JITC Editor Picks
Casey R Ager, Akash Boda, Kimal Rajapakshe, Spencer Thomas Lea, Maria Emilia Di Francesco, Priyamvada Jayaprakash, Ravaen B Slay, Brittany Morrow, Rishika Prasad, Meghan A Dean, Colm R Duffy, Cristian Coarfa, Philip Jones, Michael A Curran
Journal for ImmunoTherapy of Cancer 2021;9:e003246 (2 August 2021)
The molecular mechanisms by which STING agonists perturb myeloid cells within the tumor stroma to relieve immune suppression remain largely uncharacterized. Using deep multiomics analysis, Casey R Ager and colleagues uncover novel functions for STING agonists in creating an inflammatory tumor milieu including inhibition of Myc signaling, altered cell cycle dynamics in the myeloid compartment, and metabolic reprogramming. Notably, the transcriptional, proteomic, and functional changes induced by different STING agonists did not align with in vitro potency. In myeloid-derived suppressor cells and human M2 macrophages, stimulation with high-potency synthetic STING agonists led to dramatic downregulation of oxidative phosphorylation, mTORC1, glycolysis, and fatty acid oxidation. High-potency synthetic STING agonists led to a unique antiproliferative state characterized by differential downregulation of Myc target hallmark gene sets. In murine models of multifocal pancreatic ductal adenocarcinoma, intratumoral administration of high-potency synthetic STING agonists synergized with dual anti-CTLA-4 plus anti-PD-1 checkpoint blockade to extend survival and shrink non-target lesions. High-parameter flow cytometry revealed substantial changes across the granulocyte compartment and a single putative macrophage cluster associated with the combination therapy, as well as major effects on the frequencies and phenotypes of tumor-infiltrating CD8+ T cells. The findings identify several new pathways not previously implicated in STING signaling for future characterization as well as support STING agonism as a therapeutic strategy for immunologically cold tumors.
Pu Sun, Xi Zhang, Rong-Jing Wang, Qing-Yang Ma, Lan Xu, Yi Wang, Hui-Ping Liao, Hai-Long Wang, Lan-Dian Hu, Xiangyin Kong, Jian Ding, Ling-Hua Meng
Journal for ImmunoTherapy of Cancer 2021;9:e003093 (8 August 2021)
Using a variety of immune-competent murine models for solid tumors, Pu Sun et al show that PI3K inhibition with the novel compound CYH33 leads to immune-mediated in addition to direct anti-tumor effects. Single-cell RNA sequencing of allografted breast cancer tumors showed that CYH33 treatment led to cell cycle arrest in immune-competent, but not nude, mice. The myeloid compartment of the tumor microenvironment in immune-competent mice was shifted toward a pro-inflammatory signature after CYH33 treatment with fewer myeloid-derived suppressor cells and increased infiltration of dendritic cells. In vitro, CYH33 shifted the polarization of M1 macrophages toward an M2 phenotype and reversed their suppressive effects on CD8+ T cells. Treatment with CYH33 increased the intratumoral proportions of naïve, effector, and helper CD8+ T cells while decreasing the frequencies of exhausted CD8+ T cells and regulatory T cells. High proportions intratumoral of effector memory and central memory T cells with low PD-1 expression were seen after CYH33 treatment, and immune memory was confirmed with rechallenge. Infiltrating T cells from murine 4T1 breast tumors had elevated cytotoxic activity after CYH33 treatment, as measured by intracellular levels of granzyme B. CYH33 also caused a shift toward fatty acid metabolism in infiltrating T cells, and anti-tumor synergy was seen in vivo with C75, a small molecule fatty acid synthase inhibitor that causes an increase in free fatty acids in the tumor microenvironment. The results offer comprehensive evidence for immune-modulatory activities of PI3K inhibition, providing rationale for future combination immunotherapy approaches.
