MIT and Stanford researchers have engineered a new class of “plug-and-play” immunotherapy molecules that help immune cells recognize and attack tumors. The approach could extend the benefits of cancer immunotherapy to many more patients.
A team of scientists from MIT and Stanford University has unveiled a new kind of cancer immunotherapy that aims to help the immune system recognize and destroy tumors that currently evade treatment.
The experimental approach, described in the journal Nature Biotechnology, targets a lesser-known set of immune “brakes” controlled by sugar molecules on the surface of cancer cells. By lifting those brakes, the researchers hope to extend the power of immunotherapy to many more patients and tumor types.
Lead author Jessica Stark, the Underwood-Prescott Career Development Professor in the MIT departments of Biological Engineering and Chemical Engineering and a member of the Koch Institute for Integrative Cancer Research, said her team’s goal was to design a new tool for unleashing the immune system on cancer.
“We created a new kind of protein therapeutic that can block glycan-based immune checkpoints and boost anti-cancer immune responses,” Stark said in a news release.
Most current checkpoint inhibitor drugs work by blocking proteins such as PD-1 and PD-L1. These drugs have transformed care for some cancers, putting a fraction of patients into long-lasting remission. But many people do not respond at all, and others eventually relapse, suggesting that tumors use multiple ways to shut down immune attacks.
The MIT-Stanford team focused on a different pathway involving glycans — complex sugar molecules that decorate the surface of nearly every cell in the body. Tumor cells often display unusual glycans, including ones that contain a sugar called sialic acid.
On immune cells, specialized receptors called Siglecs recognize sialic acids. When these receptors bind to sialic acids on cancer cells, they send a signal that suppresses the immune response.
“When Siglecs on immune cells bind to sialic acids on cancer cells, it puts the brakes on the immune response. It prevents that immune cell from becoming activated to attack and destroy the cancer cell, just like what happens when PD-1 binds to PD-L1,” Stark added.
Drug developers have tried to interfere with this interaction before, for example by using lectins — proteins that bind sugars — to soak up sialic acids on tumor cells. But lectins on their own tend to bind too weakly and do not accumulate on cancer cells in high enough numbers to be effective.
The new work solves that problem by fusing lectins to antibodies that home in on specific tumor markers. The resulting hybrid molecules, called AbLecs (short for antibody-lectin chimeras), use the antibody portion as a targeting system to deliver the lectin directly to cancer cells.
Once there, the lectin portion can latch onto sialic acids and block them from engaging Siglec receptors on immune cells. In effect, AbLecs are designed to remove one more layer of immune suppression and allow cells such as macrophages and natural killer (NK) cells to attack.
“This lectin binding domain typically has relatively low affinity, so you can’t use it by itself as a therapeutic. But, when the lectin domain is linked to a high-affinity antibody, you can get it to the cancer cell surface where it can bind and block sialic acids,” added Stark.
In the new study, the researchers first built an AbLec using trastuzumab, a widely used antibody drug that targets HER2, a protein found on some breast, stomach and colorectal cancers. They replaced one arm of trastuzumab with a lectin domain from either Siglec-7 or Siglec-9.
In lab dishes, these AbLecs changed how immune cells behaved, prompting them to attack and kill cancer cells more effectively than trastuzumab alone.
The team then moved to a mouse model engineered to carry human versions of Siglec receptors and antibody receptors, making the animals more relevant for testing human-like therapies. After injecting the mice with cancer cells that spread to the lungs, the researchers treated some animals with AbLecs and others with standard trastuzumab.
Mice that received AbLecs developed fewer lung metastases than those treated with trastuzumab alone, suggesting that blocking glycan-based checkpoints can add to the effects of existing antibody drugs.
To show how flexible the platform could be, the scientists also swapped in other clinically used antibodies, including rituximab, which targets CD20 on certain blood cancers, and cetuximab, which targets EGFR, a protein involved in several solid tumors. They further demonstrated that different lectin domains could be used to target other immunosuppressive glycans, and that AbLecs could be combined with antibodies against checkpoint proteins like PD-1.
“AbLecs are really plug-and-play. They’re modular,” Stark added. “You can imagine swapping out different decoy receptor domains to target different members of the lectin receptor family, and you can also swap out the antibody arm. This is important because different cancer types express different antigens, which you can address by changing the antibody target.”
That modularity is key to the technology’s promise. Because glycans help restrain immune responses in many tumor types, a platform that can be retuned for different cancers could become a versatile addition to the immunotherapy toolbox.
Stark notes that the concept opens a new front in the effort to overcome tumor immune evasion.
“Because glycans are known to restrain the immune response to cancer in multiple tumor types, we suspect our molecules could offer new and potentially more effective treatment options for many cancer patients,” she added.
To move the technology toward the clinic, Stark, senior author and Stanford chemist Carolyn Bertozzi, and collaborators have launched a startup, Valora Therapeutics. The company is working to refine lead AbLec candidates and aims to begin human clinical trials within the next two to three years.
If successful, AbLecs could eventually be combined with existing checkpoint inhibitors, targeted therapies or cell-based treatments to create multi-pronged regimens that attack cancer from several angles at once.
For now, the work highlights an emerging idea in cancer immunology: that the sugars coating tumor cells are not just passive decorations, but active players in turning the immune system’s “brake” on and off. Learning how to control that switch could help more patients benefit from the promise of immunotherapy.