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Article: Immunogenic cell stress and injury versus immunogenic cell death: implications for improving cancer treatment with immune checkpoint blockade.

Sriram, Ganapathy / Emmons, Tiffany R / Milling, Lauren E / Irvine, Darrell J / Yaffe, Michael B

Molecular & cellular oncology

2022 Volume 9, Issue 1, Page(s) 2039038

Abstract: Inducing immunogenic tumor cell death to stimulate the response to immune checkpoint blockade has not yet been effectively translated into clinical practice. We recently discovered that stressed/injured but still viable tumor cells are critical for T- ... ...

Abstract	Inducing immunogenic tumor cell death to stimulate the response to immune checkpoint blockade has not yet been effectively translated into clinical practice. We recently discovered that stressed/injured but still viable tumor cells are critical for T-cell priming and substantially improve responses to systemic anti-PD1/CTLA4. Therapeutic tumor cell injury, rather than complete killing, in the tumor microenvironment may enhance efficacy of immunotherapy in various cancers.
Language	English
Publishing date	2022-04-03
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2022.2039038
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Article ; Online: Framework for in vivo T cell screens.

Milling, Lauren E / Markson, Samuel C / Tjokrosurjo, Qin / Derosia, Nicole M / Streeter, Ivy S L / Hickok, Grant H / Lemmen, Ashlyn M / Nguyen, Thao H / Prathima, Priyamvada / Fithian, William / Schwartz, Marc A / Hacohen, Nir / Doench, John G / LaFleur, Martin W / Sharpe, Arlene H

The Journal of experimental medicine

2024 Volume 221, Issue 4

Abstract: In vivo T cell screens are a powerful tool for elucidating complex mechanisms of immunity, yet there is a lack of consensus on the screen design parameters required for robust in vivo screens: gene library size, cell transfer quantity, and number of mice. ...

Abstract	In vivo T cell screens are a powerful tool for elucidating complex mechanisms of immunity, yet there is a lack of consensus on the screen design parameters required for robust in vivo screens: gene library size, cell transfer quantity, and number of mice. Here, we describe the Framework for In vivo T cell Screens (FITS) to provide experimental and analytical guidelines to determine optimal parameters for diverse in vivo contexts. As a proof-of-concept, we used FITS to optimize the parameters for a CD8+ T cell screen in the B16-OVA tumor model. We also included unique molecular identifiers (UMIs) in our screens to (1) improve statistical power and (2) track T cell clonal dynamics for distinct gene knockouts (KOs) across multiple tissues. These findings provide an experimental and analytical framework for performing in vivo screens in immune cells and illustrate a case study for in vivo T cell screens with UMIs.
MeSH term(s)	Animals ; Mice ; CD8-Positive T-Lymphocytes ; Gene Knockout Techniques
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20230699
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Article ; Online: THE EFFICACY OF HYPNOSIS AS A TREATMENT FOR ANXIETY:

Valentine, Keara E / Milling, Leonard S / Clark, Lauren J / Moriarty, Caitlin L

The International journal of clinical and experimental hypnosis

2019 Volume 67, Issue 3, Page(s) 336–363

Abstract: This meta-analysis quantifies the effectiveness of hypnosis in treating anxiety. Included studies were required to utilize a between-subjects or mixed-model design in which a hypnosis intervention was compared with a control condition in alleviating the ... ...

Abstract	This meta-analysis quantifies the effectiveness of hypnosis in treating anxiety. Included studies were required to utilize a between-subjects or mixed-model design in which a hypnosis intervention was compared with a control condition in alleviating the symptoms of anxiety. Of 399 records screened, 15 studies incorporating 17 trials of hypnosis met the inclusion criteria. At the end of active treatment, 17 trials produced a mean weighted effect size of 0.79 (
MeSH term(s)	Anxiety/therapy ; Humans ; Hypnosis/methods ; Treatment Outcome
Language	English
Publishing date	2019-06-27
Publishing country	England
Document type	Journal Article ; Meta-Analysis
ZDB-ID	218267-1
ISSN	1744-5183 ; 0020-7144
ISSN (online)	1744-5183
ISSN	0020-7144
DOI	10.1080/00207144.2019.1613863
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Article ; Online: Delivering safer immunotherapies for cancer.

