scholarly journals Novel personalized cancer vaccine platform based on Bacillus Calmette-Guèrin

2021 ◽  
Vol 9 (7) ◽  
pp. e002707
Author(s):  
Erkko Ylösmäki ◽  
Manlio Fusciello ◽  
Beatriz Martins ◽  
Sara Feola ◽  
Firas Hamdan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Outer Membrane ◽  
Cancer Vaccine ◽  
Tumor Antigens ◽  
Growth Control ◽  
Therapeutic Effects ◽  
Vaccine Platform ◽  
Bcg Immunotherapy ◽  
Bcg Therapy ◽  
Personalized Cancer

BackgroundIntratumoral BCG therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumor. However, an increase in the number of BCG-induced tumor-specific T cells in the tumor microenvironment could lead to enhanced therapeutic effects.MethodsHere, we have developed a novel cancer vaccine platform based on BCG that can broaden BCG-induced immune responses to include tumor antigens. By physically attaching tumor-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoral T cell-specific immune responses toward the attached tumor antigens. These therapeutic peptides can be efficiently attached to the mycobacterial outer membrane using a poly-lysine sequence N-terminally fused to the tumor-specific peptides.ResultsUsing two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the antitumor immune responses of BCG could be improved by coating the BCG with tumor-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-programmed death 1 (anti-PD-1) immune checkpoint inhibitor (ICI) therapy, the number of responders to anti-PD-1 immunotherapy was markedly increased.ConclusionsThis study shows that intratumoral BCG immunotherapy can be improved by coating the bacteria with modified tumor-specific peptides. In addition, this improved BCG immunotherapy can be combined with ICI therapy to obtain enhanced tumor growth control. These results warrant clinical testing of this novel cancer vaccine platform.

scholarly journals Novel personalized cancer vaccine platform based on Bacillus Calmette-Guerin

2021 ◽  
Author(s):  
Erkko Ylosmaki ◽  
Beatriz Martins ◽  
Manlio Fusciello ◽  
Sara Feola ◽  
Firas Hamdan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Outer Membrane ◽  
Cancer Vaccine ◽  
Peptide Sequence ◽  
Bacillus Calmette Guerin ◽  
Vaccine Platform ◽  
Bcg Therapy ◽  
Therapeutic Peptides ◽  
Tumour Antigens ◽  
Personalized Cancer

Intratumoural bacillus Calmette-Guerin (BCG) therapy, one of the earliest immunotherapies, can lead to infiltration of immune cells into a treated tumour. Here, we have developed a novel cancer vaccine platform based on BCG that can direct BCG-induced immune responses against tumour antigens. By physically attaching tumour-specific peptides onto the mycobacterial outer membrane, we were able to induce strong systemic and intratumoural T cell-specific immune responses towards the attached tumour antigens. These therapeutic peptides can be attached to the mycobacterial outer membrane using a cell-penetrating peptide sequence derived from human immunodeficiency virus Tat, N-terminally fused to the tumour-specific peptides. Alternatively, therapeutic peptides can be conjugated with a poly-lysine sequence N-terminally fused to the tumour-specific peptides. Using two mouse models of melanoma and a mouse model of colorectal cancer, we observed that the anti-tumour responses of BCG can be significantly improved by coating the BCG with tumour-specific peptides. In addition, by combining this novel cancer vaccine platform with anti-PD-1 immune checkpoint inhibitor therapy, the number of responders to anti-PD-1 immunotherapy can be significantly increased.

scholarly journals Personalized neoantigen-pulsed dendritic cell vaccines show superior immunogenicity to neoantigen-adjuvant vaccines in mouse tumor models

2019 ◽  
Vol 69 (1) ◽  
pp. 135-145 ◽  
Author(s):  
Rui Zhang ◽  
Fengjiao Yuan ◽  
Yang Shu ◽  
Yaomei Tian ◽  
Bailing Zhou ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Immune Responses ◽  
Cancer Vaccines ◽  
Therapeutic Effects ◽  
Mouse Tumor ◽  
Pulsed Dc ◽  
Dendritic Cell Vaccines ◽  
Dc Vaccines ◽  
T Cell Immune Responses ◽  
Personalized Cancer

