Optimizing In Situ Vaccination During Radiotherapy

Effective in situ cancer vaccines require both a means of tumor cell death and a source of adjuvant to activate local dendritic cells. Studies have shown that the use of radiotherapy (RT) to induce tumor cell death and anti-CD40 to activate dendritic cells can result in in situ vaccination in animal models. Here, investigations are carried out on potential strategies to enhance such in situ vaccination. Strategies investigated include the use of smart immunogenic biomaterials (IBM) loaded with anti-CD40 in different tumor types including immunologically cold tumors like pancreatic and prostate tumors. The use of downstream checkpoint inhibitors to further boost such in situ vaccination is also examined. Results indicate that the use of IBM to deliver the anti-CD40 significantly enhances the effectiveness of in situ vaccination with anti-CD40 compared with direct injection in pancreatic and prostate cancers (p < 0.001 and p < 0.0001, respectively). This finding is consistent with significant increase in infiltration of antigen-presenting cells in the treated tumor, and significant increase in the infiltration of CD8+ cytotoxic T lymphocyte into distant untreated tumors. Moreover, in situ vaccination with IBM is consistently observed across different tumor types. Meanwhile, the addition of downstream immune checkpoint inhibitors further enhances overall survival when using the IBM approach. Overall, the findings highlight potential avenues for enhancing in situ vaccination when combining radiotherapy with anti-CD40.

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Cellular cytotoxicity is a form of immunogenic cell death

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000325 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000325 ◽

Cited By ~ 3

Author(s):

Luna Minute ◽

Alvaro Teijeira ◽

Alfonso R Sanchez-Paulete ◽

Maria C Ochoa ◽

Maite Alvarez ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Dendritic Cells ◽

Tumor Cell ◽

Tumor Cells ◽

Cd8 T Cells ◽

Immunogenic Cell Death ◽

Cell Debris ◽

Tumor Cell Death ◽

Mhc Multimer

BackgroundThe immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.MethodsIn this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.ResultsWe observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.ConclusionThese results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.

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Parvovirus H-1-Induced Tumor Cell Death Enhances Human Immune Response In Vitro via Increased Phagocytosis, Maturation, and Cross-Presentation by Dendritic Cells

Human Gene Therapy ◽

10.1089/hum.2005.16.ft-92 ◽

2005 ◽

Vol 0 (0) ◽

pp. 050701034702004

Author(s):

Markus H. Moehler ◽

Maja Zeidler ◽

Vanessa Wilsberg ◽

Jan J. Cornelis ◽

Thomas Woelfel ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Dendritic Cells ◽

Tumor Cell ◽

Tumor Cell Death ◽

Cross Presentation ◽

Human Immune Response ◽

Human Immune ◽

Immune Response In Vitro

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Dominant-negative ATF5 rapidly depletes survivin in tumor cells

Cell Death and Disease ◽

10.1038/s41419-019-1872-y ◽

2019 ◽

Vol 10 (10) ◽

Author(s):

Xiaotian Sun ◽

James M. Angelastro ◽

David Merino ◽

Qing Zhou ◽

Markus D. Siegelin ◽

...

Keyword(s):

Cell Death ◽

Tumor Cell ◽

Cancer Cells ◽

Dominant Negative ◽

Tumor Cell Death ◽

Cell Penetrating ◽

Selective Death ◽

Tumor Types

Abstract Survivin (BIRC5, product of the BIRC5 gene) is highly expressed in many tumor types and has been widely identified as a potential target for cancer therapy. However, effective anti-survivin drugs remain to be developed. Here we report that both vector-delivered and cell-penetrating dominant-negative (dn) forms of the transcription factor ATF5 that promote selective death of cancer cells in vitro and in vivo cause survivin depletion in tumor cell lines of varying origins. dn-ATF5 decreases levels of both survivin mRNA and protein. The depletion of survivin protein appears to be driven at least in part by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss is rapid and precedes the onset of cell death triggered by dn-ATF5. Although survivin downregulation is sufficient to drive tumor cell death, survivin over-expression does not rescue cancer cells from dn-ATF5-promoted apoptosis. This indicates that dn-ATF5 kills malignant cells by multiple mechanisms that include, but are not limited to, survivin depletion. Cell-penetrating forms of dn-ATF5 are currently being developed for potential therapeutic use and the present findings suggest that they may pose an advantage over treatments that target only survivin.

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CBP501 induces immunogenic tumor cell death and CD8 T cell infiltration into tumors in combination with platinum, and increases the efficacy of immune checkpoint inhibitors against tumors in mice

Oncotarget ◽

10.18632/oncotarget.20968 ◽

2017 ◽

Vol 8 (45) ◽

pp. 78277-78288 ◽

Cited By ~ 5

Author(s):

Keiichi Sakakibara ◽

Takuji Sato ◽

Donald W. Kufe ◽

Daniel D. VonHoff ◽

Takumi Kawabe

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cd8 T Cell ◽

Tumor Cell Death ◽

T Cell Infiltration ◽

Immunogenic Tumor Cell

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Parvovirus H-1-Induced Tumor Cell Death Enhances Human Immune Response In Vitro via Increased Phagocytosis, Maturation, and Cross-Presentation by Dendritic Cells

Human Gene Therapy ◽

10.1089/hum.2005.16.ft-102 ◽

2005 ◽

Vol 0 (0) ◽

pp. 050719131035001

Author(s):

Markus H. Moehler ◽

Maja Zeidler ◽

Vanessa Wilsberg ◽

Jan J. Cornelis ◽

Thomas Woelfel ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Dendritic Cells ◽

Tumor Cell ◽

Tumor Cell Death ◽

Cross Presentation ◽

Human Immune Response ◽

Human Immune ◽

Immune Response In Vitro

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A Comparison of Distinct Modes of Tumor Cell Death in Hodgkin's Disease Using Morphology and in Situ DNA Fragmentation

Ultrastructural Pathology ◽

10.3109/01913129609016354 ◽

1996 ◽

Vol 20 (6) ◽

pp. 497-505 ◽

Cited By ~ 11

Author(s):

Daniel Benharroch ◽

Isebrand Prinsloo ◽

Jed Goldstein ◽

Pierre Brousset ◽

Leonid Kachko ◽

...

Keyword(s):

Cell Death ◽

Tumor Cell ◽

Dna Fragmentation ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Tumor Cell Death

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Dendritic Cells Trigger Tumor Cell Death by a Nitric Oxide-Dependent Mechanism

The Journal of Immunology ◽

10.4049/jimmunol.179.2.812 ◽

2007 ◽

Vol 179 (2) ◽

pp. 812-818 ◽

Cited By ~ 26

Author(s):

Alexandra Nicolas ◽

Dominique Cathelin ◽

Nicolas Larmonier ◽

Jennifer Fraszczak ◽

Pierre-Emmanuel Puig ◽

...

Keyword(s):

Nitric Oxide ◽

Cell Death ◽

Dendritic Cells ◽

Tumor Cell ◽

Tumor Cell Death ◽

Dependent Mechanism

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Structure and Optimization of Checkpoint Inhibitors

Cancers ◽

10.3390/cancers12010038 ◽

2019 ◽

Vol 12 (1) ◽

pp. 38 ◽

Cited By ~ 11

Author(s):

Sarah L. Picardo ◽

Jeffrey Doi ◽

Aaron R. Hansen

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Clinical Activity ◽

Binding Affinities ◽

Protein Targets ◽

Dosing Regimens ◽

Cancer Types ◽

Tumor Types

With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.

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