In an effort to better understand outcomes of patients with extramedullary myeloma — which typically has a poorer outcome — researchers have shown preliminary data to suggest that using nanoparticles to track the biodistribution of chimeric antigen receptor (CAR) T-cell therapy is feasible, according to findings presented at the 66th American Society of Hematology Annual Meeting and Exposition in San Diego.
Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen CAR-T therapy, is effective and has durable responses in patients with relapsed or refractory multiple myeloma (MM), but those with extramedullary disease (EMD) seem to have a lower progression-free survival compared with other subgroups, according to trial results and real-world evidence.
Therefore, researchers set out to track how CAR T cells are distributed throughout the body in the hope that they would be able to assess the resistance in these patients and find new avenues to improve outcomes, said presenter Simon Harrison, MBBS, PhD, director of the Centre of Excellence for Cellular Immunotherapy at the Peter MacCallum Cancer Center in Australia.
“Cells go in, and we think they go to all the areas of disease,” Dr. Harrison said. “But maybe they don’t, and the progression is at sites where the cells didn’t migrate to, or there’s an effect of migration to these sites, and the tumor microenvironment does the rest.”
Researchers used copper-64 (Cu-64) SPION — also known as super paramagnetic iron oxide nanoparticles, a dual PET-CT and PET-MRI cell tracking technology suitable for following the trafficking of therapy that uses a patient’s own cells.
Initially, they began with preclinical work to assess how Cu-64 SPION labeling affects CAR-T function. They then enrolled patients with MM who also had EMD and had received two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug. They received 70% cilta-cel that was unmanipulated and 30% cilta-cel loaded with Cu-64 SPION. Dual imaging was performed over the first four days, followed by MRI alone at later time points.
The patients have all had a response to cilta-cel, and researchers found no harmful effects of labeling with Cu-64 SPION on cilta-cel viability, phenotype, cell killing, or cytokine release in vitro. In the four patients for whom data are available so far, researchers saw dynamic biodistribution initially within the lung and then migration of cells into the systemic circulation over time, including the liver, spleen, and bone marrow. Observations of therapy tracking to lesions were mixed.
For example, in one patient who had a pre-infusion lesion in the right pelvis, a rim of activity was seen on the Cu-64 PET, suggesting cilta-cel trafficking, but images at day 1 showed that the trafficking might not have been optimal, Dr. Harrison said.
“The lesion is surrounded by CAR T cells, but they don’t seem to be able to penetrate at this early time point,” Dr. Harrison said. “That’s a really fascinating observation that we’re really trying to understand and also look at some of the biopsy samples that we were able to take.”
Dr. Harrison said the results so far are encouraging, but longer-term tracking has been difficult.
“We had hoped that we would be able to use the MRI component to use the ion part of the nanoparticle to track later time points, and that’s proving a little more challenging than we had anticipated due to noise in the MRI signal that we’re still working on.” Correlative immunologic studies are ongoing, he said.
He said the product is likely to be tweaked to extend its half-life “to really extend the duration of being able to go longer into the post-infusion phase.”
When asked whether this could be scaled to routine practice in the next five years, and maybe even used at first infusion, Dr. Harrison said it’s “tricky” because a cyclotron is needed to produce the radioisotope, so it’s likely to be done only at large centers and not as part of the manufacturing process.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Dowling MR, Scott HW, Connor TL, et al. CAR-T cell therapy in advanced myeloma with extramedullary disease — an in vivo imaging and molecular monitoring study (CARAMEL): first results of Cu-64 radiolabelled nanoparticle PET-CT and PET-MRI. Abstract 1029. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