Milling, Lauren / Zhang, Yuan / Irvine, Darrell J

Advanced drug delivery reviews

2017 Volume 114, Page(s) 79–101

Abstract: Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double- ... ...

Abstract	Cancer immunotherapy is now a powerful clinical reality, with a steady progression of new drug approvals and a massive pipeline of additional treatments in clinical and preclinical development. However, modulation of the immune system can be a double-edged sword: Drugs that activate immune effectors are prone to serious non-specific systemic inflammation and autoimmune side effects. Drug delivery technologies have an important role to play in harnessing the power of immune therapeutics while avoiding on-target/off-tumor toxicities. Here we review mechanisms of toxicity for clinically-relevant immunotherapeutics, and discuss approaches based in drug delivery technology to enhance the safety and potency of these treatments. These include strategies to merge drug delivery with adoptive cellular therapies, targeting immunotherapies to tumors or select immune cells, and localizing therapeutics intratumorally. Rational design employing lessons learned from the drug delivery and nanomedicine fields has the potential to facilitate immunotherapy reaching its full potential.
MeSH term(s)	Adoptive Transfer ; Animals ; Drug Delivery Systems ; Humans ; Immune System/drug effects ; Immune System/immunology ; Immunotherapy/adverse effects ; Immunotherapy/methods ; Immunotherapy/trends ; Nanomedicine ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy
Language	English
Publishing date	2017-05-22
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639113-8
ISSN	1872-8294 ; 0169-409X
ISSN (online)	1872-8294
ISSN	0169-409X
DOI	10.1016/j.addr.2017.05.011
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Article ; Online: Engineering kinetics of TLR7/8 agonist release from bottlebrush prodrugs enables tumor-focused immune stimulation.

Bhagchandani, Sachin H / Vohidov, Farrukh / Milling, Lauren E / Tong, Evelyn Yuzhou / Brown, Christopher M / Ramseier, Michelle L / Liu, Bin / Fessenden, Timothy B / Nguyen, Hung V-T / Kiel, Gavin R / Won, Lori / Langer, Robert S / Spranger, Stefani / Shalek, Alex K / Irvine, Darrell J / Johnson, Jeremiah A

Science advances

2023 Volume 9, Issue 16, Page(s) eadg2239

Abstract: Imidazoquinolines (IMDs), such as resiquimod (R848), are of great interest as potential cancer immunotherapies because of their ability to activate Toll-like receptor 7 (TLR7) and/or TLR8 on innate immune cells. Nevertheless, intravenous administration ... ...

Abstract	Imidazoquinolines (IMDs), such as resiquimod (R848), are of great interest as potential cancer immunotherapies because of their ability to activate Toll-like receptor 7 (TLR7) and/or TLR8 on innate immune cells. Nevertheless, intravenous administration of IMDs causes severe immune-related toxicities, and attempts to improve their tissue-selective exposure while minimizing acute systemic inflammation have proven difficult. Here, using a library of R848 "bottlebrush prodrugs" (BPDs) that differ only by their R848 release kinetics, we explore how the timing of R848 exposure affects immune stimulation in vitro and in vivo. These studies led to the discovery of R848-BPDs that exhibit optimal activation kinetics to achieve potent stimulation of myeloid cells in tumors and substantial reductions in tumor growth following systemic administration in mouse syngeneic tumor models without any observable systemic toxicity. These results suggest that release kinetics can be tuned at the molecular level to provide safe yet effective systemically administered immunostimulant prodrugs for next-generation cancer immunotherapies.
MeSH term(s)	Mice ; Animals ; Prodrugs/pharmacology ; Toll-Like Receptor 7/agonists ; Kinetics ; Adjuvants, Immunologic/pharmacology ; Neoplasms/drug therapy
Chemical Substances	Prodrugs ; Toll-Like Receptor 7 ; Adjuvants, Immunologic
Language	English
Publishing date	2023-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adg2239
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Article ; Online: X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system.

