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Anti-PD1 Antibody ‘Rejuvenates’ T Cells

Carlson, Robert H.

doi: 10.1097/01.COT.0000419314.58976.0a

CHICAGO—A new antibody directed against the PD-1 pathway, which some solid tumor types use to shield themselves from the immune system, can be administered safely and produces durable clinical benefit in heavily pretreated patients, according to data reported here at the ASCO Annual Meeting and highlighted in a news briefing about promising targeted therapies for patients with difficult-to-treat cancers.

The effect of the therapy has been described as rejuvenating T cells that were blocked by tumor activation of the PD-1 pathway.

The Phase I study presented on the anti-PD-1 agent BMS-936558 (MDX-1106) showed impressive activity in otherwise treatment-refractory patients with advanced disease: a 28 percent objective-response rate in melanoma, 18 percent in non-small-cell lung cancer (NSCLC), and 27 percent in renal cell carcinoma (RCC) (Abstract CRA2509). These compare with rates of only about 10 to 15 percent, at most, seen with prior immunotherapy approaches.

The study results also point to a potential biomarker of response for the agent, said the first author, Suzanne L. Topalian, MD, Professor of Surgery and Oncology and Director of the Melanoma Program at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

A second study reported at the meeting, by Scott S. Tykodi, MD, PhD, Assistant Professor at the University of Washington, Division of Medical Oncology, and Assistant Member at Fred Hutchinson Cancer Research Center, Clinical Research Division, described the safety and activity of the BMS-936559 antibody, which targets the PD-1 ligand, PD-L1 (Abstract 2510).

Articles on each of the antibody studies also appeared online ahead of print in the New England Journal of Medicine the same day of their oral presentations at the meeting, and they were subsequently published in the June 28 print issue – NEJM 2012;366:2443–2454 and NEJM 2012;366:2455–2565, respectively, along with an accompanying editorial by Antoni Ribas, MD, PhD (NEJM 2012;366:2517–2519).

“In the past, immune therapies were tried with limited success as they were non-specific, but anti-PD-1 is a very specific immune therapy that has shown activity across multiple tumor types,” Topalian said at the news conference, explaining that the PD-1 molecule is expressed on the surface of activated immune cells and has a role in suppressing antitumor immunity.

Expression of PD-1 will turn the T-cell off, and if the T cell encounters a partner molecule, PD-L1 (PDLigand-1) on the tumor cell, the interaction between these two molecules creates a shield that protects the tumor from immune attack.

“Even if the T cell recognizes the tumor, if the T cell is expressing PD-1 and the tumor is expressing PD-L1, T cells will be turned off,” she said.

BMS-936558 is a blocking antibody against PD-1 that interrupts this interaction, rescuing or reinvigorating exhausted T cells and enhancing anti-tumor immunity.

In the Phase I trial she reported, which was supported by funding from Bristol-Myers Squibb, Ono Pharmaceutical, the National Institutes of Health, and the Melanoma Research Alliance, the drug was given in the outpatient clinic once every two weeks. Patients received four treatments over eight weeks, after which they were restaged.

Patients were eligible for the trial if they had advanced metastatic melanoma, kidney cancer, lung cancer, colorectal cancer, or prostate cancer with progressive disease after having at least one, but not more than five, prior therapies. Patients were followed for up to two years.

Serious side effects were experienced by 14 percent of patients, the most common being fatigue, rash, diarrhea, and pruritus. Topalian called the treatment well tolerated, with only five percent of patients (5/296) discontinuing treatment due to related adverse events.

There were three treatment-related deaths (1% of the total population) due to pneumonitis or lung inflammation, which were believed to have an immune-related etiology, she noted.

“Over the course of time we have developed better ways to identify people who are at risk for this side effect and better ways to detect it early on and treat it aggressively.”

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Clinical Activity

The study showed clinical activity in 236 patients with at least six months' follow-up. Among 94 patients with melanoma, 26 (28%) had objective responses, defined as either complete regression or significant partial regression of cancer. Stable disease, defined as lasting at least six months, occurred in another six percent.

In 76 patients with NSCLC, 14 (18%) had objective responses and five (7%) had stable disease.

And in 33 patients with RCC, nine (27%) had objective responses and another nine (27%) had stable disease.

