Identifying “On-Target, Off-Tumor” Toxicities in Treatment for GI Cancers

In an interview with CancerNetwork®, Raed M. Al-Rajabi, professor of Medicine in the Division of Medical Oncology at the University of Kansas Medical Center and lead of the Gastrointestinal (GI) Medical Oncology Group, discussed which toxicities might emerge while treating patients with immunotherapy options such as CAR T cells and bispecific antibodies in those with GI malignancies. The discussion was contextualized by a presentation on immune effector cells in GI malignancies he gave at the 2025 Immune Cell Effector Therapy (ICE-T) Congress.

He began by explaining that as his team has sought to improve efficacy in patients with GI cancers, an emergence of “on-target, off-tumor toxicities” had been documented. He noted that GI toxicities like nausea, vomiting, and diarrhea may occur while targeting Claudin 18.2. Highlighting a high propensity for patients to have comorbidities, he suggested the treatments may present with a greater toxicity burden among this population.

To help alleviate these toxicities, Al-Rajabi explained that better defining patient benefit with immunotherapy options and more effectively sequencing treatments may enhance outcomes.

Transcript:

As we are trying to improve the effect of these treatments on cancers, we are also realizing 1 big aspect of these treatments include “on-target, off-tumor toxicities.” Patients [in whom] we target Claudin 18.2 have significant GI toxicities—including nausea, vomiting, and diarrhea—because these receptors that we are targeting can be apparent on normal tissue. A lot of the colon cancer trials are also showing similar effects with colitis and sometimes even pneumonitis [as well as] skin toxicities.

These patients [often] have significant comorbidities. Some of them have liver damage and cirrhosis. Some of them are severely malnourished, as the GI tract is critical in that aspect. These treatments are not easy to tolerate, especially with things like conditioning regimens, hospitalizations, CRS, and neurological toxicities that could affect these patients. We need to better define which patients are going to be the best candidates for these treatments, when to pull the trigger on sequencing these therapies, [and determining] the different treatment options we have for a GI malignancy. It is an ongoing discussion, but there are [many] aspects that we must take into consideration when choosing patients for these treatments.

Reference

Al-Rajabi RM. IEC in GI malignancies. Presented at the 2025 Immune Cell Effector Therapy (ICE-T) Congress; September 27-28, 2025. Kansas City, KS