Giving medicine a reason to stick around

MIT scientists develop a strategy to keep potent anti-cancer drugs stuck inside tumors.

Immunotherapy has revolutionized cancer treatment. Doctors have observed that tumors which are traditionally untreatable with conventional chemo- or radiotherapy can be shrunk (or sometimes cured altogether) by teaching a patient’s immune system to fight it off.

Cancer immunotherapy is the process of instructing your immune system on how to fight off an existing tumor. Over the course of the pandemic, the world has heard a lot about using vaccines to protect people against COVID-19. These vaccines teach your body how to fight off the virus which causes COVID-19 before it infects you. Cancer immunotherapy is a little different: in this case, these drugs teach your body how to fight off a tumor that is already there. Both approaches, however, rely on what’s known as the adaptive immune system and are powerful biomedical tools.

In 2018, Professors Jim Allison and Tasuku Honjo shared the Nobel Prize in Physiology or Medicine for the discovery of drugs that could enable a patient’s immune system to fight off tumors. These drugs, broadly referred to as immune checkpoint blockade (ICB) therapy, can be given to a patient through an IV drip. This means the drug enters their blood and goes nearly everywhere in their body – including the tumor.

Not every patient responds to ICB. To treat particularly aggressive and immune-suppressive tumors, scientists have looked to another class of drugs called cytokines. These molecules are the signaling molecules the immune system uses to talk to itself. Administering them to a patient pushes their immune system to respond potently. 

Unfortunately, these drugs are too toxic to be given through an IV drip. When they enter the bloodstream and travel all over a patient’s body, they unnecessarily activate the immune system too strongly everywhere, which can have disastrous side effects. Even injecting the drugs directly into a tumor does little to fix the problem. There is nothing anchoring the drugs to the tumor, and so they quickly leak out into the bloodstream and cause the same toxic side effects.

Engineers at MIT recently devised a strategy to overcome this problem. The drugs were first attached to an anchor. These anchors, once injected into a tumor, tend to stay there. When cytokines which were attached to an anchor were injected into tumors in mice, the drugs stayed in the tumor, did not rapidly leakout, and were highly efficacious with minimal side-effects. An anchor based on the biocompatible nanoparticle alum, and an anchor based on collagen-binding proteins were published in Nature Biomedical Engineering and Nature Communications respectively earlier this week.

The alum-based work, led by MIT graduate student Yash Agarwal jointly in the Wittrup and Irvine laboratories, focused on the use of the cytokine IL12 to provide a safe and potent anti-cancer immune response in mouse models. The collagen-binding system, led by MIT alumni Dr. Noor Momin from the Wittrup laboratory, carefully examined how the collagen affinity (i.e. the strength of the anchor) changed the biodistribution of the drugs through experimental and computational methods. Two companies, Ankyra Therapeutics and Cullinan Amber, are working to bring these technologies to the clinic. 

Taken together, these papers demonstrate that attaching cytokines to anchors is a safe and efficacious strategy to treat aggressive tumors in mice.  Clinical trials which will determine how efficacious they are in humans are set to begin soon. Promising results there would likely lead to even further exploration of tumor-anchored drugs for hard-to-treat cancers.

Ph.D. Candidate at the Massachusetts Institute of Technology