSCLC), hematological malignancies, renal cell cancer (RCC), bladder cancer, colon cancer and some other cancers [10][11][12][13][14][15][16][17][18][19][20]. However, systematic evaluation of the overall efficiency of anti-PD-1/PD-L1 antibodies for advanced or refractory cancer patients was limited.…”

Section: Introductionmentioning

confidence: 97%

The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: A meta-analysis.

Zhang

Fan

Shi

et al. 2017

JCO

View full text Add to dashboard Cite

Purpose: To systematically evaluate the overall efficacy and safety of current anti-PD-1/PD-L1 antibodies for treatment of patients with advanced or refractory cancer.Results: Fifty-one trials including 6,800 patients were included. The overall response rates for melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) were 29% (95% CI: 1.53−2.41), 21% (95% CI: 17%−25%) and 21% (95% CI: 16%−27%) respectively. While the overall adverse effects rate for melanoma, NSCLC, RCC were 16% (95% CI: 6%−28%), 11% (95% CI: 8%−14%) and 20% (95% CI :

show abstract

“…Rash/pruritus, pancreatitis, and thyroiditis/hypothyroidism were found to be the most common treatment-related adverse events, occurring in approximately 10% of patients. This phase II clinical trial proved that patients with mismatch-repair deficient tumors associated with a heavy load of somatic mutations respond to anti-PD1 therapy [3]. Based on this promising study, phase III trials investigating the effect of anti-PD-1 therapy in MSI-H colorectal cancer have been initiated.…”

Section: Results Of Clinical Trials With Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…However, CRC appears to be one of the tumor types that shows a poor response to immune checkpoint inhibitors, apart from the MSI CRC subtype which accounts for about 5% [2] of advanced and metastatic CRC [3]. So why don't immune checkpoint inhibitors work in MSS CRC?…”

Section: Introductionmentioning

confidence: 99%

Why Don’t Immune Checkpoint Inhibitors Work in Colorectal Cancer?

Shi¹,

Zou²,

Kerr³

2017

J Gastrointest Cancer Stromal Tumor

View full text Add to dashboard Cite

In recent years, immune checkpoint inhibitors have been shown to be effective in treating manifold types of cancer but less robust in colorectal cancer (CRC). While, the subgroup of CRC with microsatellite instability (MSI; also termed as mismatch repair deficient) showed a moderate response to Pembrolizumab in a single arm phase II clinical trial, microsatellite stable (MSS) cancers were unresponsive. Possible mechanisms that affect immune response in colorectal cancer will be reviewed in this article. We will also propose that histone deacetylase (HDAC) inhibition may reverse the immune editing commonly seen in advanced CRC and render them sensitive to immune checkpoint blockade.

show abstract

PD-1 blockade in tumors with mismatch repair deficiency.

Abstract: BACKGROUND-Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

Cited by 587 publications

References 26 publications

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: A meta-analysis.

Why Don’t Immune Checkpoint Inhibitors Work in Colorectal Cancer?

Contact Info

Product

Resources

About