Induction of anti-tumor cytotoxic T cell responses through PLGA-nanoparticle mediated antigen delivery

Zhang, Zhiping; Tongchusak, Songsak; Mizukami, Yo; Kang, Yoon‐Suk; Ioji, Tetsuya; Touma, Maki; Reinhold, Bruce B.; Keskin, Derin B.; Reinherz, Ellis L.; Sasada, Tetsuro

doi:10.1016/j.biomaterials.2011.01.067

Cited by 211 publications

(165 citation statements)

References 48 publications

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“…4B) induced by targeting the vaccine to the tdLN led to regression of early-stage tumors and more impressively of tumors having reached the Swiss legal limit of 1 cm 3 . In the literature, cancer vaccines are usually administered when the tumors are 5 to 7 mm in diameter or even before they are detectable, and also do not usually induce this high number of TAA-specific CD8 þ T cells in the blood and the LNs (17,19,30,38,44), thus emphasizing the benefits of nanoparticle-mediated targeting of antigen and adjuvant to DCs in the tdLN (18,38,45). We noted, however, that after regressing some tumors grew back.…”

Section: Discussionmentioning

confidence: 80%

“…Compared with current published studies, our TRP-2-based therapeutic nanoparticle vaccine is very potent at the low doses used for antigen and adjuvant (18,39,40). Similarly, other studies have shown improved therapeutic outcomes by either conjugating the adjuvant or the antigen onto or into delivery systems, such as poly(lactideco-glycolide) particles and liposomes, but, to our knowledge, this is the first study to show enhanced co-uptake of both adjuvant and antigen by LN-resident APCs after nanoparticle conjugation (14)(15)(16)(17)(18)(19). Furthermore, it has been shown recently that encapsulating antigens or TLR agonists in nanoparticles enhanced humoral responses compared with immunization with soluble antigen or adjuvant (41,42).…”

Section: Discussionmentioning

confidence: 98%

“…17, 31, 38). Our nanoparticles were in the range of 30 nm, thus smaller than particles used in many vaccination studies, hence affording enhanced lymphatic drainage and targeting of the skin-draining LNs (14)(15)(16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…Strategies based on delivering adjuvants or antigens carried by nanoparticles or liposomes have led to improved targeting of LNs, activation of LN-resident DCs, and enhanced induction of antigen-specific CD8 þ T cells, hence better protection in tumor challenge studies (14)(15)(16)(17)(18)(19). Ultrasmall, functionalizable nanoparticles (NP) developed in our laboratory effectively target DCs in skin-draining LNs upon intradermal delivery (20,21).…”

Section: Introductionmentioning

confidence: 99%

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Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

169

133

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The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in nontumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8 þ T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. Cancer Immunol Res; 2(5); 436-47. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

169

133

View full text Add to dashboard Cite

show abstract

“…The star indicates a statistically signifi cant difference. (Kovacsovics-Bankowski and Rock, 1995;Zhang et al, 2011;Ma et al, 2012). PLGA particles can protect the antigen from enzymatic degradation (Kovacsovics-Bankowski and Rock, 1995), increase the effi ciency of antigenloading (Hanlon et al, 2011;Ma et al, 2012), facilitate cross-presentation of the antigen (Ma et al, 2011), and co-deliver adjuvant into DCs (Zhang et al, 2007).…”

mentioning

confidence: 99%