AbstractDevelopment of personalized cancer vaccines based on neoantigens has become a new direction in cancer immunotherapy. Two forms of cancer vaccines have been widely studied: tumor-associated antigen (including proteins, peptides, or tumor lysates)-pulsed dendritic cell (DC) vaccines and protein- or peptide-adjuvant vaccines. However, different immune modalities may produce different therapeutic effects and immune responses when the same antigen is used. Therefore, it is necessary to choose a more effective neoantigen vaccination method. In this study, we compared the differences in immune and anti-tumor effects between neoantigen-pulsed DC vaccines and neoantigen-adjuvant vaccines using murine lung carcinoma (LL2) candidate neoantigens. The enzyme-linked immunospot (ELISPOT) assay showed that 4/6 of the neoantigen-adjuvant vaccines and 6/6 of the neoantigen-pulsed DC vaccines induced strong T-cell immune responses. Also, 2/6 of the neoantigen-adjuvant vaccines and 5/6 of the neoantigen-pulsed DC vaccines exhibited potent anti-tumor effects. The results indicated that the neoantigen-pulsed DC vaccines were superior to the neoantigen-adjuvant vaccines in both activating immune responses and inhibiting tumor growth. Our fundings provide an experimental basis for the selection of immune modalities for the use of neoantigens in individualized tumor immunotherapies.

scholarly journals Personalized Cancer Vaccine Platform for Clinically Relevant Oncolytic Enveloped Viruses

2018 ◽  
Vol 26 (9) ◽  
pp. 2315-2325 ◽  
Author(s):  
Erkko Ylösmäki ◽  
Cristina Malorzo ◽  
Cristian Capasso ◽  
Oona Honkasalo ◽  
Manlio Fusciello ◽  
...  
Keyword(s):  
Cancer Vaccine ◽  
Vaccine Platform ◽  
Enveloped Viruses ◽  
Personalized Cancer

scholarly journals Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Keman Cheng ◽  
Ruifang Zhao ◽  
Yao Li ◽  
Yingqiu Qi ◽  
Yazhou Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Outer Membrane ◽  
Tumor Antigens ◽  
Tumor Vaccine ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Melanoma Metastasis ◽  
Vaccine Platform ◽  
Display Technology ◽  
Tumour Vaccines

AbstractAn effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines.

scholarly journals OMV Vaccines and the Role of TLR Agonists in Immune Response

2020 ◽  
Vol 21 (12) ◽  
pp. 4416 ◽  
Author(s):  
Francesca Mancini ◽  
Omar Rossi ◽  
Francesca Necchi ◽  
Francesca Micoli
Keyword(s):  
Immune Responses ◽  
Outer Membrane ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Outer Membrane Vesicles ◽  
Optimal Size ◽  
Vaccine Platform ◽  
Tlr Agonists

Outer Membrane Vesicles (OMVs) are bacterial nanoparticles that are spontaneously released during growth both in vitro and in vivo by Gram-negative bacteria. They are spherical, bilayered membrane nanostructures that contain many components found within the external surface of the parent bacterium. Naturally, OMVs serve the bacteria as a mechanism to deliver DNA, RNA, proteins, and toxins, as well as to promote biofilm formation and remodel the outer membrane during growth. On the other hand, as OMVs possess the optimal size to be uptaken by immune cells, and present a range of surface-exposed antigens in native conformation and Toll-like receptor (TLR) activating components, they represent an attractive and powerful vaccine platform able to induce both humoral and cell-mediated immune responses. This work reviews the TLR-agonists expressed on OMVs and their capability to trigger individual TLRs expressed on different cell types of the immune system, and then focuses on their impact on the immune responses elicited by OMVs compared to traditional vaccines.

scholarly journals Protective and Therapeutic Effects of an IL-15:IL-15Rα-Secreting Cell-Based Cancer Vaccine Using a Baculovirus System

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4039
Author(s):  
Van Anh Do-Thi ◽  
Hayyoung Lee ◽  
Hye-Jin Jeong ◽  
Jie-Oh Lee ◽  
Young-Sang Kim
Keyword(s):  
Cancer Cells ◽  
Cancer Vaccine ◽  
Treg Cells ◽  
Effector Memory ◽  
Therapeutic Effects ◽  
Vaccine Platform ◽  
Therapeutic Cancer Vaccine ◽  
Baculovirus System

This study reports the use of the BacMam system to deliver and express self-assembling IL-15 and IL-15Rα genes to murine B16F10 melanoma and CT26 colon cancer cells. BacMam-based IL-15 and IL-15Rα were well-expressed and assembled to form the biologically functional IL-15:IL-15Rα complex. Immunization with this IL-15:IL-15Rα cancer vaccine delayed tumor growth in mice by inducing effector memory CD4+ and CD8+ cells and effector NK cells which are tumor-infiltrating. It caused strong antitumor immune responses of CD8+ effector cells in a tumor-antigen specific manner both in vitro and in vivo and significantly attenuated Treg cells which a control virus-infected cancer vaccine could induce. Post-treatment with this cancer vaccine after a live cancer cell injection also prominently delayed the growth of the tumor. Collectively, we demonstrate a vaccine platform consisting of BacMam virus-infected B16F10 or CT26 cancer cells that secrete IL-15:IL-15Rα. This study is the first demonstration of a functionally competent soluble IL-15:IL-15Rα complex-related cancer vaccine using a baculovirus system and advocates that the BacMam system can be used as a secure and rapid method of producing a protective and therapeutic cancer vaccine.

