Soniya Pinto, MBBS, MSCI

Using imaging to diagnose therapy-related complications 

CAR T-cell therapy was first approved by the FDA in 2017 for the treatment of relapsed and refractory B-cell malignancies. Many of these FDA-approved therapies direct autologous T cells to target CD19, a B-cell specific cell surface protein. The engagement of CAR T cells with CD19 induces cellular apoptosis and activates the monocyte-macrophage system, stimulating the release of pro-inflammatory cytokines including interleukins (IL)-1, IL-2 and IL-6 and tumor necrosis factor-alpha (TNF-α). The release of these cytokines into systemic circulation increases circulating angiopoietin levels, which in turn increases the permeability of the blood-brain barrier. 

Treatment-related modulation of the permeability of the blood-brain barrier can cause an inflammatory neurotoxicity called ICANS. ICANS presents with symptoms ranging from encephalopathy to seizures and, in rare instances, fatal cerebral edema. MRI plays a crucial role in diagnosis, and the characteristic pattern of bilateral deep white matter and thalamic and brainstem edema is important to recognize. These imaging findings are at least partially reversible once the symptoms of ICANS improve. 

Newer CAR T cells include targeting CD22 to treat B-cell malignancies and targeting B7H3 in brain and solid tumors. B7H3, also called CD276, is a transmembrane protein with high expression in various solid and brain tumors and low expression in normal human tissues. B7H3 CAR T cells are locally administered using an Ommaya catheter, an implantable port in the ventricle in the brain, and given to certain patients experiencing relapsed or refractory brain tumors. However, the intracranial release of cytokines can cause a syndrome called TIAN. TIAN has two distinct subtypes. TIAN 1 is characterized by mechanical obstruction to the outflow of cerebrospinal fluid and is usually seen in patients with a heavy tumor burden that causes displacement of the brain (mass effect). TIAN 2 is an electrophysiological disturbance, presenting with neurological symptoms localizing to the site of tumor involvement. MRI is again crucial in recognizing subtle changes in tumor volume and enhancement, which are suggestive of this inflammatory syndrome. 

I have also explored the use of an MRI parameter called Apparent Diffusion Coefficient (ADC) to characterize the microstructural changes occurring in individuals who develop TIAN and ICANS, allowing clinicians to better understand their impact. Additionally, I am interested in using Neurite Orientation and Dendrite Dispersion Imaging (NODDI) to prospectively study microstructural changes in the brains of CAR T-cell recipients and using synthetic MRI to quantify cerebral volume loss and myelination changes in long-term survivors of CD19 CAR T-cell therapy.  

My research, combined with advocacy efforts to help neuroradiologists and neuro-oncologists understand the classic and atypical imaging presentations of ICANS and TIAN, advance our understanding of CAR T cell-related complications, allow us to provide better patient care and improve quality of life for our patients.