Markus Manz

Potent Immunotherapies

Markus Manz treats patients with blood cancer. The hematologist has high hopes for immunotherapies.

By Thomas Gull and Roger Nickl; translated by Philip Isler

When conventional treatment methods have been exhausted, CAR T cell therapy is currently one of the most potent weapons against cancer. “It’s very active, very selective,” raves Markus Manz, “it goes exactly where it’s supposed to.” The professor of hematology at UZH treats blood cancer patients at the UniversityHospital Zurich. “Making the body’s own immune cells attack tumor cells has a tremendous effect.”

The idea behind immunotherapy is to use our body’s own defense system in the fight against cancer. This strategy is based on the fact that a healthy immune system is able to detect and destroy degenerated cells. But this doesn’t always work. For the immune cells to become active, they must recognize the tumor cells as foreign and not be prevented from attacking them. For both of these aspects, immunotherapies come into play. First, CAR T therapy rewires the T cells’ genes so that the cells are “trained” to attack cancerous cells, much like a guard dog attacks intruders.

And the second strategy, the checkpoint inhibitor therapy, ensures that immune cells aren’t prevented from attacking the cancer cells, which are protected by a clever mechanism: Cancer cells have inhibitor proteins on their surface that prevent T cells from binding to and eliminating them. Tumor cells thus also take advantage of one of the body’s own mechanisms – after the battle is won, when the immune system has fought off foreign invaders such as viruses or bacteria, it has to be scaled back again. This is done by inhibitors.

These inhibitors are misused by cancer cells as a protective shield. Checkpoint inhibitors make sure that this protective mechanism of the tumor is switched off and that the immune cells can start doing what they do best: Killing off degenerated cells.

Potent and dangerous

Even so, the potency of immunotherapies also has its dangers: When T cells kill tumor cells en masse, neurotransmitters are released that can cause severe reactions in the body. “It’s like with a bad bout of the flu, when the immune system wages all-out war against viruses,” explains Manz, “this can make the body reach its limit.”

And so it can happen that patients end up in intensive care. This is why at the same time as Kymriah, Novartis’ CAR T cell therapy against leukemia, the US Food and Drug Administration approved Roche’s drug Actemra, which can be used to counter these side effects. The medical quandary is obvious: On the one hand, the body’s immune system is a powerful tool to combat cancer cells. On the other, immunotherapies may trigger an overreaction and attack healthy cells, which can lead to dangerous autoimmune diseases. While these can be stopped, doing so also thwarts the immune reaction aimed at the cancer. “Our goal therefore has to be to balance the therapy so that it removes the tumor before the onset of the autoimmune disease,” explains Manz.

As promising as the new therapies are, there’s still a long way to go until they can be safely and efficiently put to clinical use. In the coming years, Manz and neuro-oncologists Patrick Roth and Michael Weller from the UniversityHospital Zurich thus want to join forces with experimental immunologists at UZH and scientists from ETH Zurich to set up a large-scale clinical research program that will investigate and improve the clinical use of immunotherapies.