Seite - 73 - in Cancer Nanotheranostics - What Have We Learnd So Far?

Conniotet al. Nanocarriers for immunecell targetingand tracking responses.AsmanyTAAsare intracellularproteins, fragmentsof these peptides must be presented on the cell surface bound to MHCclass Imolecules to be recognized by the immune system (Henderson et al., 2005). Indeed, after the recognition of TAA- MHCIcomplexes, inlymphnodes(Manolovaetal.,2008),CD8+ T lymphocytes canproliferate anddifferentiate intoCTLs.CTLs are thenable tomigrate toperipheral tissues todevelopcontact- mediated cytotoxicity activity and secrete effector cytokines as IFN-γ and TNF-α, leading to local inflammation (Ahlers and Belyakov,2010). Pattern recognition receptors, mainly the toll-like receptor (TLR) family, are suitable targets to potentiate the presenta- tion of TAAs through MHCI pathway to CD8+ T cells and increase cancer immunotherapy efficacy. Among TLR agonists, both cytosine phosphorothioate-guanine motifs (CpG; TLR9- ligand), double stranded RNAmimic polyinosinic:polycytidylic acid (poly(I:C); TLR3-ligand) and monophosphoryl lipid A (MPL) have been associated to stronger anti-tumor immune responses (Banchereau et al., 2003;Hildner et al., 2008;Radford andCaminschi,2013). Generally, TAAs andTLR ligands carried bypolymeric parti- cleshave the ability to escape thedegradation in endosomes and reach the cytosol in higher concentrations than those adminis- tered in soluble form. Those antigens can thus be presented by MHC-Imoleculesmoreeffectivelyandforlongerperiodsoftime, leadingtoaneffectivecellularresponse,whichis fundamental for asuccessful eradicationofcancercells. PASSIVECANCERIMMUNOTHERAPY Passive immunotherapy isbasedontheadministrationof exvivo generated immuneeffectormoleculesor cells, suchasantibodies andCTLs,respectively.Thesemoleculesorcellscantargetspecific receptors, leading to enhanced efficacyof the treatment andalso to fewersideeffects. Monoclonalantibodies (mAbs) Monoclonal antibodies are the main cancer immunotherapy used currently in clinic to treat solid tumors and lymphomas (Krishnamacharietal.,2011).Forexample,trastuzumabhasbeen used to treatHER2+ breast cancer and adenocarcinoma, whilst alemtuzumabhasbeenapplied inchronic lymphocytic leukemia treatment(Leeetal., 2013). The mechanism of action of mAbs is related to their abil- ity to interferewith both growth factor ligands and receptors or pro-apoptotic targets, inducingapoptosisofcancercells.Besides, mAbsmay activate components of the immune system through Fc-region-basedmechanisms. This leads to antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) responses by macrophages and NK cells (Krishnamachari etal., 2011). The use of mAbs in clinic has been increasing in the last decades. The first generation of mAbs used in cancer therapy wasoriginatedfrommouse.Theiroriginoftenresulted in limited half-life, decreasingmAbsefficacy. Furtherprogresses conducted to the development of chimeric mAbs, with enhanced proper- ties, and then humanizedmAbs. Nowadays, fully humanmAbs are already available (Lee et al., 2013). Several novel mAbs for different cancer types are presently in clinical trials, as reviewed by Lee et al. (2013). For example, ganitumab—for pancreatic cancer–andnecitumumab—fornon-small cell lung cancer—are nowinphase IIIofclinical trials. AdoptiveT-cell therapy This approach is basedon the transfer ofmature tumor-reactive T lymphocytes toact against tumorcells.Unlikecancervaccines, this strategy is independent fromanimmuneresponseelicitedby an exogenous antigen. Instead, it relies on thedeliveryof a great amount of ex vivo-expanded cells (Gajewski, 2012; Kirkwood etal., 2012;Helmyetal., 2013). Adoptive T-cell therapy with tumor-infiltrating lymphocytes (TILs) has been proposed. In a successful study, autologous TILs—T cells with potent antitumor activity found within tumors—were harvested, activated ex vivo and reinfused in patients. The total remissionwas reported inmore than 20%of the treatedpatients (Rosenbergetal., 2011). Complementary research has been made to improve T-cell adoptivetherapies.GeneticallyengineeredTcellsareunderstudy, in order tomanipulate the properties of the administeredT-cell population, such as proliferation andmigration characteristics (Liu and Rosenberg, 2001; Hinrichs et al., 2011). Also, T cells have been geneticallymodified to have antitumor specificity by introducingaT-cell receptor foraparticular tumor,aspreviously described inareviewbyHelmyetal. (2013). DELIVERYSTRATEGIESFORIMMUNECELLTARGETINGAND TRACKING STRATEGIESFORDCTARGETING Since the role of DCs in inducingCTL immunity is well estab- lished, several studies havebeenmade inorder touseDC-based cancervaccines in tumor immunotherapy. Exvivo These vaccines use isolated CD14+monocytes or CD34+DC precursors from an individual. After being isolated, these cells are then cultured and differentiated in immatureDCs (Romani et al., 1994;Chapuis et al., 1997). The followingprocess isTAA- loading of DCs, which consists in adding proteins, peptides or tumor lysates to its culture medium or through transfec- tion. Additional maturation stimuli, such as CD40L or pro- inflammatory cytokines, may be used to ensure DCs will be able to induce a strong cellular immune response. Finally, loaded mature DCs are administered back into the patient by intravenous (i.v.), subcutaneous (s.c.), intradermal (i.d.), intratumoral (i.t.) or intralymphatic (i.l.) route (Hamdy et al., 2011). Theuseofatumorcell tostimulateDCsseemstoinduceabet- ter immune response, but it is limitedbyapossible inductionof autoimmunediseases,duetothelackofantigenspecificityamong theundefinedantigenfoundatcancercell surface. Whichever the typeof antigenused topulseDCs, although it has been reported that this approach is safe and able to induce CTL immunity, the clinical observed goal is low, possibly due to the in vivo general complex interactions between immune cells (Rosenbergetal., 2004). Frontiers inChemistry | ChemicalEngineering November2014 |Volume2 |Article105 | 73