The Society for Immunotherapy of Cancer (SITC) held its annual meeting online this year. Notable were the presentations in New Approaches for CAR-T Cell Therapies: Technology Symposium Featuring GeoMx® Digital Spatial Profiler (DSP) and nCounter CAR-T Characterization Panel. Two speakers from the University of Pennsylvania were on hand to discuss their recent technology advances and the early data generated. Chimeric antigen receptor (CAR) T cells have led to promising therapies in cancer treatment by T cells isolated from patients, modifying them with a chimeric antigen receptor specific to cancer cells, expanding the population of cells, and infusing them into the patient.
CAR-T cell therapy has received FDA approval in recent years and is the best available option for those suffering from refractory Acute Lymphoblastic Lymphoma (ALL). Dr. Ryan Golden, MD, Ph.D. is a third-year resident in Clinical Pathology and presented “Applying Digital Spatial Profiling to Capture CAR-T Cell Activity in Human Tissues”. Prior to CAR-T therapy, refractory ALL had a grim prognosis but now ~90% of patients treated achieve and remain in remission. What remains unclear is how these CAR-T cells are interacting in the tumor microenvironment. To investigate the activity in solid tumors, Dr. Golden and his team focused on mesothelin, a highly antigenic, GPI-anchored protein expressed in high levels in solid tumors. They designed CAR-T cells against mesothelin-positive targets to study the molecular architecture of the tumor microenvironment in FFPE tissues. Using the xenograft systems in the lab to create ovarian and pancreatic cancers, they are seeking to identify factors involved in the CAR-T cell response in the solid tumor. Through a partnership with NanoString and ACD, they created a novel RNA label specific to the mesothelin-CAR-T cells and can differentiate between tumor cells and infiltrating immune cells. Now they are able to designate multiple ROIs based on not just the presence or absence of mesothelin-CAR-T cells but the relative levels of infiltration. Ongoing work in profiling these regions with the 80 genes of the Human Immuno-Oncology Panel before moving on to the more extensive GeoMx Human Whole Transcriptome Atlas as the team seeks to understand the mechanisms that drive this life-saving therapy.
Another therapy of note is anti-CD19 CAR-T cell therapy, used in the treatment of leukemia and lymphoma. While it is highly successful in treating patients that respond well to the infusions, there remains a significant population that does not respond. Clearly, there is a need to find additional therapies to support these patients, as discussed by Dr. Marco Ruello, Scientific Director of the Lymphoma Program, in his presentation “Novel Platforms to Understand Resistance to CAR-T Immunotherapy in Lymphoma”. It has been observed that patients that don’t demonstrate a positive response to CAR19 treatment have a higher incidence of T cell exhaustion and decreased development of memory cells. The team used the nCounter® CAR-T Characterization gene expression panel of 780 human genes (including eight specific molecules for CAR-T biology) that was customized by the addition of CAR19-specific probes to study the tumors of 46 lymphoma patients treated with CAR19 therapy. Preliminary results show an expected clustering of patients in complete remission that are characterized by Cytokine Release Syndrome (CRS), longer CAR19 persistence, and T cell activation. Interestingly, there were two non-responding populations that became apparent: one displayed CRS and increased gene expression for innate and Th2 pathways and a second group that showed no CRS and increased expression in tumor-related pathways. The team is now investigating the role of CAR19 in the lymphoma tumor microenvironment using GeoMX DSP to identify different ROIs by B cell, T cell, or macrophage levels. Their goal is to determine the difference between the genes at play in responders and non-responders, leading to the development of new therapies for lymphoma and leukemia.
In case you missed the CAR-T Symposium at SITC, please view it on-demand here.
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