JITC Editor Picks
Yu-Li Chen, Han-Wei Lin, Chung-Liang Chien, Yen-Ling Lai, Wei-Zen Sun, Chi-An Chen & Wen-Fang Cheng
Journal for ImmunoTherapy of Cancer 2019, 7:313 (21 November 2019)
Research
Summary:
Epithelial ovarian carcinomas (EOCs) have a relatively poor prognosis when treated with standard of care surgery followed by platinum/paclitaxel-based chemotherapy, with an overall survival rate of roughly 35%. To investigate potential immunotherapeutic approaches for the treatment of EOCs, Chen and colleagues treated tumor-bearing mice with a monoclonal antibody directed against the immune checkpoint molecule B and T lymphocyte attenuator (BTLA). The survival of tumor-bearing mice receiving the anti-BTLA antibody was not significantly different than those treated with paclitaxel. However, a combination regimen significantly prolonged survival, with 100% of mice receiving both anti-BTLA antibody and paclitaxel remaining alive for more than 100 days after tumor challenge. Pro-inflammatory cytokines including IL-12 and TNF-alpha were elevated in ascites from mice treated with a combination of anti-BTLA antibody and paclitaxel compared to those that received either single agent. BTLA was predominantly expressed on CD19high B lymphocytes, and IL-6 as well as IL-10 further increased BTLA expression on CD19high B cells through AKT/STAT3 signaling. Detectable BTLA by qPCR in tumor samples from 254 human EOC patients was associated with higher incidence of advanced disease (p<0.001) and disease-related death (P<0.001). The results suggest BTLA inhibition may hold clinical potential when used in combination with chemotherapy for EOC patients.
Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Henia Darr, Daniel B. Henderson, Amanda A. Bouffard, Rebecca C. Larson, Irene Scarfò, Stefanie R. Bailey, Genevieve M. Gerhard, Matthew J. Frigault, Mark B. Leick, Andrea Schmidts, Jason G. Sagert, William T. Curry, Bob S. Carter & Marcela V. Maus
Journal for ImmunoTherapy of Cancer 2019, 7:304 (14 November 2019)
Short Report
Summary:
CAR T cell therapies have had limited success in the treatment of solid tumors, in part due to profound immune suppression within the tumor microenvironment including marked upregulation of PD-L1. To overcome tumor-induced T cell exhaustion and also develop an “off-the-shelf” universal allogenic CAR T cell product for the treatment of glioblastoma, Bryan Choi and colleagues deployed CRISPR-Cas9 for multiplex genome editing to disrupt the PD-1 gene (PDCD1) in addition to the endogenous T cell receptor (TRAC) and beta-2-microglobin loci (B2M) prior to introducing an anti-EGFRvIII CAR on an adenoviral vector (which allows for integration into the genome at a specific site) during the manufacturing process. The gene-edited CAR T cells lacking PD-1 showed significantly more cytotoxic activity against U87vIII glioblastoma cell lines in vitro than PD-1 proficient CAR T cells after up to 120 hours in coculture. In mouse models of EGFRvIII expressing glioblastoma, treatment with the gene-edited CAR T cells significantly prolonged survival with some animals displaying durable, long-term responses, but only when the cells were administered intracranially through intraventricular injection. This is the first report of triple deletion of TRAC, B2M and PDCD1 in CAR T cells tested in a solid tumor model, possibly overcoming some of the shortcomings of previous attempts to utilize CAR T cells for the treatment of glioblastoma.