“One of the more remarkable features of this therapy was that it induced very durable responses in otherwise treatment-refractory patients with advanced disease,” she said.

Twenty patients had a response lasting more than one year. No objective responses, however, were seen in the 19 colon cancer or the 13 prostate cancer patients.

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In the PD-L1 study, which had similar funding support, from Bristol-Myers Squibb, the NIH, and the Melanoma Research Alliance, Tykodi reported that among 207 patients, objective responses were seen in 17 percent of melanoma patients (9/52); 10 percent of NSCLC patients (5/49); 12 percent of patients with RCC (2/17); and six percent of the ovarian cancer patients (1/17).

There were no responses among those with other cancer types, including prostate cancer.

The anti-PD-L1 therapy caused grade 3 or 4 treatment-related adverse events in nine percent of patients, but no deaths, Tykodi reported.

Pretreatment biopsies of 42 patients analyzed for the presence of PD-L1 showed a correlation between PD-L1 expression and objective response rate, as 36 percent of patients (9/25) in that group had an objective response. If that expression was not seen on the surface of tumor cells, there was no response.

Topalian stressed that these are preliminary data, “but they give us an important lead in investigations and potential biomarker development.”

She said controlled clinical registration trials of both PD-1 and PD-L1 in the three type cancers in this trial are planned.

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Topalian characterized the two antibodies as “bookends” for treatment of PD-1/PD-L1-related cancers: “In both studies we saw objective tumor responses in patients with three lines of cancer: melanoma, kidney cancer, and lung cancer. And we saw additional patients with stable disease, and toxicities were generally manageable on both.

“In terms of ‘bookends,’ we have two drugs blocking two sides of the same interaction, and we're seeing similar results in terms of clinical responses.”

This suggests, that the interaction of those two molecules is an important pathway to target in cancer therapy, she said. “Whether you block one site or the other, I think the story is still out on what is going to be the most effective.”

Asked in the news conference about therapy with the two antibodies in combination, she said it is a possibility but it is not something she knows of being developed right now, “although it is theoretically interesting.”

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Mobilizing the Immune System

The Discussant for both studies, James P. Allison, PhD, Director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, noted that immunotherapy was not successful over many years of research because, in part, researchers didn't suspect how complex the regulation of T cell responses is.

The question raised by Topalian's study, he said, is whether efficacy is restricted to tumors that express PD-L1. If so, “that will make it easy to target the therapy against those patients who actually have a chance to respond to the drug,” he said.

“We have seen that many of the responses are a year to two years out now, but the question will be to see if these can go out as far as the response to ipilimumab.”

Another question is: how can these immune therapies be combined to increase response for more than just a fraction of patients?

Many labs are exploring combinations with vaccines to increase the efficacy of immune checkpoint blockade, he said. Blockade of additional immune checkpoints could also be done with combinations of targeted therapies with conventional therapies such as radiotherapy or cryoablation.

“And we should think about stimulation of additional co-stimulatory pathways such as CD137 [tumor necrosis factor 4–1BB], OX40, and ICOS [inducible costimulators].”

Considering the complexity of the immune system with all its negative regulators, it is surprising that any single drug can have the effects it has, Allison said.

“We are lucky in that in a two-year period we have two distinct pathways [targeted by ipilimumab and now anti PD-1] that show clinical activity in a large number of patients.”

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Success after Disappointments

The moderator of the news conference, Carol Aghajanian, MD, Chief of the Gynecologic Medical Oncology Service of Memorial Sloan-Kettering Cancer Center and a member of ASCO's Cancer Communications Committee, said that through studies such as those on PD-1 and ipilimumab, “we've learned a lot about how to assess immune therapies.

“And through these studies, we have learned that immune therapies do need to be assessed differently, and now an immune response criteria has been established that is quite useful in evaluating these agents.”

She said researchers have learned to differentiate newly recognized responses, such as delayed responses, and to tolerate what might be considered progression with standard agents at first scan, giving the immune therapy more time to work as long as the patient is clinically well.

She called this study a welcome success story for the immunological treatment of cancer: “Years of science and discovery in immunology have led to these very specific treatments, after a lot of disappointment early on with immune therapy when immunology was not well understood, but now we're getting to very specific targets, and I think this holds great promise.”

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© 2012 Lippincott Williams & Wilkins, Inc.
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