JITC Digest September 2021

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Inside this Issue:

Letter from the Editor

Hello JITC Readers,pedro-romero_1__1_.jpg

For many of us, this edition of the digest coincides with the beginning of the academic year. As we look ahead, you can also take some time to reacquaint yourself with papers from the JITC archive in this month’s special feature. If you are seeking more contemporary recommendations, be sure to browse the monthly JITC's Reading List for selections by our editors of exciting research from other journals. Our colleagues in academia might find these resources useful to round out the reading lists in their syllabi.
 
Even if you left the classroom long ago, there is always more to learn in the immunotherapy field. The papers selected for this month’s digest emphasize how new insights may be found in familiar pathways or strategies as our field continues to advance.
 
Two papers provide surprising insights into mechanisms of anti-tumor efficacy for familiar families of agents. Casey R Ager and colleagues reveal several novel mechanisms of myeloid reprogramming induced by cyclic dinucleotides, revealing STING signaling as a potential target to potentiate checkpoint blockade in immunologically cold tumors. Pu Sun et al show that PI3K inhibitors modulate T cell metabolism as well as suppressive myeloid cells in the tumor microenvironment, identifying unappreciated immune mechanisms of action.
 
Another strategy to target myeloid suppressive cells is described by David G DeNardo and colleagues, who explain the preclinical rationale and study design for an ongoing phase I/II trial of a first-in-class CD11b modulator for solid tumors.
 
Finally, Michael J Wagner et al provide the first prospective trial data for combination ipilimumab and nivolumab immunotherapy for the rare tumor angiosarcoma.
 
Whether you are an early-career trainee or an emeritus, or at any other stage, I wish everyone a safe and smooth September.
 
Best,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer


JITC Editor Picks

High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege

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)
Research

Summary:

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.

PI3Kalpha inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8+T cells and promoting fatty acid metabolism

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)

Research

Summary:

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.

GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors

David G DeNardo, Anna Galkin, Jakob Dupont, Lei Zhou, Johanna Bendell
Journal for ImmunoTherapy of Cancer
 
2021;9:e003005 (27 August 2021)
Research

Summary:

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.

Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART)”

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)

Research

Summary:

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.

view other articles from this issue


JITC's Reading List

Each month, a JITC editor is invited to share publications of interest from other journals with our readership in JITC’s Reading List. Click through the link to see what has the attention of this month's featured editor and view past Reading Lists highlighting research on tumor immunology and cancer immunotherapy.


Popular Archive Articles

The selections below represent some of the most popular content published in JITC over the past few years. Explore additional thematic content in JITC's Collections or access the rest of JITC's archives for a look at all the journal has to offer.


Identification of tumor immune infiltration-associated lncRNAs for improving prognosis and immunotherapy response of patients with non-small cell lung cancer

Jie Sun, Zicheng Zhang, Siqi Bao, Congcong Yan, Ping Hou, Nan Wu, Jianzhong Su, Liangde Xu, Meng Zhou
Journal for ImmunoTherapy of Cancer 2020;8:e000110 (10 February 2020)

Research

Dual targeting of TGF-beta and PD-L1 via a bifunctional anti-PD-L1/TGF-betaRII agent: status of preclinical and clinical advances

Hanne Lind, Sofia R Gameiro, Caroline Jochems, Renee N. Donahue, Julius Strauss, James L Gulley, Claudia Palena, Jeffrey Schlom
Journal for ImmunoTherapy of Cancer 2020;8:e000433 (19 February 2020)

Review

Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project

Diana M Merino, Lisa M McShane, David Fabrizio, Vincent Funari, Shu-Jen Chen, James R White, Paul Wenz, Jonathan Baden, J Carl Barrett, Ruchi Chaudhary, Li Chen, Wangjuh (Sting) Chen, Jen-Hao Cheng, Dinesh Cyanam, Jennifer S Dickey, Vikas Gupta, Matthew Hellmann, Elena Helman, Yali Li, Joerg Maas, Arnaud Papin, Rajesh Patidar, Katie J Quinn, Naiyer Rizvi, Hongseok Tae, Christine Ward, Mingchao Xie, Ahmet Zehir, Chen Zhao, Manfred Dietel, Albrecht Stenzinger, Mark Stewart, Jeff Allen
Journal for ImmunoTherapy of Cancer 2020;8:e000147 (26 March 2020)
Research

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

Lorenzo Galluzzi, Ilio Vitale, Sarah Warren, Sandy Adjemian, Patrizia Agostinis, Aitziber Buqué Martinez, Timothy A Chan, George Coukos, Sandra Demaria, Eric Deutsch, Dobrin Draganov, Richard L Edelson, Silvia C Formenti, Jitka Fucikova, Lucia Gabriele, Udo S Gaipl, Sofia R Gameiro, Abhishek D Garg, Encouse Golden, Jian Han, Kevin J Harrington, Akseli Hemminki, James W Hodge, Dewan Md Sakib Hossain, Tim Illidge, Michael Karin, Howard L Kaufman, Oliver Kepp, Guido Kroemer, Juan Jose Lasarte, Sherene Loi, Michael T Lotze, Gwenola Manic, Taha Merghoub, Alan A Melcher, Karen L Mossman, Felipe Prosper, Øystein Rekdal, Maria Rescigno, Chiara Riganti, Antonella Sistigu, Mark J Smyth, Radek Spisek, John Stagg, Bryan E Strauss, Daolin Tang, Kazuki Tatsuno, Stefaan W van Gool, Peter Vandenabeele, Takahiro Yamazaki, Dmitriy Zamarin, Laurence Zitvogel, Alessandra Cesano, Francesco M Marincola
Journal for ImmunoTherapy of Cancer 2020;8:e000337 (9 March 2020)
Review

Phase 2 study of pembrolizumab in patients with advanced rare cancers

Aung Naing, Funda Meric-Bernstam, Bettzy Stephen, Daniel D Karp, Joud Hajjar, Jordi Rodon Ahnert, Sarina A Piha-Paul, Rivka R Colen, Camilo Jimenez, Kanwal P Raghav, Renata Ferrarotto, Shi-Ming Tu, Matthew Campbell, Linghua Wang, Sarjeel H Sabir, Coya Tapia, Chantale Bernatchez, Michael Frumovitz, Nizar Tannir, Vinod Ravi, Saria Khan, Jeane M Painter, Abulrahman Abonofal, Jing Gong, Anas Alshawa, Lacey M McQuinn, Mingxuan Xu, Sara Ahmed, Vivek Subbiah, David S Hong, Shubham Pant, Timothy A Yap, Apostolia M Tsimberidou, Ecaterina E Ileana Dumbrava, Filip Janku, Siqing Fu, Richard M Simon, Kenneth R Hess, Gauri R Varadhachary, Mouhammed Amir Habra
Journal for ImmunoTherapy of Cancer 2020;8:e000347 (17 March 2020)
Research

SITC Members Receive 50 Percent Submission Discount in 2021

*As a way to thank the SITC members who work tirelessly to advance the science and improve the lives of cancer patients, SITC will provide members with a 50 percent discount on processing fees for all JITC articles accepted in 2021.