Claire L. Ihle, Meredith D. Provera, Desiree M. Straign, E. Erin Smith, Susan M. Edgerton, Adrie Van Bokhoven, M. Scott Lucia & Philip Owens
Journal for ImmunoTherapy of Cancer 2019, 7:293 (8 November 2019)
Short Report
Summary:
Primary prostate tumors are considered immunologically “cold” with low immune cell infiltration and minimal neoantigen expression, yet the immune environment within metastases has been less well-characterized, including any potential differences between the two primary types of secondary lesions: blastic and lytic. Claire Ihle and colleagues analyzed decalcified formalin-fixed and paraffin-embedded patient specimens from bone that contained metastatic prostate cancer with either lytic or blastic features using immunohistochemistry, the NanoString platform for gene expression analysis and the emerging Digital Spatial Profiling technology for molecular characterization of both tumor and stroma regions in the lesions. Both lytic and blastic lesions displayed evidence of sporadic infiltrating T cell populations by IHC. Lytic samples were enriched for expression of genes associated with the PI3K-AKT pathway, whereas blastic lesions displayed enrichment for expression of JAK-STAT signaling. Blastic-type samples showed increased expression of checkpoint inhibitor targets compared to lytic lesions, including PD-L1, PD-1, VISTA, OX40L and IDO-1. The study offers rationale for analyzing biopsies of secondary lesions to help identify optimal immunotherapeutic treatments for metastatic prostate cancer.
Philipp Metzger, Sabrina V. Kirchleitner, Michael Kluge, Lars M. Koenig, Christine Hörth, Carlotta A. Rambuscheck, Daniel Böhmer, Julia Ahlfeld, Sebastian Kobold, Caroline C. Friedel, Stefan Endres, Max Schnurr & Peter Duewell
Journal for ImmunoTherapy of Cancer 2019, 7:288 (6 November 2019)
Research
Summary:
No immunotherapy-based approaches have been approved for the treatment of pancreatic ductal adenocarcinoma (PDAC), which is the second most common cause of cancer fatality among western nations. The use of Rig-I-like helicase (RLH) ligands to convert tumor microenvironments into immunologically “hot” sites has entered early clinical trials, and Philipp Metzger et al. provide mechanistic evidence that RLH ligands contribute to tumor control by T cells through reprogramming of myeloid-derived suppressor cells (MDSCs). Here they demonstrate in mouse models that the PDAC tumor microenvironment is characterized by low T cell infiltration and large populations of both monocytic and polymorphonuclear myeloid-derived suppressor cells ((M)-MDSC and (PMN)-MDSC), and that those suppressor cells profoundly suppress T cell activation (measured by interferon gamma production) in vitro. Treatment with the RLH ligand poly(I:C)c partially rescued the MDSC-mediated T cell suppression and shifted gene expression profiles toward a neutrophil-associated gene signature for PMN-MDSC and an M1-like signature M-MDSC. Type I interferon signaling was necessary for tumor control and MDSC reprogramming after poly(I:C)c treatment. The results offer rationale for the use of RLH-ligands in combination with other immunotherapy strategies such as checkpoint inhibitors or CAR T cells.
Eleanor M. Scott, Egon J. Jacobus, Brian Lyons, Sally Frost, Joshua D. Freedman, Arthur Dyer, Hena Khalique, William K. Taverner, Alison Carr, Brian R. Champion, Kerry D. Fisher, Len W. Seymour & Margaret R. Duffy
Journal for ImmunoTherapy of Cancer 2019, 7:320 (21 November 2019)
Research
Summary:
Selective depletion of M2-like tumor-associated macrophages (TAMs) within the tumor microenvironment could eliminate a key obstacle to the success of immunotherapy by eliminating stromal cells that promote disease progression through a tissue-remodeling and immunosuppressive phenotype, while sparing the M1-like TAMS that contribute to direct cancer cell killing in addition to T helper 1 immune responses. Eleanor Scott and colleagues have developed novel bivalent and trivalent antibodies recognizing CD3-epsilon and either CD206 or folate receptor beta (FR-beta) to redirect endogenous T cell toxicity specifically toward M2-like TAMs. In whole malignant ascites from cancer patients, the multi-specific antibodies triggered interferon gamma production and depletion of CD11b+ CD64+ (M2-like) macrophages. To alleviate potential on-target/off tumor effects if the agents were administered systemically, Scott et al. inserted the T cell engagers into the genome of EnAd, an oncolytic adenovirus currently being tested in phase 1/2 clinical trials. The engineered viruses retained oncolytic activity, while also causing a robust decline in CD11b+ CD64+ macrophages in malignant ascites from 5 cancer patients. Intriguingly, the remaining macrophages in the ascites displayed a general increase in M1-like marker expression. The study is the first to achieve selective depletion of M2-like TAM subsets, and describes an innovative two-in-one approach combining tumor microenvironment modification with oncolytic virotherapy.
