Microparticulate mucosal vaccine for triple-negative breast cancer

ABSTRACT Triple negative breast cancerTNBCis a molecular subtype of breast cancer that is negative for expression of estrogen and progesterone receptors and human epidermal growth factor receptorHERClinicallyit is characterized by aggressive behaviordistinct patterns of metastasisand high rates of recurrence and mortalitySince TNBC tumor cells lack the necessary receptorsthe disease does not respond to hormonal therapysuch as Tamoxifen or aromatase inhibitorsor therapies that target HERsuch as trastuzumabHerceptinor lapatinibTykerbImmunotherapeutic strategiesincluding active immunization with tumor specific antigens that results in cytotoxic T lymphocyteCTLmediated antitumor response may serve as an alternative to control the recurrence or progression of TNBCCancer testis antigensCTAsare protein antigens whose expression in normal tissues is restricted to the germ cells of the adult testisbut which are aberrantly activated and expressed in various malignant human tumorsWe have identified that the CTA sperm proteinSPis expressed in malignant TNBC cell lines and patient tumor samplesmaking it a novel candidate for immunotherapeutic targetingIn this proposalwe will evaluate the efficacy of oral microparticulate vaccine based on recombinant SPantigen combined with specific immunomodulatory agents to prevent retard the progression of TNBCMore specificallyvaccine components will be encapsulated into microparticles composed of a polymer matrix containing a mixture of enteric and sustained release polymers to prevent degradation of cargo molecules under acidic conditions in the stomach and enabling their controlled release at intestinal target sitesrespectivelyThe particles are targeted to M cells present in Peyer s patches of the gut associated lymphoid tissuewhich take up the encapsulated vaccine and transport it to mucosal dendritic cells via transcytosis to generate immunogenic responseIn order to overcome tumor associated immunosuppression mediated by CDregulatory T cellsTregsour vaccine formulation incorporates also interleukinILand pmitogen activated protein kinaseMAPKinhibitorwhich act synergistically in antagonizing CDT reg induction and promoting tumor antigenspecific pro inflammatory T helpercellThresponses that correlate with strong CDCTL activationThe vaccine microparticles will be administered to female CBLmice bearing TNBC tumors together with the indoleaminedioxygenaseIDOinhibitormethyl tryptophanMTto further mitigate the risk of tumorinduced immunotoleranceFollowing vaccinationthe systemic immune response and therapeutic efficacy will be determined by observing the change in the tumor burden and serum levels of SPspecific IgGIn additionthe spleen and draining lymph nodes of vaccinated mice will be analyzed for the presence of T regs to determine the effect of the vaccination on tumor associated immunosuppressionIf proven successfulour oral vaccination approach combining ease of administrationlow manufacturing costsand high patient acceptability will provide a novel therapeutic option for TNBCa disease which at present lacks effective treatments