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New Advances in Therapies: Five-Drug Combo

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Arnold’s advanced pancreas cancer that had spread to his liver was eliminated with a low-dose, five-drug combination being studied in a clinical trial led by Dung Le.

Le is now testing new iterations of the therapy to see if she can help more patients. A new drug cocktail adds immunotherapy and a PARP inhibitor to the mix. Immunotherapies are aimed at unleashing the body’s natural defense against foreign invaders, including cancer. PARP inhibitors are called targeted therapies because they block enzymes that help cancer cells repair DNA damage caused by radiation therapy and chemotherapy. Such DNA damage also makes cancer cells more visible to the immune system.

Le and colleagues believe one reason Simon’s cancer responded well to the therapy was that it contained a BRCA mutation, at once predisposing him to cancer, and with this therapy, becoming the cancer’s Achille’s heel.  BRCA genes act as DNA repair mediators. Using a PARP inhibitor in patients with other DNA repair defects may also have similar effects and could have immune-stimulatory effects in other patients as well.

Michael Pishvaian and Katie Bever are looking more deeply into the PARP/BRCA  DNA repair mechanisms and how they impact responses to treatment. They wonder if adding a PARP inhibitor to therapies in patients who have BRCA mutations augments responses. A subset of patients with BRCA mutations have good responses to treatment, but in many others, the mutation has no effect. Some research studies showed that inhibiting PARP can make unresponsive tumors respond to immunotherapy. Pishvaian and Bever want to see if PARP inhibitors may do the same thing for patients with BRCA mutations whose cancers are resistant to treatment.

“PARP is another way cancer cells make repairs,” says Le. “If we block it, they can’t make repairs and they die.” Targeting more than one repair mechanism may expand responses to more patients.

From the molecular standpoint, they can’t find evidence that tells them why one patient with BRCA mutations responds to treatment and another does not. Nilofer Azad, gastrointestinal cancer expert and Cancer Biology Program co-director, is exploring whether immune cells called macrophages could be playing a role. Macrophages are linked to inflammation, which alone is cancer-promoting, but it may also be turning away cancer-fighting T cells. The drug entinostat is being studied for its ability to target macrophages and create a T cell friendlier environment.

A series of studies combining the listeria vaccine—which uses a weakened version of the bacterium listeria safe for humans—to stimulate an immune response in combination with different immune checkpoint blocking drugs. Checkpoint blockers target the on and off signals of the immune system, which are often hijacked by cancer cells, to release the brakes on the immune response to cancer.  One combination involves a new checkpoint, called CXCR4, which clears the way for more T cells to traffic to the tumor. Other combinations, include PD-1, and IDO blockers. The researchers will study tissue samples to see what immune cells are showing up, and here again to see if targeted macrophages improve the immune system’s ability to attack the cancer.

This research is being led by Katie Bever and is funded by the Lustgarten Foundation, Swim Across America, and the Cynthia Boscov Fund.