Pancreatic Cancer Drug Takes Multi-Faceted Approach

A drug once thought to only prevent cancer cell proliferation was recently observed to switch immune cells that dampen the body’s attack into the kind of cells that increases anti-cancer activity, according to a new study published by Cancer Immunology Research.

When mice were treated with nab-paclitaxel (Abraxane), macrophages—immune cells that engulf foreign pathogens—changed the cells to trigger a powerful anti-cancer effect.

"Our study reveals a previously unappreciated role for Abraxane in tumor immunology," says corresponding study author Dafna Bar-Sagi, PhD. "In doing so, it suggests ways to improve the drug and argues for its inclusion in new kinds of combination treatments.”

Abraxane contains paclitaxel in combination with nanoparticles of the albumin protein. This treatment has shown efficacy against pancreatic cancer, while paclitaxel monotherapy has not had this effect. While the combination therapy is part of the standard treatment for the disease, the drug’s mechanisms were largely unknown.

Paclitaxel prevents microtubules from breaking inside cancer cells, which allows them to proliferate and spread. Previously, researchers believed that nab-paclitaxel worked in the same manner, and used albumin to enter the cells with fewer toxic side effects.

However, these new findings show that nab-paclitaxel may also affect macrophages, which are found in the bloodstream and can build up in tumors, according to the study.

In healthy immune systems, macrophages trigger an attack on foreign substances, including cancer cells, but cancer cells can secrete factors that lessen the immune response. Cancer cells have the ability to change normal macrophages (M1) to cells that have suppressed function (M2).

In cell line studies, the researchers discovered that nab-paclitaxel is more effective compared with paclitaxel monotherapy because albumin allows the macrophages to engulf the drug through micropinocytosis. Once the drug is inside macrophages, nab-paclitaxel transforms immune-suppressing M2 cells into M1 cells to increase anti-cancer immune system activity in mice, according to the study.

Other studies have found that paclitaxel is similar in structure to substances from bacteria that elicit a macrophage response. In this new study, nab-paclitaxel was observed to elicit a macrophage response.

The discovery of the underlying mechanisms of nab-paclitaxel may lead to novel treatments that target cancer macrophages to amplify the immune system response. These immunotherapy treatments are also known to reduce side effects compared with standard treatment, which may improve patient outcomes.

"Our findings argue that it may be possible to develop more treatments that selectively target macrophages by coupling albumin to immune-activating agents," said lead study author Jane Cullis, PhD. "We may also be able to adjust albumin's structure such that drugs attached to it stay in macrophages longer, or combine Abraxane with T-cell treatments for greater therapeutic effect. In principle, such treatments should be useful against the many tumor types infiltrated by macrophages."