IND enabling studies for a personalized immunotherapy for triple negative breast cancer

Abstract The worldwide incidence of breast cancer ismillionTriple negative breast cancersTNBCaccount forof total breast cancer casesworldwideAnnuallyovernew cases of TNBC are diagnosed in the US aloneThe treatment options for TNBC patients are limitedTriple negative breast cancerTNBCincludes breast cancers that lack estrogen receptorprogesterone receptorand HERproteinsLack of known targets and patient to patient variation of target antigens make TNBC one of the most challenging cancers for developing an effective therapyNew therapies are critically neededas TNBC is also resistant to checkpoint blockade inhibition aloneWe propose to develop an immunotherapy administered in combination with checkpoint blockade to treat metastatic TNBC using an approach that is personalizedthus incorporating patient specific neoantigens and other tumor antigens that are upregulated or altered in glycosylation patternsuch as MUCMetaclipse s immunotherapyautologous therapeutic vaccineconsists of Tumor Membrane VesiclesTMVsmade from patient specific tumor tissuewhich carry membrane associated tumor antigens and also antigenic epitopes derived from cytosolic proteins as MHC associated peptidesThese TMVs are then directly conjugated to potent glycolipid anchored immunostimulatory moleculesGPI ISMsby a novel protein transfer technologyThe novelty of the proposed vaccine lies not in the use of ISMsbut in the way they are employedThis direct physical linkage of TMVs and GPI ISMs allows for simultaneous delivery of the patient s unique tumor antigen signature and ISMs at the vaccination site to induce a robust antitumor immune responseSince the TMV vaccine is prepared from whole tumor tissue encompassing not only patient specific variation but also all of the heterogeneity of the tumorsA key advantage of our approach is that the immunotherapy product can be prepared within a weekwhich is critical during treatment of aggressive cancers such as TNBCThe company has successfully completed proof of concept studies using an immune checkpoint inhibitorICIresistant pre clinical mouse model of TNBCThe results demonstrate that immunization with TMV vaccine sensitizes the ICI resistant TNBC to become responsive to ICI therapyThe SBIR direct Phase II award is requested to support further IND enabling preclinical studieswhich will facilitate IND meetings with the FDA to advance the TMV vaccine product to the clinicThe following are specific aims of the SBIR direct Phase II grantdetermine optimal dose and dosing schedule of the immunotherapy product in inducing an effective antitumor immune responsealone and in combination with immune checkpoint blockade therapyevaluate safety of the administered immunotherapy product in miceandprepare for GMP production of human GPI ISMs and establish benchmarks for a GMP compliant TMV vaccine productThe proposed plan represents Metaclipse s critical path for product development to enter into a Phaseclinical trial PROJECT NARRATIVETriple negative breast cancerwhich accounts forof all breast cancerscases worldwideis an aggressive cancer subtypewith metastasis occurring more frequently and at earlier times than receptor positive breast cancerLack of known targets and patient to patient variation make this breast cancer type one of the most challenging for developing an effective therapyMetaclipse Therapeutics has developed a novel personalized cancer immunotherapyneeded to address patient to patient variationwhich can be manufactured and administered in a cost effective mannerThis current proposal will support dose responsetoxicity profile and cGMP manufacturing scale up studies required for IND submission ! !