Immune Checkpoint Inhibition for Pancreatic Ductal Adenocarcinoma: Current Limitations and Future Options DOI Creative Commons
Derya Kabacaoğlu,

Katrin J. Ciecielski,

Dietrich Alexander Ruess

et al.

Frontiers in Immunology, Journal Year: 2018, Volume and Issue: 9

Published: Aug. 15, 2018

Pancreatic ductal adenocarcinoma (PDAC), as the most frequent form of pancreatic malignancies, still has a dismal prognosis. Due to its late detection patients are ineligible for surgery, and chemotherapeutic options limited. Tumor heterogeneity characteristic structure with crosstalk between cancer/malignant cells an abundant tumor microenvironment make PDAC very challenging puzzle solve. So far, targeted therapies have failed substantially improve overall survival patients. Immune checkpoint inhibition, emerging therapeutic option in cancer treatment shows promising results different solid types hematological malignancies. However, doesn't respond efficiently immune inhibitors anti PD-1 or CTLA-4 alone combination. immune-privileged nature, starting from early pre-neoplastic state, seems escape anti-tumor response unlike other entities. Different mechanisms postulated how achieve status. Among them decreased antigenicity impaired immunogenicity via both cell intrinsic augmented immunosuppressive microenvironment. Here we seek shed light on recent advances bench bedside investigation immunotherapeutic PDAC. Besides, aim compile data about adopts mechanisms, these might be exploited therapeutically combination such antibodies.

Language: Английский

State-of-the-art strategies for targeting the DNA damage response in cancer DOI
Patrick G. Pilié, Chad Tang, Gordon B. Mills

et al.

Nature Reviews Clinical Oncology, Journal Year: 2018, Volume and Issue: 16(2), P. 81 - 104

Published: Oct. 24, 2018

Language: Английский

Citations

975
Detection of immunogenic cell death and its relevance for cancer therapy DOI Creative Commons
Jitka Fučíková, Oliver Kepp, Lenka Kašíková

et al.

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(11)

Published: Nov. 26, 2020

Abstract Chemotherapy, radiation therapy, as well targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by exposure release numerous damage-associated molecular patterns (DAMPs), altogether confer a robust adjuvanticity dying cancer cells, they favor recruitment activation antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) secreted ATP, annexin A1 (ANXA1), type I interferon, high-mobility group box 1 (HMGB1). Additional hallmarks ICD encompass phosphorylation eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known eIF2α), autophagy, global arrest in transcription translation. Here, we outline methodological approaches for measuring markers vitro ex vivo discovery next-generation antineoplastic agents, development personalized regimens, identification optimal therapeutic combinations clinical management cancer.

Language: Английский

Citations

759
BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial DOI
Bruno Bockorny,

Valerya Semenisty,

Teresa Macarulla

et al.

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(6), P. 878 - 885

Published: May 25, 2020

Language: Английский

Citations

414
Inflammation-induced DNA damage, mutations and cancer DOI
Jennifer E. Kay, Elina Thadhani,

Leona D. Samson

et al.

DNA repair, Journal Year: 2019, Volume and Issue: 83, P. 102673 - 102673

Published: July 25, 2019

Language: Английский

Citations

342
Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy DOI Open Access
Priyamvada Jayaprakash,

Midan Ai,

Arthur Liu

et al.

Journal of Clinical Investigation, Journal Year: 2018, Volume and Issue: 128(11), P. 5137 - 5149

Published: Sept. 6, 2018

Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical and resisted T cell infiltration even in context CTLA-4 PD-1 blockade. demonstrated hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia these tumors. Combination therapy with this hypoxia-prodrug cooperated to cure more than 80% transgenic adenocarcinoma mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed drives an influx cells into zones, which expanded by Further, combination reduced myeloid-derived suppressor density 50%, durably capacity tumor replenish granulocytic subset. Spontaneous TRAMP mice, completely resist blockade, minimal burden at 36 weeks age no evidence neuroendocrine therapy. Survival Pb-Cre4, Ptenpc-/-Smad4pc-/- mice aggressive was also significantly extended Hypoxia disruption may sensitize some most therapeutically resistant cancers immunotherapy.

