Cytokines are small signaling molecules in the immune system. In cancer therapy, cytokines can boost the body's immune response against cancer but can become toxic when present at excessive levels. 

Stanford Cancer Institute member Chris Garcia, PhD, the Younger Family Professor and professor of structural biology, has been working in his lab to re-tune these molecules, refining them for clinical use. 

"They’re very potent immune modulators, and we have some different approaches for how to tune them up as anti-cancer therapeutics in the clinic," Garcia said. 

Mitigating cytokine toxicity 

One of the primary hurdles in utilizing cytokines has been their toxicity. Cytokine release syndrome, also known as a cytokine storm, occurs when cytokine levels become excessively high or uncontrolled, which can cause organ damage, organ failure, or even death.

 While vital for immune responses, this overproduction overwhelms the body's regulatory mechanisms, resulting in a harmful overamplification of the immune response.

 To address this issue, Garcia has pioneered techniques to engineer cytokines that selectively activate signaling pathways in targeted cells while minimizing effects on bystander cells that can overamplify the response. 

This engineering makes cytokines much better tolerated and allows higher dosing, a critical factor that could enhance the treatment's anti-tumor efficacy.

"It’s a better therapeutic and will be more tolerable by the patient," Garcia remarked. 

“Our first generation of cytokines is now in the clinic, and we have a whole new set of concepts that we’re working on that I think will change everything for cytokines.”

Cracking the immune code

While cytokines are a major focus, the Garcia Lab’s work spans the entire immune system’s communication network. The goal is to understand how the body distinguishes between normal healthy tissue and cancer cells. 

A major focus of Garcia’s research is on T cell receptors (TCRs). In the immune system, TCRs act as scanners to detect antigens, molecular flags indicating to the immune system that something is present that does not belong in the body, like a cancer cell or virus.

"We want to understand how these receptors recognize what is self and what is foreign," Garcia explained. 

To do this, the lab uses a sophisticated library of millions of different protein fragments displayed on the surface of yeast cells.

It might seem strange that a cancer research lab is filled with the same organism used to bake bread or brew beer, but yeast cells are biologically similar enough to human cells that they can fold complex proteins correctly. Like microscopic origami, a protein must be twisted and folded from a flat chain into a specific 3D shape before it can do its job. Because yeast can replicate this delicate process, it serves as a powerful tool in cancer research.

This allows them to test how T cells react to different signals, helping them identify the specific antigens that trigger autoimmune diseases or allow the body to fight off viruses and tumors.

Redesigning the cellular toggle switch

The lab is also collaborating with Stanford Cancer Institute Director Emeritus Irving Weissman, MD, Virginia & D.K. Ludwig Professor of Clinical Investigation in Cancer Research, Professor of Pathology, and of Developmental Biology, to study a fascinating survival mechanism known as the "don't eat me" signal. In a healthy body, certain cells express a protein called CD47 that signals macrophages, specialized immune cells that destroy germs, damaged cells, and cancer cells, not to engulf them. Cancer cells, however, evade this signal, effectively putting on a disguise that tells the immune system they are normal, healthy tissue.

Garcia’s team is working to engineer a toggle switch for this signal, which would allow researchers to flip the switch off, stripping away the disguise so macrophages can successfully identify and kill the tumor. 

This research has potential implications in stem cell transplants as well. 

“However, this same mechanism results in the destruction of newly engrafted stem cells, which is a major problem for bone marrow transplantation,” Garcia explained. “We are attempting to use structure and engineering to toggle the ‘don’t eat me’ signal on or off, depending on the desired therapeutic endpoint.” 

The Garcia Lab is looking forward to making more great strides in T cell receptor therapies and cell therapies, developing new engineering strategies to enhance their effectiveness in cancer immunotherapy. 

It’s early days, but I think cytokines are only going to become more powerful and useful clinical agents in cancer.”

"I fully believe that we’re going to have some really, really interesting molecules," Garcia said. “It’s early days, but I think cytokines are only going to become more powerful and useful clinical agents in cancer.”