Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens

Lynn, Geoffrey M.; Sedlik, Christine; Baharom, Faezzah; Zhu, Yaling; Ramirez-Valdez, Ramiro A.; Coble, Vincent; Tobin, Kennedy K S; Nichols, Sarah R.; Itzkowitz, Yaakov; Zaidi, Neeha; Gammon, Joshua M.; Blobel, Nicolas J.; Denizeau, Jordan; Rochere, Philippe De La; Francica, Brian J.; Decker, Brennan; Maciejewski, Mateusz; Cheung, Justin; Yamane, Hidehiro; Smelkinson, Margery; Francica, Joseph R.; Laga, Richard; Bernstock, Joshua D.; Seymour, Leonard W.; Drake, Charles G.; Jewell, Christopher M.; Lantz, Olivier; Piaggio, Eliane; Ishizuka, Andrew S.; Seder, Robert A.

doi:10.1038/s41587-019-0390-x

Cited by 259 publications

(241 citation statements)

References 70 publications

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“…Different clinical trials with peptide vaccines have shown the efficacy of adjuvants like Montanide and Freud's adjuvant (61)(62)(63). Also addition of Addavax and poly I:C or other TLR ligands like CpG to peptide vaccines has shown good efficacy in pre-clinical models (64)(65)(66)(67). Furthermore, the role of αGC as adjuvanting component has been extensively described in multiple studies (68)(69)(70)(71)(72).…”

Section: Discussionmentioning

confidence: 99%

Lipo-Based Vaccines as an Approach to Target Dendritic Cells for Induction of T- and iNKT Cell Responses

Stolk

Haas

Vree³

et al. 2020

Front. Immunol.

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In this study we developed a liposome-based vaccine containing palmitoylated synthetic long peptides (SLP) and alpha galactosylceramide (αGC) to specifically target dendritic cells (DC) for activation of both innate (invariant natural killer T-cells [iNKT]) and adaptive (CD8 + T-cells) players of the immune system. Combination of model tumor specific antigens (gp100/MART-1) formulated as a SLP and αGC in one liposome results in strong activation of CD8 + and iNKT, as measured by IFNγ secretion. Moreover, addition of lipo-Lewis Y (Le Y) to the liposomes for C-type lectin targeting increased not only uptake by monocyte-derived dendritic cells (moDC), dermal dendritic cells and Langerhans cells but also enhanced gp100-specific CD8 + T-and iNKT cell activation by human skin-emigrated antigen presenting cells in an ex vivo explant model. Loading of moDC with liposomes containing Le Y also showed priming of MART-1 26−35L specific CD8 + T-cells. In conclusion, chemically linking a lipid tail to a glycan-based targeting moiety and SLP combined with αGC in one liposome allows for easy generation of vaccine formulations that target multiple skin DC subsets and induce tumor antigen specific CD8 + T-and iNKT cells. These liposomes present a new vaccination strategy against tumors.

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Section: Discussionmentioning

confidence: 99%

Lipo-Based Vaccines as an Approach to Target Dendritic Cells for Induction of T- and iNKT Cell Responses

Stolk

Haas

Vree³

et al. 2020

Front. Immunol.

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“…This ensures that the same APC that take up antigen receive additional danger signals and thus are competent to provide costimulatory signals to T cells. This approach has been successful in animal models that conjugate long peptides to a TLR agonists 81‐83 . Peptides can also be expressed as fusions with proteins that direct them towards antigen processing machinery and HLA presentation 84 .…”

Section: Vaccine Designmentioning

confidence: 99%

Polyomavirus‐driven Merkel cell carcinoma: Prospects for therapeutic vaccine development

Tabachnick-Cherny

Pulliam

Church

et al. 2020

Molecular Carcinogenesis

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Great strides have been made in cancer immunotherapy including the breakthrough successes of anti-PD-(L)1 checkpoint inhibitors. In Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, PD-(L)1 blockade is highly effective. Yet,~50% of patients either do not respond to therapy or develop PD-(L)1 refractory disease and, thus, do not experience long-term benefit. For these patients, additional or combination therapies are needed to augment immune responses that target and eliminate cancer cells. Therapeutic vaccines targeting tumor-associated antigens, mutated self-antigens, or immunogenic viral oncoproteins are currently being developed to augment T-cell responses. Approximately 80% of MCC cases in the United States are driven by the ongoing expression of viral T-antigen (T-Ag) oncoproteins from genomically integrated Merkel cell polyomavirus (MCPyV). Since T-Ag elicits specific B-and T-cell immune responses in most persons with virus-positive MCC (VP-MCC), and ongoing T-Ag expression is required to drive VP-MCC cell proliferation, therapeutic vaccination with T-Ag is a rational potential component of immunotherapy. Failure of the endogenous T-cell response to clear VP-MCC (allowing clinically evident tumors to arise) implies that therapeutic vaccination will need to be potent anśd synergize with other mechanisms to enhance T-cell activity against tumor cells. Here, we review the relevant underlying biology of VP-MCC, potentially applicable therapeutic vaccine platforms, and antigen delivery formats. We also describe early successes in the field of therapeutic cancer vaccines and address several clinical scenarios in which VP-MCC patients could potentially benefit from a therapeutic vaccine. K E Y W O R D S cancer therapeutic vaccine, immunotherapy, MCPyV, Merkel cell carcinoma

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“…The free polymer chains conjugated with imidazoquinoline were liberated, which triggered the TLR7/8 pathway [ 30 ]. Furthermore, nanomedicines incorporating both adjuvants and tumor antigens have also been exploited as cancer vaccines to mount an adaptive immune response against overexpressed self-antigens or neo-antigens that arise from somatic mutations in the tumor [ 31 ]. In addition to synthetic materials, cell-derived nanocarriers have shown their potential in delivering antigens for immunotherapy.…”

Section: Opportunities Of Nanomedicine In Immunotherapymentioning

confidence: 99%

Cancer nanomedicine meets immunotherapy: opportunities and challenges

et al. 2020

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Cancer nanomedicines have shown promise in combination immunotherapy, thus far mostly preclinically but also already in clinical trials. Combining nanomedicines with immunotherapy aims to reinforce the cancer-immunity cycle, via potentiating key steps in the immune reaction cascade, namely antigen release, antigen processing, antigen presentation, and immune cell-mediated killing. Combination nano-immunotherapy can be realized via three targeting strategies, i.e., by targeting cancer cells, targeting the tumor immune microenvironment, and targeting the peripheral immune system. The clinical potential of nano-immunotherapy has recently been demonstrated in a phase III trial in which nano-albumin paclitaxel (Abraxane®) was combined with atezolizumab (Tecentriq®) for the treatment of patients suffering from advanced triple-negative breast cancer. In the present paper, besides strategies and initial (pre)clinical success stories, we also discuss several key challenges in nano-immunotherapy. Taken together, nanomedicines combined with immunotherapy are gaining significant attention, and it is anticipated that they will play an increasingly important role in clinical cancer therapy.

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Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens

Cited by 259 publications

References 70 publications

Lipo-Based Vaccines as an Approach to Target Dendritic Cells for Induction of T- and iNKT Cell Responses

Lipo-Based Vaccines as an Approach to Target Dendritic Cells for Induction of T- and iNKT Cell Responses

Polyomavirus‐driven Merkel cell carcinoma: Prospects for therapeutic vaccine development

Cancer nanomedicine meets immunotherapy: opportunities and challenges

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