Hepatotoxicity with Combination of Vemurafenib and Ipilimumab

Ribas, Antoni; Hodi, F. Stephen; Callahan, Margaret K.; Konto, Cyril; Wolchok, Jedd D.

doi:10.1056/nejmc1302338

Cited by 645 publications

(447 citation statements)

References 5 publications

Supporting

Mentioning

424

Contrasting

Unclassified

Order By: Relevance

“…The toxicity that emerges after combination therapy can be unexpected, as illustrated when ipilimumab was combined with vemurafenib 67 ; in this case, neither agent, when given as a single agent, resulted in unacceptable liver toxicity; the combination, however, elicited severe liver toxicity that resulted in termination of the trial. Biomarker studies of tumor biopsies have identified tumor and immune markers predictive of beneficial anti-tumor responses to checkpoint therapy 68 , including PD-L1 expression on tumor cells and CD8 + T cell infiltration of the TME.…”

Section: Autoimmune Consequencesmentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

308

View full text Add to dashboard Cite

Section: Autoimmune Consequencesmentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

308

View full text Add to dashboard Cite

“…An important clinical experiment combined the BRAF inhibitor, vemurafenib, with ipilimumab in the treatment of melanoma. This combination suffered from excessive toxicity, particularly in the liver (21). This experience serves as a warning when combining new agents.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

Sagiv-Barfi

Kohrt

Czerwinski

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

390

323

View full text Add to dashboard Cite

Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.ibrutinib | PD-1/PD-L1 blockade | lymphoma | solid tumors

show abstract

“…However, an early attempt to combine this drug with ipilimumab was aborted when trial participants showed signs of possible liver damage 5 . No one was injured, but for some it was an important reminder that combinations can yield unantici pated side effects.…”

Section: Riding the Wavementioning

confidence: 99%

Cocktails for cancer with a measure of immunotherapy

Ledford¹

2016

Nature

View full text Add to dashboard Cite

Hepatotoxicity with Combination of Vemurafenib and Ipilimumab

Cited by 645 publications

References 5 publications

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

Cocktails for cancer with a measure of immunotherapy

Contact Info

Product

Resources

About