Preclinical Evaluation of VAX014 in Combination with Immune Checkpoint Inhibitors

PROJECT SUMMARY Vaxiion Therapeutics has developed a novelnon living oncolytic bacterial minicell based product candidatecalled VAXInitially designed for use in the topical intravesical treatment of non muscle invasive bladder cancerNMIBCthe IND for this initial indication will soon be openData from our recent publication in Nature Molecular TherapyOncolytics demonstrate that VAXminicellspublished under the research name VAXIPselectively kill cancer cells that express unligated cancer associatedandintegrins via an oncolytic mechanism of actionMoAThese two integrin subtypes are over expressed in many cancer subtypes and are clinically validated negative prognostic factors for bladder cancerovarian cancerand melanomaIn addition to the direct integrin targeted tumoricidal effects afforded by VAXs oncolytic MoAVAXalso exerts indirect synergistic immunotherapeutic effects against tumorssimilar to the standard of care in NMIBCintravesicular immunotherapy with live Bacillus Calmette GuerinBCG vaccineBased on all of these factorsVAXwas evaluated in a pilot study in combination with anti PD Limmune checkpoint blockade using the preclinical syngeneic orthotopic MBmurine bladder cancer model used to evaluate activity of VAXfor use in NMIBCThe results of these studies were quite remarkable and despite these animals having largedigitally palpableulcerated bladder tumors at the onset of therapyan overall survival rate ofwas achieved in combination therapy versusandin single agent comparator study armsAnimals that survived combination therapy were rechallenged with a second round of orthotopic MBtumors and an impressiveof animals rejected tumors and are disease freeThese data strongly suggest that the combination of VAXand PD LPDblockade results in potent anti tumor responses made durable by the likely development of long term anti tumor immunological memoryWhile marketed immune checkpoint inhibitors against the PD LPDaxis result in profound durable clinical responses in some patientsthe reality is that they haven t worked in the majority of patientsincluding most recently in the JAVELINstudy in ovarian cancerClinical trials using combinations of T cell directed inhibitorse ganti PD Land anti CTLAhave resulted in better response ratesbut come at the cost of increased and in some casesdeadly immunotoxicitiesThis creates a need for better combination partner agents and based on Vaxiion s preclinical results in combination with anti PD Ltherapy to dateVAXmay represent an attractive and effective optionFor the many reasons described in this proposalVaxiion now intends to expand the preclinical evaluation of VAXin immune competent mouse models of ovarian cancer and melanoma to study and understand the role of key immune cells behind the immunological MoAs of VAXalone and in combination with PD LblockadeBolstered by big pharma partnering interestour GMP manufacturing experience and soon to be open IND in NMIBCsuccessful outcome sin these important Phase I SBIR studies will enable Vaxiion to springboard VAXinto the clinic to perform combination therapy trials in these indications PROJECT NARRATIVE Vaxiion is expanding its preclinical development surrounding its lead bacterial minicell based productVAXfor eventual potential future clinical evaluation for the parenteral treatment of ovarian cancer and melanoma in combination with PD LPDblockadeWhile close to opening an IND for a Phasetrial of VAXfor use in the intravesical treatment of non muscle invasive bladder cancerNMIBCresults from recent preliminary studies conducted in the preclinical murine model of bladder cancer using VAXin combination with immune checkpoint inhibitor against PD Lare so compelling that we are expanding our efforts to evaluate this combination in other immune competent mouse tumor models of ovarian cancer and melanomaBoth cancer types have been shown to overexpress one or both of VAXsand ortarget integrins and each has demonstrated low but durable clinical response rates to PD LPDblockadeIn addition to evaluating efficacy in these modelswe propose to investigate the role of different immune cell types behind VAXactivity and in combination with PD LblockadeWith a soon to be open reference IND in another indicationNMIBCany promise from combination therapy in these studies could catapult VAXinto the clinic in these indications where an effective product used in combination to improve survival outcomes in these difficult to treat patient populations would be considered a very meaningful advance in the field