LaFleur, Martin W / Lemmen, Ashlyn M / Streeter, Ivy S L / Nguyen, Thao H / Milling, Lauren E / Derosia, Nicole M / Hoffman, Zachary M / Gillis, Jacob E / Tjokrosurjo, Qin / Markson, Samuel C / Huang, Amy Y / Anekal, Praju V / Montero Llopis, Paula / Haining, W Nicholas / Doench, John G / Sharpe, Arlene H

Nature immunology

2023 Volume 25, Issue 1, Page(s) 178–188

Abstract: Annotation of immunologic gene function in vivo typically requires the generation of knockout mice, which is time consuming and low throughput. We previously developed CHimeric IMmune Editing (CHIME), a CRISPR-Cas9 bone marrow delivery system for ... ...

Abstract	Annotation of immunologic gene function in vivo typically requires the generation of knockout mice, which is time consuming and low throughput. We previously developed CHimeric IMmune Editing (CHIME), a CRISPR-Cas9 bone marrow delivery system for constitutive, ubiquitous deletion of single genes. Here we describe X-CHIME, four new CHIME-based systems for modular and rapid interrogation of gene function combinatorially (C-CHIME), inducibly (I-CHIME), lineage-specifically (L-CHIME) or sequentially (S-CHIME). We use C-CHIME and S-CHIME to assess the consequences of combined deletion of Ptpn1 and Ptpn2, an embryonic lethal gene pair, in adult mice. We find that constitutive deletion of both PTPN1 and PTPN2 leads to bone marrow hypoplasia and lethality, while inducible deletion after immune development leads to enteritis and lethality. These findings demonstrate that X-CHIME can be used for rapid mechanistic evaluation of genes in distinct in vivo contexts and that PTPN1 and PTPN2 have some functional redundancy important for viability in adult mice.
MeSH term(s)	Mice ; Animals ; CRISPR-Cas Systems/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics ; Mice, Knockout ; Immune System ; Gene Editing
Chemical Substances	Protein Tyrosine Phosphatase, Non-Receptor Type 2 (EC 3.1.3.48) ; Ptpn2 protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2023-11-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01689-6
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 42: Show issues

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Article: ABC triblock bottlebrush copolymer-based injectable hydrogels: design, synthesis, and application to expanding the therapeutic index of cancer immunochemotherapy.

Vohidov, Farrukh / Milling, Lauren E / Chen, Qixian / Zhang, Wenxu / Bhagchandani, Sachin / Nguyen, Hung V-T / Irvine, Darrell J / Johnson, Jeremiah A

Chemical science

2020 Volume 11, Issue 23, Page(s) 5974–5986

Abstract: Bottlebrush copolymers are a versatile class of macromolecular architectures with broad applications in the fields of drug delivery, self-assembly, and polymer networks. Here, the modular nature of graft-through ring-opening metathesis polymerization ( ... ...

Abstract	Bottlebrush copolymers are a versatile class of macromolecular architectures with broad applications in the fields of drug delivery, self-assembly, and polymer networks. Here, the modular nature of graft-through ring-opening metathesis polymerization (ROMP) is exploited to synthesize "ABC" triblock bottlebrush copolymers (TBCs) from polylactic acid (PLA), polyethylene glycol (PEG), and poly(
Language	English
Publishing date	2020-06-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d0sc02611e
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Article ; Online: The injury response to DNA damage in live tumor cells promotes antitumor immunity.

Sriram, Ganapathy / Milling, Lauren E / Chen, Jung-Kuei / Kong, Yi Wen / Joughin, Brian A / Abraham, Wuhbet / Swartwout, Susanne / Handly, Erika D / Irvine, Darrell J / Yaffe, Michael B

Science signaling

2021 Volume 14, Issue 705, Page(s) eabc4764

Abstract: Although immune checkpoint blockade (ICB) has strong clinical benefit for treating some tumor types, it fails in others, indicating a need for additional modalities to enhance the ICB effect. Here, we identified one such modality by using DNA damage to ... ...

