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Sep 20, 2012
 |  BC Innovations  |  Tools & Techniques

Strategic synergy

Researchers from the New York University School of Medicine have shown that induction of NKG2D ligands on poorly immunogenic tumor cells is a key molecular mechanism that contributes to the synergy of radiotherapy plus anti-CTLA-4 mAbs.1 The findings could be used to identify patients most likely to respond to anti-CTLA-4 treatments such as Bristol-Myers Squibb Co.'s melanoma drug Yervoy ipilimumab and could help pinpoint radiation regimens that enhance the treatment to potentially provide a new standard of care in the disease.

CTLA-4 (CD152)-mediated inhibition of T cell activation can prevent the development of antitumor T cell responses. Although there is a clear rationale for blocking CTLA-4, monotherapy with such agents is more successful in treating intrinsically immunogenic tumors than poorly immunogenic ones.

Researchers have been trying to increase the priming of antitumor T cells and establish greater anti-CTLA-4 mAb-mediated antitumor immunity in poorly immunogenic tumors. The three main routes of promoting a more immunogenic environment are vaccination, chemotherapy and radiotherapy.

Of those three options, the NYU researchers have been focused on using local radiation in combination with immunotherapy. In 2005, the team first showed in mice that local radiotherapy converted an unresponsive tumor into a tumor responsive to an anti-CTLA-4 mAb.2 In 2009, they showed that metastases located away from the site of local irradiation also responded to anti-CTLA-4 mAb treatment, a phenomenon dubbed an abscopal effect.3

More recently, three pilot studies, each highlighting one patient with metastatic melanoma, demonstrated that patients receiving radiotherapy plus Yervoy showed an abscopal effect and underwent complete remission.4,5

These studies led to clinical trials of the combination in melanoma by Stanford University and in prostate cancer by Bristol-Myers.

Bristol-Myers markets Yervoy as a monotherapy to treat melanoma. The drug is in...

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