Language: Английский

Citations

329
Metal Drugs and the Anticancer Immune Response DOI
Bernhard Englinger, Christine Pirker, Petra Heffeter

et al.

Chemical Reviews, Journal Year: 2018, Volume and Issue: 119(2), P. 1519 - 1624

Published: Nov. 29, 2018

The immune system deploys a multitude of innate and adaptive mechanisms not only to ward off pathogens but also prevent malignant transformation ("immune surveillance"). Hence, clinically apparent tumor already reflects selection for those cell clones capable evading recognition evasion"). Metal drugs, besides their well-investigated cytotoxic anticancer effects, massively interact with the cancer-immune interface can reverse important aspects evasion. This topic has recently gained intense attention based on combination approaches immunotherapy (e.g., checkpoint inhibitors), strategy delivering first exciting results in clinical settings. review summarizes promising still extremely fragmentary knowledge interplay metal drugs fidelity responses role adverse effects. It highlights that, at least some cases, induce long-lasting responses. Important steps this process comprise altered visibility susceptibility cancer cells toward immunity, as well direct impacts populations microenvironment. On basis gathered information, we suggest initiating joint multidisciplinary programs implement comprehensive analyses into strategies develop novel smart compounds.

Language: Английский

Citations

307
PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers DOI Open Access
Patrick G. Pilié, Carl M. Gay, Lauren A. Byers

et al.

Clinical Cancer Research, Journal Year: 2019, Volume and Issue: 25(13), P. 3759 - 3771

Published: Feb. 13, 2019

Abstract A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across wide spectrum molecular backgrounds tumor types. Although class display many similarities, critical differences in structure can translate into tolerability antitumor activity important implications clinic. Furthermore, while demonstrated clear role treating tumors with underlying homologous recombination deficiencies, there is biological early clinical support their use other subsets cancer, including associated high levels replication stress such small-cell lung cancer. In this article, we highlight key similarities between individual We discuss data currently extending benefit beyond BRCA-mutant cancers, toward broader populations patients through novel biomarkers repair deficiency (HRD), well predictive rooted mechanisms sensitivity outside HRD. also explore application earlier treatment settings, neoadjuvant, adjuvant, even chemoprevention approaches. Finally, focus on promising therapeutic strategies, those DNA damage response (DDR) ATR inhibitors, immune checkpoint non–DDR-targeted agents induce “chemical BRCAness.”

Language: Английский

Citations

292
The plasticity of DNA replication forks in response to clinically relevant genotoxic stress DOI

Matteo Berti,

David Cortez, Massimo Lopes

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(10), P. 633 - 651

Published: July 1, 2020

Language: Английский

Citations

279
Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies DOI Creative Commons
Antonio Marra, Dario Trapani, Giulia Viale

et al.

npj Breast Cancer, Journal Year: 2020, Volume and Issue: 6(1)

Published: Oct. 16, 2020

Triple-negative breast cancer (TNBC) is not a unique disease, encompassing multiple entities with marked histopathological, transcriptomic and genomic heterogeneity. Despite several efforts, classifications have remained merely theoretic most of the patients are being treated chemotherapy. Driver alterations in potentially targetable genes, including PIK3CA AKT, been identified across TNBC subtypes, prompting implementation biomarker-driven therapeutic approaches. However, biomarker-based treatments as well immune checkpoint inhibitor-based immunotherapy provided contrasting limited results so far. Accordingly, better characterization contexture underpinning TNBC, translation lessons learnt metastatic disease to early setting would improve patients' outcomes. The application multi-omics technologies, biocomputational algorithms, assays for minimal residual monitoring novel clinical trial designs strongly warranted pave way toward personalized anticancer treatment TNBC.

Language: Английский

Citations

261
Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy DOI Creative Commons
Minlin Jiang, Keyi Jia, Lei Wang

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2021, Volume and Issue: 11(10), P. 2983 - 2994

Published: Jan. 10, 2021

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression programmed death ligand 1 (PD-L1) interact with signaling such as cyclic GMP–AMP synthase-stimulator interferon genes (cGAS–STING) signaling. Here, we review basic knowledge DDR pathways, mechanisms induced by alterations, impacts alterations on immune system, potential applications biomarkers therapeutic targets in immunotherapy.

Language: Английский

Citations

216