scholarly journals Barring the gates to the battleground: DDR1 promotes immune exclusion in solid tumors

2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Dimitrios L. Wagner ◽  
Enrico Klotzsch
2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2509-2509
Author(s):  
Todd Michael Bauer ◽  
Chia-Chi Lin ◽  
Richard Greil ◽  
Maria-Elisabeth Goebeler ◽  
Marie Luise Huetter-Kroenke ◽  
...  

2509 Background: TGF-β plays a key role in regulating the tumor microenvironment. Emerging evidence suggests TGF-β is a key activator of cancer-associated fibroblasts, leading to fibrotic network development and immune exclusion. Preclinical data in murine models showed that TGF-β blockade alleviates intratumoral fibrosis, augmenting the efficacy of PD-1 immunotherapy. NIS793 is a human IgG2 mAb that binds to TGF-β. This study investigates NIS793 + spartalizumab in pts with advanced solid tumors. Methods: Pts initially received NIS793 (0.3–1 mg/kg Q3W) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 + spartalizumab (NIS793 0.3–30 mg/kg Q3W + spartalizumab 300 mg Q3W; or NIS793 20–30 mg/kg Q2W + spartalizumab 400 mg Q4W) in pts with/without prior anti-PD-(L)1 therapy. In dose expansion, pts with non-small cell lung cancer (NSCLC) resistant to prior anti-PD-(L)1 or pts with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). Paired tumor biopsies were required from all pts. The primary objectives were to characterize safety and tolerability of the combination and determine the RDE. Results: By December 1, 2020, 60 pts were treated in the dose-escalation phase, mainly with NIS793 + spartalizumab (n = 49), and 60 pts were treated in dose expansion (MSS-CRC: n = 40; NSCLC: n = 20). Two pts were still receiving treatment. No dose-limiting toxicities were observed, and the RDE was established as 30 mg/kg (2100 mg) NIS793 + 300 mg spartalizumab Q3W. Overall 50% pts experienced ≥1 treatment-related AE (TRAE). The most common were rash (n = 15/120), pruritus (n = 10/120), fatigue (n = 9/120), and nausea (n = 8/120). Grade 3/4 TRAEs occurred in 11% pts, with rash (3%) being the most common. Treatment-related serious AEs were reported in 8 pts; 6 were grade 3/4 in severity. No deaths occurred due to AEs; 3 (2.5%) pts discontinued due to AEs. PK for NIS793 was linearly dose proportional with no obvious correlation between exposure and response. Two pts achieved a partial response (PR; one confirmed in clear cell renal cell carcinoma and one unconfirmed in NSCLC) during dose escalation of the combination. Two confirmed PRs were achieved in the MSS-CRC dose-expansion group. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression and protein analyses in tumor biopsies displayed decreased TGF-β target genes, decreased TGF-β signatures and increased immune signatures suggesting modulation of the TGF-β pathway and preliminary evidence of biological activity. Conclusions: Data showing target engagement and TGF-β pathway inhibition supported the proof of mechanism of NIS793. The RDE of the combination was established and well tolerated in pts with advanced solid tumors. Clinical trial information: NCT02947165.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Violena Pietrobon ◽  
Francesco M. Marincola

AbstractOver the last few years, cancer immunotherapy experienced tremendous developments and it is nowadays considered a promising strategy against many types of cancer. However, the exclusion of lymphocytes from the tumor nest is a common phenomenon that limits the efficiency of immunotherapy in solid tumors. Despite several mechanisms proposed during the years to explain the immune excluded phenotype, at present, there is no integrated understanding about the role played by different models of immune exclusion in human cancers. Hypoxia is a hallmark of most solid tumors and, being a multifaceted and complex condition, shapes in a unique way the tumor microenvironment, affecting gene transcription and chromatin remodeling. In this review, we speculate about an upstream role for hypoxia as a common biological determinant of immune exclusion in solid tumors. We also discuss the current state of ex vivo and in vivo imaging of hypoxic determinants in relation to T cell distribution that could mechanisms of immune exclusion and discover functional-morphological tumor features that could support clinical monitoring.


2021 ◽  
Vol 11 ◽  
Author(s):  
Violena Pietrobon ◽  
Alessandra Cesano ◽  
Francesco Marincola ◽  
Jakob Nikolas Kather

In recent years, cancer immunotherapy experienced remarkable developments and it is nowadays considered a promising therapeutic frontier against many types of cancer, especially hematological malignancies. However, in most types of solid tumors, immunotherapy efficacy is modest, partly because of the limited accessibility of lymphocytes to the tumor core. This immune exclusion is mediated by a variety of physical, functional and dynamic barriers, which play a role in shaping the immune infiltrate in the tumor microenvironment. At present there is no unified and integrated understanding about the role played by different postulated models of immune exclusion in human solid tumors. Systematically mapping immune landscapes or “topographies” in cancers of different histology is of pivotal importance to characterize spatial and temporal distribution of lymphocytes in the tumor microenvironment, providing insights into mechanisms of immune exclusion. Spatially mapping immune cells also provides quantitative information, which could be informative in clinical settings, for example for the discovery of new biomarkers that could guide the design of patient-specific immunotherapies. In this review, we aim to summarize current standard and next generation approaches to define Cancer Immune Topographies based on published studies and propose future perspectives.


Author(s):  
L. Z. de Tkaczevski ◽  
E. de Harven ◽  
C. Friend

Despite extensive studies, the correlation between the morphology and pathogenicity of murine leukemia viruses (MLV) has not yet been clarified. The virus particles found in the plasma of leukemic mice belong to 2 distinct groups, 1 or 2% of them being enveloped A particles and the vast majority being of type C. It is generally believed that these 2 types of particles represent different phases in the development of the same virus. Particles of type A have been thought to be an earlier form of type C particles. One of the tissue culture lines established from Friend leukemia solid tumors has provided the material for the present study. The supernatant fluid of the line designated C-1A contains an almost pure population of A particles as illustrated in Figure 1. The ratio is, therefore, the reverse of what is unvariably observed in the plasma of leukemic mice where C particles predominate.


JAMA ◽  
1966 ◽  
Vol 197 (4) ◽  
pp. 237-241 ◽  
Author(s):  
R. J. Papac
Keyword(s):  

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