The programmed death-ligand 1 (PD-L1), the primary ligands of the programmed death 1 (PD-1) protein, aT-cell coinhibitory receptor andimmunoinhibitory receptor of the CD28 family, plays a pivotal role in the ability of tumor cells to evade the host’s immune system. PD-L1 is selectively expressed on many tumorsand on cells within the tumor microenvironment in response to inflammatory stimuli. Researchershave found thatPD-L1 is up-regulated in solid tumors, where it can inhibit cytokine production and the cytolytic activity of PD-1+, tumor-infiltrating CD4+ and CD8+ T cells.They have also found that the blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models.The unique properties of PD-L1 make is a promising target for cancer immunotherapy.

Results of a phase I study presented at the annual meeting of the American Association for Cancer Research(AACR) held in Washington, D.C., April 6-10, 2013, demonstrates that the engineered antibody MPDL3280A (Genentech), which targets a protein called PD-L1, was safe and effective for several cancers.

?Our PD-L1 antibody was well tolerated, and there were no limiting toxicities,? noted Michael S. Gordon, M.D., research director at Pinnacle Oncology Hematology in Scottsdale, Arizona. ?It was active with antitumor activity across a broad range of cancers, and we have developed biomarker tools that we are testing, which may allow us to optimize patient selection for this novel therapy.?

Mechanism of Action explained
PD-L1, a protein found on the surface of many cancer cells, impairs the immune system?s ability to fight cancer, according to Gordon.?PD-L1 is essentially a plug, which inserts into an outlet (PD-1) on the surface of the immune T cells,? he explained. ?As the T cells come close to the tumor, for example, they are engaged by PD-L1, which inserts into the outlet on the surface of the T cell. That starts a signal inside the T cell that blocks the T cell?s ability to kill the cancer cell.?

MPDL3280A, a human monoclonal antibody under development by Genentech, a member of the Roche Group, binds to PD-L1 and blocks this action.

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Gordon and colleagues administered an escalating intravenous dose of MPDL3280A once every three weeks to 30 patients with a variety of locally advanced or metastatic solid tumors. They escalated the dose from 0.01 mg/kg to as high as 20 mg/kg. The data being presented are the preliminary data from the dose escalation cohorts of the ongoing phase I trial.

No dose-limiting toxicities or grade 4 adverse events have been reported. ?We were able to escalate to the top dose without being limited by any serious side effects,? Gordon said.?From a therapeutic standpoint, we were able to identify a number of patients with a broad range of diseases, including lung cancer, kidney cancer, colon cancer and stomach cancer, who responded to the treatment.?

Noncancerous tissue: PD-L2 not blocked
PD-1 has two known ligands, PD-L1 and PD-L2. Each one is endowed with a different spectrum of expression and regulation. PD-L1 is expressed in a variety of tumors, includingmelanoma, lung cancers, breast and ovarian, pancreatic and esophagus adenocarcinoma, kidney tumors and bladder cancers as well as inmost hematopoietic cells and some parenchymal cells (including pancreatic islet cells and vascular endothelial cells). Furthermore, research has shown thatinrenal cell carcinoma (RCC), tumor ?and/or tumor infiltrating lymphocyte-associated PD-L1 expression is generally associated with a 4.5 fold increased risk of dying from the RCC.On the other hand, PD-L2 expression is restricted to macrophages and dendritic cells.

PD-L2, “fits” into the same T-cell ?outlet? as PD-L1, according to Gordon. However, MPDL3280A is specific for PD-L1 and it does not block PD-L2, which is expressed in noncancerous tissues including the lung, he added.?One would anticipate, compared with drugs being developed to specifically block the T-cell outlet (PD-1) and, therefore, block the relationship between the outlet and both PD-L1 and PD-L2, that we might see less lung or pulmonary toxicity with MPDL3280A. But we need to conduct larger studies to confirm this,? Gordon said.

For more information:

Clinical Trials
NCT01656642– A Study of The Safety and Pharmacology of MPDL3280A Administered in Combination With Vemurafenib (Zelboraf?) in Patients With Previously Untreated BRAFV600-Mutation Positive Metastatic Melanoma

NCT01375842– Study of the Safety and Pharmacokinetics of MPDL3280A Administered Intravenously As a Single Agent to Patients With Locally Advanced or Metastatic Solid Tumors or Hematologic Malignancies

NCT01633970-A Study of MPDL3280A in Combination With Avastin (Bevacizumab) or With Avastin Plus Chemotherapy in Patients With Advanced Solid Tumors

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