Abstract	Although immune checkpoint blockade (ICB) has strong clinical benefit for treating some tumor types, it fails in others, indicating a need for additional modalities to enhance the ICB effect. Here, we identified one such modality by using DNA damage to create a live, injured tumor cell adjuvant. Using an optimized ex vivo coculture system, we found that treating tumor cells with specific concentrations of etoposide, mitoxantrone, or doxorubicin markedly enhanced dendritic cell–mediated T cell activation. These immune-enhancing effects of DNA damage did not correlate with immunogenic cell death markers or with the extent of apoptosis or necroptosis; instead, these effects were mediated by live injured cells with activation of the DNA-PK, ATR, NF-κB, p38 MAPK, and RIPK1 signaling pathways. In mice, intratumoral injection of ex vivo etoposide–treated tumor cells in combination with systemic ICB (by anti-PD-1 and anti-CTLA4 antibodies) increased the number of intratumoral CD103
MeSH term(s)	DNA Damage
Language	English
Publishing date	2021-10-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.abc4764
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Article ; Online: Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity.

Agarwal, Yash / Milling, Lauren E / Chang, Jason Y H / Santollani, Luciano / Sheen, Allison / Lutz, Emi A / Tabet, Anthony / Stinson, Jordan / Ni, Kaiyuan / Rodrigues, Kristen A / Moyer, Tyson J / Melo, Mariane B / Irvine, Darrell J / Wittrup, K Dane

Nature biomedical engineering

2022 Volume 6, Issue 2, Page(s) 129–143

Abstract: Anti-tumour inflammatory cytokines are highly toxic when administered systemically. Here, in multiple syngeneic mouse models, we show that the intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant ... ...

Abstract	Anti-tumour inflammatory cytokines are highly toxic when administered systemically. Here, in multiple syngeneic mouse models, we show that the intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide (alum) (via ligand exchange between hydroxyls on the surface of alum and phosphoserine residues tagged to the cytokine by an alum-binding peptide) leads to weeks-long retention of the cytokines in the tumours, with minimal side effects. Specifically, a single dose of alum-tethered interleukin-12 induced substantial interferon-γ-mediated T-cell and natural-killer-cell activities in murine melanoma tumours, increased tumour antigen accumulation in draining lymph nodes and elicited robust tumour-specific T-cell priming. Moreover, intratumoural injection of alum-anchored cytokines enhanced responses to checkpoint blockade, promoting cures in distinct poorly immunogenic syngeneic tumour models and eliciting control over metastases and distant untreated lesions. Intratumoural treatment with alum-anchored cytokines represents a safer and tumour-agnostic strategy to improving local and systemic anticancer immunity.
MeSH term(s)	Alum Compounds/pharmacology ; Animals ; Cytokines ; Immunotherapy ; Interleukin-12 ; Mice
Chemical Substances	Alum Compounds ; Cytokines ; Interleukin-12 (187348-17-0) ; aluminum sulfate (34S289N54E)
Language	English
Publishing date	2022-01-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-021-00831-9
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Article ; Online: STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity.

Dane, Eric L / Belessiotis-Richards, Alexis / Backlund, Coralie / Wang, Jianing / Hidaka, Kousuke / Milling, Lauren E / Bhagchandani, Sachin / Melo, Mariane B / Wu, Shengwei / Li, Na / Donahue, Nathan / Ni, Kaiyuan / Ma, Leyuan / Okaniwa, Masanori / Stevens, Molly M / Alexander-Katz, Alfredo / Irvine, Darrell J

Nature materials

2022 Volume 21, Issue 6, Page(s) 710–720

Abstract: Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated ... ...

Abstract	Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.
MeSH term(s)	Humans ; Immunotherapy ; Lipids ; Membrane Proteins/metabolism ; Membrane Proteins/pharmacology ; Nanoparticles/therapeutic use ; Neoplasms/drug therapy
Chemical Substances	Lipids ; Membrane Proteins
Language	English
Publishing date	2022-05-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2088679-2
ISSN	1476-4660 ; 1476-1122
ISSN (online)	1476-4660
ISSN	1476-1122
DOI	10.1038/s41563-022-01251-z
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