Targeting a Common Thread Across Squamous Cancers

Immunotherapy has transformed cancer care, extending survival and giving many patients options where there were none before. While squamous cell carcinomas (SCCs), including those of the lung, head and neck, and esophagus, were among the earlier cancers to see approvals for immunotherapy drugs, fewer than one in five patients experience meaningful, lasting benefit. 

“We see remarkable responses in a subset of patients, but the majority either don’t respond at all or eventually progress,” says Brian Henick, MD, a medical oncologist at Columbia and lead investigator of a new clinical trial that recently opened at the Herbert Irving Comprehensive Cancer Center (HICCC). “One of the biggest unanswered questions in the field is what to do for patients who need something else.” 

Henick and colleagues have opened a first-in-human study at Columbia with a new drug designed to tackle that challenge from a new angle. By targeting a shared vulnerability across squamous cancers, rather than treating each tumor type in isolation, the new drug could offer benefits across cancer types. 

A common cancer, a shared challenge

Squamous cell carcinomas arise from the flat, surface-lining cells that make up the skin and the linings of organs such as the lungs, esophagus, and head and neck. While these cancers occur in different parts of the body, they often share key biological features, including how they interact with the immune system. 

That similarity has made squamous cell carcinomas (SCCs) an attractive target for immunotherapy. But it has also revealed a paradox: even when these tumors look alike under the microscope and are treated with the same drugs, patient responses can vary dramatically. 

Part of the challenge lies in how these cancers interact with the immune system. Many SCCs are able to blunt or sidestep immune attack—creating environments where cancer cells can persist even in the presence of checkpoint inhibitors, limiting the benefit for many patients. 

A different kind of immunotherapy

The new trial is testing an investigational therapy designed to actively redirect the immune system toward cancer cells. 

Rather than simply boosting existing immune responses, the drug is a T cell engager—an engineered molecule that brings T cells into direct contact with tumor cells. By physically linking the two, it helps overcome some of the barriers that prevent immune recognition. 

If we can better understand these cancers and design therapies that directly address their shared biology, we can start to change outcomes for a much larger group of patients.

In this case, the therapy targets a set of related proteins that are expressed across multiple squamous cancers. 

“The drug works by essentially forcing interaction between the immune system and the tumor,” Henick explains. “It’s a way of trying to overcome some of the resistance mechanisms we see with standard immunotherapy.” 

Because these targets are shared across tumor types, the strategy could have pan-squamous potential, spanning cancers of the lung, esophagus, and head and neck. 

Connecting the lab and the clinic

The work builds on a strong foundation of squamous cancer research at Columbia. Investigators including Anil K. Rustgi, MD and Hiroshi Nakagawa, MD, PhD, have helped develop patient-derived organoid models that capture how these tumors grow, evolve, and respond to treatment. In parallel, a Columbia-led Stand Up To Cancer team is advancing new immunotherapy strategies for esophageal squamous cancers, efforts that are helping bridge discovery and clinical testing.

The new trial builds on that foundation, connecting discovery in the lab with care in the clinic. Henick is working with laboratory investigators at the HICCC to integrate tissue collection and molecular analysis into the study, laying the groundwork for a pan-squamous biobank that could support future research. 

“We have a unique opportunity to connect what we’re seeing in patients with what’s happening at the molecular level,” Henick says. “By bringing together clinical trials and laboratory science, we can start to understand the biology driving response, as well as resistance.”

Expanding options for patients

For patients with advanced squamous cancers, especially those who have not benefited from existing immunotherapies, new approaches are urgently needed. 

The hope is that therapies like T cell engagers can broaden the reach of immunotherapy, extending its benefits to more patients, and across more cancer types. 

“This is about moving beyond a one-size-fits-all approach,” Henick says. “If we can better understand these cancers and design therapies that directly address their shared biology, we can start to change outcomes for a much larger group of patients.”