Jonathan A. Trujillo, Jason J. Luke, Yuanyuan Zha, Jeremy P. Segal, Lauren L. Ritterhouse, Stefani Spranger, Karen Matijevich & Thomas F. Gajewski
Journal for ImmunoTherapy of Cancer 2019, 7:295 (8 November 2019)
Research
Summary:
As many as 60% of melanoma patients who initially display objective responses to immunotherapy will subsequently relapse. Through molecular analyses of tumor biopsies, Jonathan Trujillo and colleagues describe two novel mechanisms of immunotherapy resistance in two patients, one of whom had been treated with a melanoma-peptide IL-12 vaccine and the other who received combination anti-CTLA-4/anti-PD-1 checkpoint blockade. Distinct from previously described mechanisms of immunotherapy resistance, antigen loss was not seen in either of the recurrent tumors after treatment. In both cases, initial treatment and partial responses were associated with CD8+ T cell infiltration into the tumor microenvironment, which was lost in secondary lesions—even though circulating tumor-specific memory T cells were still detected. T cell exclusion in the patient who was treated with the melanoma-peptide/IL-12 vaccine was associated with strong upregulation and nuclear localization of beta-catenin with an associated increase in beta-catenin regulated transcripts in relapsed tumor samples. Relapse after dual checkpoint blockade therapy was associated with bi-allelic loss of the tumor-suppressor gene PTEN in a new metastatic lesion. The study reveals new mechanisms of tumor outgrowth after immunotherapy, adding alterations in oncogenic signaling to the growing list of immunotherapy resistance pathways.
Harm Westdorp, Jeroen H. A. Creemers, Inge M. van Oort, Gerty Schreibelt, Mark A. J. Gorris, Niven Mehra, Michiel Simons, Anna L. de Goede, Michelle M. van Rossum, Alexandra J. Croockewit, Carl G. Figdor, J. Alfred Witjes, Erik H. J. G. Aarntzen, Roel D. M. Mus, Mareke Brüning, Katja Petry, Martin Gotthardt, Jelle O. Barentsz, I. Jolanda M. de Vries & Winald R. Gerritsen
Journal for ImmunoTherapy of Cancer 2019, 7:302 (14 November 2019)
Research
Summary:
The only U.S. FDA-approved cancer immunotherapy for castration-resistant prostate cancer (CRPC) is sipuleucel-T, an autologous antigen-presenting cell vaccine. The mechanism of action of sipuleucel-T remains ill-defined as the product contains roughly 60% CD3+ T cells and less than 20% CD54+ putative dendritic cells. In a randomized phase 2a trial encompassing 21 chemotherapy-naïve CRPC patients, Harm Westdorp and colleagues evaluated immunological responses as well as safety, feasibility, radiological progression-free survival (rPFS) and overall survival after intranodal vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs), plasmacytoid dendritic cells (pDCs) or a combination of the two. The dendritic cell vaccine products were loaded with NY-ESO-1, MAGE-C2 and MUC-1 peptides, and after vaccination, CD8+ T cells specific for each antigen were detected in the skin of 15 (71%), 12 (57%) and 5 (24%) patients, respectively. The median rPFS across all treatment arms was 9.5 months, and there was no significant difference between the mDC, pDC and combination groups. Interferon gamma producing tumor-antigen specific T cells were detected in skin-infiltrating lymphocytes from 5 of 13 patients with rPFS. In those 5 patients, rPFS was 18.8 months compared to 5.1 months for patients without interferon gamma producing antigen-specific T cells. No toxicities above grade 2 were reported. The trial reveals a new immune correlate that might be indicative of a beneficial response to DC vaccination.