Cancer therapy that boosts immune system ready for wider testing

June 2, 2012, Johns Hopkins University School of Medicine

Two clinical trials led by Johns Hopkins Kimmel Cancer Center researchers in collaboration with other medical centers, testing experimental drugs aimed at restoring the immune system's ability to spot and attack cancer, have shown promising early results in patients with advanced non-small cell lung cancer, melanoma, and kidney cancer. More than 500 patients were treated in the studies of two drugs that target the same immune-suppressive pathway, and the investigators say there is enough evidence to support wider testing in larger groups of patients.

Results of the Phase I clinical trials will be published online June 2 in the and presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (Abstracts #2509 and #2510).

"Based on the positive response rates to these drugs and longevity of many of these responses, we believe that new clinical trials should move forward," says Suzanne Topalian, M.D., professor of surgery and oncology at Johns Hopkins. Preliminary analysis shows that, among responding who were followed for more than one year, responses were maintained for more than one year in two-thirds of those treated on one trial and in half of those in the other trial.

The immune-based therapies tested in the two clinical trials, both made by Bristol-Myers Squibb, aim not to kill cancer cells directly, but to block a pathway that shields tumor cells from immune system components able and poised to fight cancer.

The pathway includes two proteins called programmed death-1 (PD-1), expressed on the surface of , and programmed death ligand-1 (PD-L1), expressed on cancer cells. When PD-1 and PD-L1 join together, they form a biochemical "shield" protecting from being destroyed by the immune system. Another protein involved in the pathway and also expressed by cells in the immune system, programmed death -2 (PD-L2), was originally discovered by Johns Hopkins investigators.

To make more vulnerable to attack by the , investigators tested each of two drugs -- BMS-936558, which blocks PD-1, and BMS-936559, which blocks PD-L1 -- in separate conducted at multiple U.S. hospitals. The drugs are given intravenously in an outpatient clinic every two weeks, and patients can remain on the treatment for up to two years.

The PD-1 blocking drug was tested in 296 patients with various advanced cancers who had not responded to standard therapies. Of those patients receiving the anti-PD-1 therapy, 240 who started treatment by July 2011 were analyzed for tumor response. Significant tumor shrinkage was seen in 14 of 76 (18 percent) non-small cell lung , 26 of 94 (28 percent) melanoma patients and nine of 33 (27 percent) patients.

In this trial, some patients experienced stable disease for six months or more, including five of 76 (seven percent) lung cancer patients, six of 94 (six percent) melanoma patients and nine of 33 (27 percent) kidney cancer patients. The investigators say that additional clinical studies will be needed to determine the drug's potential impact on survival.

"This level of response in patients with advanced lung cancer, which is typically not responsive to immune-based therapies, was unexpected and notable," says Julie Brahmer, M.D., associate professor of oncology at Johns Hopkins.

The anti-PD-L1 therapy also showed responses among 207 treated patients. Five of 49 (10 percent) non-small cell patients, nine of 52 (17 percent) melanoma patients, and two of 17 (12 percent) kidney cancer patients responded.

"The positive results from both drugs give us a good indication that the PD-L1/PD-1 pathway is an important target for cancer therapy," says Topalian.

The anti-PD1 therapy caused serious toxicities in 41 of 296 (14 percent) patients. Many of the toxicities were immune-related, including colon inflammation, thyroid abnormalities and three deaths from pneumonitis (lung inflammation). The investigators say they are working with colleagues across the country to develop better methods for early detection and effective treatment of pneumonitis. Other less severe toxicities included fatigue, itching and rash. The anti-PD-L1 therapy caused nine percent serious toxicities and no deaths.

Among patients receiving anti-PD-1, tumor samples collected from 42 study patients before they received the experimental therapy were evaluated at Johns Hopkins Medicine for molecular markers that may correlate with clinical response. The investigators found PD-L1, the partner protein to PD-1, in 25 of the 42 samples. Nine of the 25 patients with PD-L1-positive tumors experienced tumor shrinkage as compared with none of the patients with PD-L1 negative tumors.

"These early results indicate that PD-L1 expression in pretreatment tumor biopsies may correlate with clinical response to anti-PD-1 therapy, but more work needs to be done to confirm this, " says Brahmer.

The two therapies targeting the PD-1/PD-L1 pathway are in the same class of so-called "antibody therapies," which are made of proteins that target and bind to certain molecules on the cell surface. Other antibody therapies include such drugs as Erbitux, Herceptin, and Rituxan.

"We have just scratched the surface of laboratory and clinical research on these drugs," says Topalian.

Ultimately, they envision boosting the effectiveness of the therapy by combining it with other anti-cancer agents, including vaccines.

Explore further: Scientists discover effects of PD-1 blockade on ART therapy in SIV-infected monkeys

Related Stories

Scientists discover effects of PD-1 blockade on ART therapy in SIV-infected monkeys

March 8, 2012
Scientists have discovered that blocking PD-1 (programmed death-1), an immune molecule that inhibits the immune response to viral infections, can have a significant effect on HIV-like illness in nonhuman primates.

Persistent ocular tremors appear to be associated with Parkinson's disease

April 9, 2012
Persistent ocular tremors that prevent eye stability during fixation appear to be common among patients with Parkinson disease (PD) suggesting that precise oculomotor testing could provide an early physiological biomarker ...

Innovative new strategy to treat Parkinson's disease

December 19, 2011
Stabilizing the cell's power-generating center protects against Parkinson's disease (PD) in a rat model, according to a report published online this week in the Journal of Experimental Medicine.

Recommended for you

T-cells engineered to outsmart tumors induce clinical responses in relapsed Hodgkin lymphoma

January 16, 2018
WASHINGTON-(Jan. 16, 2018)-Tumors have come up with ingenious strategies that enable them to evade detection and destruction by the immune system. So, a research team that includes Children's National Health System clinician-researchers ...

Researchers identify new treatment target for melanoma

January 16, 2018
Researchers in the Perelman School of Medicine at the University of Pennsylvania have identified a new therapeutic target for the treatment of melanoma. For decades, research has associated female sex and a history of previous ...

More evidence of link between severe gum disease and cancer risk

January 16, 2018
Data collected during a long-term health study provides additional evidence for a link between increased risk of cancer in individuals with advanced gum disease, according to a new collaborative study led by epidemiologists ...

Researchers develop a remote-controlled cancer immunotherapy system

January 15, 2018
A team of researchers has developed an ultrasound-based system that can non-invasively and remotely control genetic processes in live immune T cells so that they recognize and kill cancer cells.

Dietary fat, changes in fat metabolism may promote prostate cancer metastasis

January 15, 2018
Prostate tumors tend to be what scientists call "indolent" - so slow-growing and self-contained that many affected men die with prostate cancer, not of it. But for the percentage of men whose prostate tumors metastasize, ...

Pancreatic tumors may require a one-two-three punch

January 15, 2018
One of the many difficult things about pancreatic cancer is that tumors are resistant to most treatments because of their unique density and cell composition. However, in a new Wilmot Cancer Institute study, scientists discovered ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.