David G DeNardo, Anna Galkin, Jakob Dupont, Lei Zhou, Johanna Bendell
Journal for ImmunoTherapy of Cancer 2021;9:e003005 (27 August 2021)
Strategies to reduce or prevent the migration of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment or inhibit their differentiation into tumor-associated macrophages (TAM), of the M2 type, have had limited success thus far. The first-in-class CD11b modulator GB1275 is currently being evaluated in a phase I/II trial in advanced solid tumors that typically do not respond to checkpoint blockade and David G DeNardo et al describe the preclinical evidence and rationale supporting the clinical development of this agent as an MDSC-targeting immunotherapy. CD11b mediates myeloid cell adhesion to the vasculature and transendothelial migration. Attempts to block CD11b with monoclonal antibodies have been unsuccessful because saturation is not achievable at a clinically tolerable dose. GB1275 stabilizes CD11b in its active state to enhance adhesion to CD54 on vascular endothelium, which impairs myeloid cell extravasation and migration into inflamed tissues. Importantly, activation of CD11b does not require saturation of the integrin and no dose-limiting toxicities were identified in the investigational new drug-enabling good laboratory practice toxicology studies for the agent. In pre-clinical models of pancreatic ductal adenocarcinoma (PDAC), breast cancer, and microsatellite stable colorectal cancers (CRC), GB1275 has demonstrated single-agent anti-tumor activity as well as reductions in TAMs in the tumor microenvironment. The ongoing study included a standard 3+3 design dose escalation and expansion phase that enrolled patients with microsatellite-stable CRC, gastric cancer, metastatic PDAC, triple-negative breast cancer, metastatic castration-resistant prostate cancer, or esophageal cancer. In the phase II basket expansion, a Simon’s two-stage optimal design will be used to evaluate GB1275 in combination with pembrolizumab. Enrollment has begun in six sites in the United States and one site in the United Kingdom, and additional sites are being recruited.
Michael J Wagner, Megan Othus, Sandip P Patel, Chris Ryan, Ashish Sangal, Benjamin Powers, G Thomas Budd, Adrienne I Victor, Chung-Tsen Hsueh, Rashmi Chugh, Suresh Nair, Kirsten M Leu, Mark Agulnik, Elad Sharon, Edward Mayerson, Melissa Plets, Charles Blanke, Howard Streicher, Young Kwang Chae, Razelle Kurzrock
Journal for ImmunoTherapy of Cancer 2021;9:e002990 (11 August 2021)
No prospective trials have evaluated checkpoint blockade in angiosarcoma. Based on anecdotal case reports, an angiosarcoma cohort was added to the phase II DART trial (Dual anti-CTLA-4 and anti-PD-1 Blockade in Rare Tumors [S1609]) and 18 patients from 11 National Clinical Trial Network institutions were enrolled between July 31, 2019 through March 19, 2020. Michael J Wagner and colleagues describe outcomes for the 16 patients who met eligibility criteria and received the protocol therapy of ipilimumab (1 mg/kg intravenously every 6 weeks) plus nivolumab (240 mg intravenously every 2 weeks). The objective response rate (ORR) by RECIST was 25% (four patients), with durations lasting 5, 7, 12+, and 13+ months. One patient had initial reduction in tumor size, but progression on the confirmatory scan, and two patients had stable disease lasting longer than 6 months. Subgroup analysis showed an ORR for patients with primary cutaneous disease of the face or scalp of 60% (3 out of 5 patients). One patient with a responding tumor had a mutation burden greater than 10 mutations per megabase and one was positive for PD-L1 expression (30% by tumor proportion score). Immune-related adverse events (irAEs) occurred in 70% of patients, with only 2 of grade 3 or 4 (elevated aminotransferases and diarrhea) and no deaths attributed to the study drug. The most common irAEs were ALT increase, AST increase, diarrhea, hypothyroidism, pneumonitis, pruritus, and rash. Correlative studies to understand molecular characteristics associated with response to treatment are ongoing. The findings lay the groundwork for further evaluation of checkpoint blockade in angiosarcoma.