Jonathan Chen, MD, PhD, on NSCLC: Predicting Response to Immunotherapy
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).
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.
David Reardon, MD, of Dana-Farber Cancer Institute, discusses phase I/II results from the EOGBM1-18/ROSALIE study, which showed the EO2401 vaccine plus nivolumab generated systemic immune responses correlating with efficacy in patients with recurrent glioblastoma. Adding bevacizumab to this combination appeared to improve efficacy. (Abstract 642).
Talal El Zarif, MD, of Dana-Farber Cancer Institute, and Abdul Rafeh Naqash, MD, of Stephenson Cancer Center at The University of Oklahoma, discuss the results of their cohort study of patients living with HIV and metastatic non–small cell lung cancer, who are often underrepresented in clinical trials, and the safety and efficacy of treating this unique population with immune checkpoint inhibitors (ICIs). The data showed that patients living with HIV and lung cancer had similar toxicity profiles and clinical outcomes as did those who did not have HIV and received ICIs (Abstract 437).
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).
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).
Michael B. Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, explores recent clinical trials in immuno-oncology in which the phase III trial produced markedly different results from the phase II trial. To help understand the potential value to patients of late-stage trials of treatment combinations, the Society for Immunotherapy of Cancer has developed a checklist for investigators, applicable to any regimen in which immune modulation is an important component of the antitumor effect.