The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Clinical trials monitor Section Editor, Leisha A. Emens, MD, PhD.
“Sustained type I interferon signaling as a mechanism of resistance to PD-1 blockade” by Nicolas Jacquelot et al.
Resistance to PD-1 blockade remains a major obstacle for immunotherapy, with roughly 60% of non-small cell lung cancer patients not responding to checkpoint blockade and disease progression after treatment reported in roughly 25% of melanoma patients. By comparing immunological phenotypes across sensitive and non-responding tumors in mice, Nicolas Jacquelot et al. identify a potential role for type I interferon signaling in mediating PD-1 blockade resistance. In mouse models of MCA205WT sarcoma, which were defined by late-onset resistance to checkpoint blockade, deletion of Ifnar1 extended tumor control and prolonged survival with anti-PD-1 therapy. Significant increases in Nos2 nitric oxide synthase gene expression were observed in tumor and CD45+ T cells from anti-PD-1 treated mice. Deletion of Nos2 as well as treatment with the non-selective nitric oxide synthase inhibitor L-NAME extended the efficacy of anti-PD-1 treatment. Analysis of pre-treatment tumor samples from 23 patients with advanced melanoma receiving combination CTLA-4/PD-1 blockade revealed higher baseline expression of several interferon-related genes as well as nitric oxide synthase among non-responders. The results point toward inhibition of nitric oxide synthase as a promising potential strategy to overcome resistance to PD-1 blockade.
“Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer” by Kroopa Joshi et al.
Tumor heterogeneity is a defining feature of non-small cell lung cancer, and a high burden of clonal non-synonymous mutations is associated with reduced recurrence and improved response to checkpoint blockade. To better understand the immunological responses to this heterogeneity, Kroopa Joshi and colleagues used a highly quantitative sequencing and analysis pipeline to characterize T cell receptor repertoires in multiregion tumor samples and matched healthy lung and blood samples from a cohort of 72 patients with early-stage untreated disease who were enrolled in the multi-institution prospective TRACERx study. Narrowing the analysis to the most expanded TCRs (a threshold corresponding to the top 1% of empirical tumor frequency distribution, which accounted for almost 20% of the total), two distinct TCR populations were defined: “regional,” which were absent from one or more areas of the tumor, and “ubiquitous,” which were found throughout. The numbers of regional TCRs correlated with the numbers of regional mutations in the tumor samples, and high numbers of ubiquitous tumor mutations correlated with improved clinical outcomes. No relationship was seen between high numbers of expanded regional or ubiquitous TCR and prognosis, however. Among the ubiquitous TCRs, evidence of convergent recombination and clusters of related CDR3 sequences were observed, suggesting the existence of a population of neoantigen-specific T cells. In blood samples taken at the time of resection, many of the expanded ubiquitous TCRs were detected, potentially providing a non-invasive method for monitoring and accessing neoantigen-specific T cells to improve outcomes foe patients receiving immunotherapies for NSCLC.
“Infiltrating myeloid cells drive osteosarcoma progression via GRM4 regulation of IL23” by Maya Kansara et al.
In the past 40 years, very few effective systemic therapies have emerged for osteosarcoma. Motivated by GWAS studies showing an association between polymorphism within the GRM4 gene and increased susceptibility to osteosarcoma, Maya Kansura et al. investigated the potential biological and therapeutic roles of the locus in mouse models. Mice lacking Grm4 displayed accelerated tumor development in radiation-induced and hereditary models of osteosarcoma, with pronounced elevation in the levels of IL-23 in bone marrow dendritic cells compared to wild type controls. Conditioned media from cultured mouse osteosarcoma cells induced significant IL-23 production while suppressing IL-12 in bone marrow dendritic cells. Deletion of IL23 protected mice from osteosarcoma, with 24/30 animals remaining tumor-free at 100 weeks in the radiation-induced model whereas all control animals developed tumors by the 90.7 week point. Treatment with an IL-23-neutralizing antibody slowed tumor growth and prolonged survival, as did the GRM4 agonist PHCCC. Notably, PHCCC displayed similar potency to doxorubicin without causing weight loss in treated mice, suggesting favorable toxicity for GRM4 as a therapeutic target. The link between GRM4 and IL-23 established by this study could be a promising therapeutic target in osteosarcoma.
Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-PD-1/PD-L1 therapy” by Jonathan Rosenberg et al.
There is an urgent need for effective and tolerable therapies for patients with advanced and metastatic urothelial carcinoma after treatment with platinum chemotherapies and checkpoint inhibitors. Jonathan Rosenberg and colleagues report a clinically meaningful response rate and tolerable safety profile in a phase 2, single arm study of the antibody-drug conjugate enfortumab vedotin, which is a fully human Nectin-4 targeting monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). During the trial, 125 patients received enfortumab vedotin and the confirmed objective response rate was 44% (95% CI 35.1% to 53.2%) with 15 complete responses. Clinical activity was consistent across all subgroups analyzed, including patients with traditionally challenging features such as liver metastases. The median duration of response was 7.6 months. Adverse events led to dose reduction in 32% of patients and treatment discontinuation in 15% of patients, with peripheral sensory neuropathy being the most common cause. No single grade 3 or higher treatment-related adverse event occurred in more than 10% of patients. The most common adverse events reported were fatigue (50%), peripheral neuropathies (50%), alopecia (49%), rash (48%), decreased appetite (44%) and dysgeusia (40%). A phase 3 trial comparing enfortumab vedotin monotherapy with single-agent chemotherapy is ongoing, and favorable results could change the treatment landscape for advanced and metastatic urothelial carcinoma.
“An innate-like V-delta 1+ gamma-delta T cell compartment in the human breast is associated with remission in triple-negative breast cancer” by Yin Wu et al.
Subsets of tissue-resident gamma-delta T cells that display innate-like activity have been characterized in mice, but their potential roles in cancer immunosurveillance in humans remain undefined. Using a recently developed grid-explant culture system that permits the recovery and characterization of large numbers of tissue-resident T cells without changing their phenotypes, Yin Wu et al. isolated lymphocytes from breast tissue samples from 29 healthy human donors, in which they detected distinct populations of V-delta 1+ gamma-delta T cells. The breast-resident V-delta 1+ gamma-delta T cells displayed increased CD107a expression (a marker of degranulation and exocytosis of cytolytic mediators) as well as interferon-gamma and tumor necrosis factor production in response to stimulation with NKGD2 ligand, an innate immune signal. Unlike CD4+ alpha-beta T cells extracted and maintained within identical breast explant cultures, the V-delta 1+ gamma-delta T cells produced negligible IL-17A. In vitro, V-delta 1+ gamma-delta T cells from healthy breast tissue reproducibly killed two tumor cell lines. Analysis of paired tumor and nonmalignant tissue in FFPE samples from 11 patients with triple-negative breast cancer revealed a correlation between abundant V-delta 1+ gamma-delta T cells and progression-free survival. The study suggests that strategies to enhance the activities of tissue-resident V-delta 1+ gamma-delta T cells could promote tumor immunogenicity to augment the effectiveness of other immune-oncology therapies.
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