Effect of the novel therapeutic cancer vaccine formulation DPX-0907 on multifunctional T-cell responses in ovarian, breast, and prostate cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2588-2588
Author(s):  
Neil Lorne Berinstein ◽  
Mohan Karkada ◽  
Rita Nigam ◽  
Michael Morse ◽  
John J. Nemunaitis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cancer Patients ◽  
Cancer Vaccine ◽  
Response Rate ◽  
The Novel ◽  
Vaccine Platform ◽  
Therapeutic Cancer Vaccine

2588 Background: To increase the efficacy of peptide cancer vaccines, we developed a novel vaccine platform called DepoVax, an adjuvanted water-free depot formulation with the ability to generate enhanced immune responses. Naturally processed HLA-A2 restricted peptides that are selectively presented by breast, ovarian and prostate cancer cell lines, but not by normal HLA-A2+ cells, were used as antigens with a proprietary adjuvant and a T helper peptide epitope to create a therapeutic cancer vaccine, DPX-0907. Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose volume cohorts in a three immunization clinical protocol. Results: DPX-0907 proved to be safe with no serious adverse effects related to the vaccine reported. Of those evaluable for immunogenicity, all breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients demonstrated immune response to one or more of seven antigenic peptides, resulting in a 61% response rate. Immune responses correlated with achievement of CR, PR or SD to last treatment. No difference in immune response rate or magnitude was seen between the two dose groups. DPX-0907 displayed strong immune induction potential, with 73% of immune responders showing responses with just one dose of vaccine. In 83% of responders, immune responses were detected at ≥2 time points post vaccination and 64% had a persistent immune response at one month post last vaccination. Immune monitoring showed peptide-specific CD8 T cells, and these T cells were able to secrete multiple Th1 cytokines indicating their multifunctionality, a feature attributable to cells that mediate protective responses. Conclusions: These data support the ability of DPX-0907 to elicit Th1 dominated, specific immunity and support the rationale for further testing in immunologically competent cancer patients. The novel DepoVax formulation may promote multifunctional memory responses with peptides from other tumor associated antigens.

scholarly journals Extracellular Vesicles of Mesenchymal Stem Cells: Therapeutic Properties Discovered with Extraordinary SuccessOK

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 667
Author(s):  
Gabriella Racchetti ◽  
Jacopo Meldolesi
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune Responses ◽  
Extracellular Vesicles ◽  
Immune Regulation ◽  
Great Increase ◽  
The Body ◽  
Cell Aging ◽  
Therapeutic Effects ◽  
Therapeutic Properties

Mesenchymal stem cells (MSCs), the cells distributed in the stromas of the body, are known for various properties including replication, the potential of various differentiations, the immune-related processes including inflammation. About two decades ago, these cells were shown to play relevant roles in the therapy of numerous diseases, dependent on their immune regulation and their release of cytokines and growth factors, with ensuing activation of favorable enzymes and processes. Such discovery induced great increase of their investigation. Soon thereafter, however, it became clear that therapeutic actions of MSCs are risky, accompanied by serious drawbacks and defects. MSC therapy has been therefore reduced to a few diseases, replaced for the others by their extracellular vesicles, the MSC-EVs. The latter vesicles recapitulate most therapeutic actions of MSCs, with equal or even better efficacies and without the serious drawbacks of the parent cells. In addition, MSC-EVs are characterized by many advantages, among which are their heterogeneities dependent on the stromas of origin, the alleviation of cell aging, the regulation of immune responses and inflammation. Here we illustrate the MSC-EV therapeutic effects, largely mediated by specific miRNAs, covering various diseases and pathological processes occurring in the bones, heart and vessels, kidney, and brain. MSC-EVs operate also on the development of cancers and on COVID-19, where they alleviate the organ lesions induced by the virus. Therapy by MSC-EVs can be improved by combination of their innate potential to engineering processes inducing precise targeting and transfer of drugs. The unique properties of MSC-EVs explain their intense studies, carried out with extraordinary success. Although not yet developed to clinical practice, the perspectives for proximal future are encouraging.

scholarly journals Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

2021 ◽  
Vol 9 (1) ◽  
pp. e001615
Author(s):  
Rachel A Woolaver ◽  
Xiaoguang Wang ◽  
Alexandra L Krinsky ◽  
Brittany C Waschke ◽  
Samantha M Y Chen ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Immune Responses ◽  
Single Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Tcr Repertoire ◽  
Underlying Mechanisms ◽  
Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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