Jonathan Chen, MD, PhD, on NSCLC: Predicting Response to Immunotherapy
SITC 2022
Jonathan Chen, MD, PhD, of Massachusetts General Hospital, discusses “immunity hubs” that interact with a reservoir of stem-like CD8 T cells and appear to be associated with subsequent response to anti–PD-1 blockade in patients with non–small cell lung cancer. Hybrid hubs, Dr. Chen says, are a favorable class of immunity hub notable for CD8-positive and TCF7-positive cells, as well as CCL19 expression (Abstract 956).
Transcript
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
In our previous study of human MSI and MSS colorectal cancer, we use single cell RNA sequencing to infer a network of CXCR3 ligands and interfering gamma positive T cells. Then using multiplex RNA ISH, we were able to stain for these components and identified a multicellular network comprised of these CXCR3 ligands, CXCL10 and 11 that spatially co-localized with interfering gamma positive cells. We called this multicellular network the Immunity Hub.
So our question leading into this study was, are these multicellular hubs, these immunity hubs, important and what is their biology? We built a cohort of 68 pre PD1 immunotherapy human non-small cell lung carcinoma cases, 20 of which went on to respond to immunotherapy. We then used the same multiplex RNA ISH panel to verify the association of immunity hubs with subsequent response to PD1 therapy. We then built a second multiplex antibody panel designed around CD8 T-cell state.
We stained a serial section and then co-registered the RNA ISH panel with the antibody panel. We then performed a clustering analysis of the spatial data based upon the phenotypic composition of the immunity hubs. This revealed an especially favorable subclass of immunity hub that we call the Hybrid Hubs, which feature enrichment of CD8, TCF7 double positives stem-like T-cells. These CD8 TCF7 rich hybrid hubs showed variable B-cell content and were not clearly associated with B-cell follicles or germinal centers.
The hybrid hubs were found at sites where both CXCL10 11, and CCL19 were found. Hence, the name hybrid hubs. We think hybrid hubs may bring together the CXCR3 network, which is associated with activated T-cells and the CCR7 network, which is more associated with stem-like cells. Additionally, we found hybrid hubs enriched for macrophages that express CXCR3 ligands.
These hybrid hubs are morphologically reminiscent of the interfollicular zone of secondary lymphoid organs. We think that hybrid hubs might serve as a reservoir of stem-like antitumor T-cells, and this might partially explain why they're associated with favorable response to PD1 immunotherapy.
The ASCO Post Staff
Antoni Ribas, MD, PhD, of the University of California, Los Angeles, discusses a phase I study that used CRISPR gene editing to simultaneously “knock out” endogenous T-cell receptors and replace them with personalized neoantigen T-cell receptors in patients with solid tumors. The edited TCR T-cell products were safely infused and trafficked to the tumor lesions (Abstract 1478).
The ASCO Post Staff
Kishu Ranjan, PhD, of Yale University School of Medicine, discusses his study findings, which identified a deficiency in the biomarker TAP2 as a prominent immune evasion mechanism in patients whose non–small cell lung cancer has resisted immunotherapy (Abstract 148).
The ASCO Post Staff
Sumanta Pal, MD, of the City of Hope Comprehensive Cancer Center, discusses phase I results from the COBALT-RCC study, a first-in-human clinical trial exploring CD70 CAR T-cell therapy in patients with clear cell renal cell carcinoma. The agent appeared to show an excellent safety profile with no unexpected toxicities and antitumor activity. One durable complete response is the first to be achieved with allogeneic CAR T-cell therapy in patients with relapsed or refractory solid tumors, offering proof of concept for further exploration of CD70-targeted CAR T cells in renal cell and other CD70-positive malignancies (Abstract 558).
The ASCO Post Staff
Saman Maleki, PhD, of Canada’s Western University and Lawson Health Research Institute, discusses modifying the gut microbiome in patients with advanced melanoma to induce a response to anti–PD-1 therapy and potentially reduce primary resistance to immunotherapy. A fecal microbiota transplant from healthy donors before treatment appears to be beneficial (Abstract 614).
The ASCO Post Staff
Roger Li, MD, of the H. Lee Moffitt Cancer Center, discusses results from a phase II single-arm study of CG0070, a cancer-selective oncolytic adenovirus that creates mechanistic synergy with immune checkpoint blockade. In this trial, the virus was combined with pembrolizumab in patients with non–muscle-invasive bladder cancer that is unresponsive to bacillus Calmette-Guérin. At 3 months, 88% of the 35 patients enrolled achieved a complete response (Abstract 666).