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Targeting T Cells: Clinical Trial Results for Metastatic Bladder Cancer

Jan 26, 2015 1:00:12 PM / by Daisy Goodrich

Cancer cells evolve to escape our immune surveillance. Newer technologies employ therapeutic regimens that target T cells to wake up the sleeping giant.

There are several therapies under the cancer immunotherapy umbrella that are already being evaluated in clinical trials. Recently, we discussed CAR T cells and solid tumors. Yet another method of engaging the patient’s immune system is using antibodies that knock down and neutralize blockades put up by cancer cells to escape the immune system.

T cells Programmed death ligand 1 protein (PD-L1) expressed by T cells and tumor cells is one target of antibody therapeutics in cancer. Image credits: http://commons.wikimedia.org/wiki/File:Protein_CD274_PDB_3BIK.png#mediaviewer/File:Protein_CD274_PDB_3BIK.png

The immune system is reactionary by nature. However, there are several mechanisms of negative regulation in place to maintain homeostasis. One such immunologic checkpoint entails the expression of the cell surface receptor, programmed death-1 (PD-1), on T cells.

In a lock-and-key mechanism, when PD-1 is engaged by its ligand, PD-L1, the immune system is suppressed. PD-L1 is expressed by several immune cells, including T cells, in response to physiological conditions and signaling by IFN-gamma. In normal times, this serves to suppress T cells and prevent unwarranted over-activation of the immune system. Unfortunately, several solid tumors have evolved to exploit this mechanism by expressing PD-L1 as well.

Metastatic bladder cancer (MBC) is one such cancer where PD-L1 is expressed in the tumor microenvironment to suppress T cells and subsequently dampen immune surveillance. A phase 1 clinical trial was designed to test the hypothesis that MBC patients may respond to MPDL3280A, a biologic or antibody therapeutic engineered to neutralize PD-L1.[1]

Overall, 205 patients entered this study. Biopsy or resection samples were used to characterize for the presence and quantity (grade designations from 0 to 3) of the PD-L1 biomarker. One unique feature of this study was that tumor samples were characterized not only for PD-L1 expression, but were also differentiated according to whether PD-L1 was expressed by tumor cells or by immune cells infiltrating in the tumor.

Patients were evaluated at a minimum of 6 and 12 weeks following therapy. At 6 weeks, the objective response rate (ORR) (proportion of patients with reduction in tumor burden) was 11% in patients who had tumors that were graded to have PD-L1 ≤ grade 1, and 43% for PD-L1 ≥ grade 2. At 12 weeks, the ORR for patients with PD-L1 ≥ grade 2 went up to 52%.

MPDL3280A treatment achieved response rates which were higher for PD-L1-positive MBC. Interestingly, of the patients with PD-L1 positive tumors, those with PD-L1-positive tumor-infiltrating immune cells and not those with PD-L1 positive tumor cells were associated with response to MPDL3280A.

On the basis of these data, the FDA granted MPDL3280A a breakthrough status for MBC, which is intended to expedite the development and review of this drug. HemaCare provides T cells for research and applauds the translation of anti-PD-L1 antibody to the clinic to rouse T cells for immune surveillance in MBC.

Reference

1: Powles T, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62.

Topics: Cancer, clinical trial, PD-L1, PD1, Basic Research, Immunotherapy (Immunology)

Daisy Goodrich

Written by Daisy Goodrich

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