The third Clinical Trials Plenary Session at the AACR Annual Meeting 2026 was dedicated to “Cellular Therapies and Complex Immunotherapies” and provided updates on sophisticated immunotherapeutic CAR-T cells strategies, with special emphasis on their application for solid tumors. 

Can CAR T-cell therapy intercept disease in patients with smoldering myeloma?

The first presenter Omar Nadeem, MD, of Dana-Farber Cancer Institute, discussed results of the CAR-PRISM trial, which evaluated the use of ciltacabtagene autoleucel (Carvykti) in patients with high-risk smoldering myeloma, an early, asymptomatic form of multiple myeloma. Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy approved for second-line treatment of relapsed/refractory multiple myeloma.

Clinical results are also published in Nature Medicine

“Due to its efficacy in relapsed multiple myeloma, and the fact that it is given as a single infusion, we reasoned that ciltacabtagene autoleucel could be a practical and effective approach for patients with high-risk SMM to intercept the disease before the patient develops any symptoms,” said Nadeem. “The other rationale was that the T cells are fitter during this early disease state, and so the efficacy of CAR T-cell therapy may be even greater when administered during SMM, when the immune system is more robust.”

The CAR-PRISM trial enrolled 20 patients with high-risk SMM based on the proportion of plasma cells in their bone marrow and the amount of plasma-cell protein products in their blood. All patients treated with ciltacabtagene autoleucel experienced low-grade cytokine release syndrome (CRS), and no patients had grade 3 or higher CRS. The most common adverse events were transient hematologic toxicities, including grade 3 or 4 neutropenia. Non-immune effector cell-associated neurotoxicity syndrome (non-ICANS) neurologic toxicities occurred in seven patients: facial nerve palsy in four patients that resolved completely, and residual, but improved, mild motor symptoms in three patients.

Within two months of treatment, all 20 patients had experienced minimal residual disease (MRD) negativity, which was sustained at a median follow-up of 15.3 months. Six patients who were followed for longer than 18 months continued to experience MRD negativity. No disease progression or deaths were observed during follow-up.

“In this pilot study, a one-time infusion of ciltacabtagene autoleucel—without any induction or bridging therapy—led to universal MRD negativity,” said Nadeem. “No instances of disease progression have been observed after a median follow-up of 15.3 months, far exceeding the progression-free survival we would expect with active monitoring.

“These results support our hypothesis that administering CAR T-cell therapy earlier—before the onset of active multiple myeloma—can lead to deep responses,” he added. “Our hope is that these responses continue to be durable in the long term to the point where we can say that patients are cured.”

KIR-CAR T-cell therapy with an on-and-off switch mechanism to limit T-cell exhaustion

The following presentation, by Janos L. Tanyi, MD, PhD, of the University of Pennsylvania Abramson Cancer Center, focused on initial results of a first-in-human dose-escalation study of SynKIR-110, a novel type of CAR T-cell therapy, in patients with advanced mesothelin-expressing solid tumors.

With few exceptions, traditional single-chain CAR T-cell therapy has generally failed to treat solid tumors and demonstrated both on- and off-target toxicities, said Tanyi. Unlike traditional single-chain CAR T-cell therapy, multichain killer immunoglobulin-like receptor (KIR)-CAR T cells are designed to have the extracellular target-binding domain separate from the intracellular costimulatory domain. The split receptor design provided a natural on-and-off switch mechanism that allows for T-cell recovery and helps prevent exhaustion, Tanyi added.

He showed in vitro data demonstrating that KIR-CAR-transduced T cells retained similar minimal activation and exhaustion markers as untransduced T cells and displayed a more specific and more effective activation response than single-chain CAR T cells. This translated into increased antitumor efficacy in a patient-derived mesothelioma mouse model.

Tanyi reviewed interim trial results from nine patients treated at the first three dose levels in the dose-escalation phase of the clinical trial of SynKIR-110. Treatment was well tolerated with no dose-limiting toxicities, and only three patients experienced low-level cytokine release storm. Persistence of KIR-CAR T cells in the blood of patients increased with dose, and tumor reductions were observed with escalating doses, with one patient experiencing a partial response that is ongoing after many months, said Tanyi. Overall, the disease stabilization rate was 55% with the early low doses. Based on these results, patient enrollment for the next dose-escalation steps is ongoing, concluded Tanyi.

Source https://www.aacr.org/