The approval last year of the immunotherapy drug Yervoy (ipilimumab) in the US and Europe was hailed as a major advance for the treatment of late-stage melanoma. The antibody drug, which promotes broad T cell function by blocking a surface protein called cytotoxic T lymphocyte antigen 4 (CTLA-4), can add years to a person's life, transforming metastatic skin cancer from a death sentence to a manageable condition. However, Yervoy works only in 20–30% of patients who take it, and the drug is often accompanied by severe or even fatal autoimmune side effects. So, the hunt has been on for safer and more broadly applicable immunotherapy strategies, and now a new class of cancer drug that boosts T cells in a more targeted fashion is showing early signs of dramatic success.
At last month's American Society of Clinical Oncology (ASCO) meeting in Chicago, researchers presented phase 1 trial data showing that blocking a protein called programmed death-1 (PD-1) could reduce tumor mass in a variety of cancers. For example, a PD-1–targeting agent from Bristol-Myers Squibb (BMS) called BMS-936558 either eliminated or shrank tumors in 49 of 203 people with advanced skin, kidney or lung cancer. Previous cancer immunotherapies have typically worked in smaller numbers of patients and in fewer types of cancer. The majority of the responses seen with BMS-936558 also lasted longer than one year, scientists reported at ASCO and concurrently in the New England Journal of Medicine (doi:10.1056/NEJMoa1200690, 2012).
Results like these are unprecedented in the field of cancer immunotherapy, says Kenneth May, a medical oncologist at the Dana-Farber Cancer Institute in Boston who was not involved with any of the current drug trials. “The exciting part about these anti–PD-1 antibodies is that they're shrinking away large metastatic tumors like lung and kidney that are typically pretty resistant to therapy,” he says.
Normally, PD-1, like CTLA-4, works to protect tissues from potentially self-reactive T cells. But in cancer some tumors have “co-opted this system as a mechanism of protecting themselves from immune attack,” explains Drew Pardoll, co-director of the Cancer Immunology and Hematopoiesis Program at the Johns Hopkins University School of Medicine in Baltimore.
Pardoll was involved in testing BMS-936558 as well as another BMS antibody directed at the PD-1 ligand (PD-L1) expressed by tumor cells. In a phase 1 trial, 16 of 118 people with skin, kidney or lung cancer treated with the PD-L1–directed agent showed an antitumor response (N. Engl. J. Med, doi:10.1056/NEJMoa1200694, 2012).
Better than Yervoy?
Because CTLA-4 binding can occur between T cells and many cells in the body—whereas PD-1's binding partner, PD-L1, is expressed at higher than normal levels on many tumor cells—researchers are hopeful that these new immunotherapy drugs will ultimately prove safer and more effective than Yervoy. The experimental antibodies have never been tested head-to-head with Yervoy, but BMS, which is headquartered in New York, is now testing BMS-936558 in combination with Yervoy in about 100 people with advanced melanoma. “It's still early days,” says Nils Lonberg, BMS's vice president of biologics discovery. But “they're interesting complementary pathways, so it could be the beginning of an arsenal of immunotherapeutic drugs.”
Several other drugmakers, including New Jersey–based Merck, Maryland-based Amplimmune and the Israeli company CureTech, are similarly targeting PD-1 in an effort to fight tumor cells. At ASCO, scientists presented preliminary data showing that Merck's drug, called MK-3475, helped shrink or stabilize solid tumors in four of nine people enrolled in an ongoing phase 1 trial. Meanwhile, South San Francisco–based Genentech has its own PD-L1–specific antibody in early clinical testing. According to Seamus Fernandez, an analyst at Leerink Swann in Boston, these drugs could collectively be worth $2 billion by the end of the decade.
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14 August 2012
In the July 2012 issue, the article entitled 'Cancer immunotherapy shows promise in multiple tumor types' (Nat. Med. 18, 993, 2012) incorrectly stated that the PD-1 ligand (PD-L1) is found only on tumor cells, when in fact it is expressed more widely. The error has been corrected in the HTML and PDF versions of the article.
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Heger, M. Cancer immunotherapy shows promise in multiple tumor types. Nat Med 18, 993 (2012). https://doi.org/10.1038/nm0712-993
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DOI: https://doi.org/10.1038/nm0712-993
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