For categorical variables, the frequency of patie nts will be provided along with the percentage based on the number of patients with available data. Summaries will be based on observed data (i.e., no missing data will be imputed). Analysis of the secondary efficacy parameters will follow the same approa ch as outlined for Phase 2 below. Phase 2 : In Phase 2 , the primary endpoint ( proportion of patients alive and disease free at one year) between the two experimental groups and the control will be compared using Fisher's exact test and presented as odds rat ios (OR) with 95% confidence intervals (CI) relative to the control group. For the statistical comparisons on the primary endpoint between the two experimental and control group s, there will be no adjustment for multiplicity. ORs will be generated with a simple logistic regression model with one year disease -free survival as the dependent variable and group as the sole independent variable (low dose and high dose vesigenurtacel -L vs. control). If the analysis of the primary endpoint does not suggest any dose response effect between the two vaccine arms, an exploratory analysis will be conducted where the two vaccine arms will be pooled and compared to the control arm for the primary endpoint (proportion of patients alive and disease -free at one year). The outcome wi ll be presented as OR with 95% CI relative to the control group. Efficacy comparisons between the monotherapy arm and any of the randomized arms will remain exploratory. However, safety and point estimates with appropriate measures of variance (SD, 95% CI) for the efficacy parameters for the fourth arm will be estimated. The binary secondary endpoints will be presented as OR with ap propriate 95% CI . DFS will also be evaluated as a time to event endpoint, defined as disease recurrence or progression or death from any cause. For time to event endpo ints, which will also include OS , time to cystectomy, and burden of repeat TURBT , survival curves will be generated by the method of Kaplan -Meier and compared with the log -rank test. In an ex ploratory analysis, the weighted log rank test will also be used. The weighted log rank preserves the statistical power that is lost due to the lag time effect in efficacy with immunotherapeutic agents. Exploratory clinical and laboratory endpoints will b e summarized descriptively by time point of collection. Statistical testing and CI will be provided as an aid in reviewing the collected data. A log10 transformation may be used as appropriate in order to determine 95% CI based on a t -test for the log -concentrations, and the bounds will be transformed back to the original scale for presentation purposes. Homogeneity between Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 64 of 86 treatment groups will be assessed using Wilcoxon rank -sum tests for numeric variables and Fisher’s exact test for categorical variab les. An unblinded Interim Analysis may be performed when all randomized patients have completed the disease assessment at Week 25. The primary goal of this analysis will be to allow selection of a dose and dosing regimen for future manufacturing efforts. A t the time of this analysis all patients will have been enrolled, and the outcome of this analysis will not impact continuation of the trial to the primary endpoint. The treatment assignment of individual patients will not be unblinded to physicians or pat ients . All of the analyses will be performed using SAS® Version 9.1 (or later). Further details of the exact analysis methods can be found in the study -specific Statistical Analysis Plan. 12.2 Analysis Populations Study populations are defined as follows Phase 1: Safety Population: defined as all patients receiving at least one dose of vesigenurtacel -L Phase 2 : Intent -to-Treat (ITT): defined as all patients randomized into the study and who will be classified according to their assigned treatment group, regardle ss of the actual treatment received. Safety Population: defined as all randomized patients who receive at least one dose of treatment (BCG, HS - 410, or any combination thereof) Per-protocol population: defined as all patients in the ITT population who do not have any major protocol deviations (including being non -compliant to the study drug) Other sub -populations of patients for secondary and exploratory analyses may be defined at the time of statistical analysis and will be identified in any reporting of results. Patients will be randomized to Arms 1 -3 centrally using a stratified block design according to risk of recurrence (strata: high vs. intermediate risk) and CIS (strata: yes vs. no). The intent for stratification is to ensure balance between groups with respect to these important prognostic factors. Given the limited sample size, a formal subgroup analysis based on the stratification variables will not be undertaken. Patients who will not receive BCG will be consecutively allocated (non-randomized ) into Arm 4 consisting of vaccine monotherapy . Due to delays in the batch release of certain doses of vaccine, the randomization schedule may be temporarily revised from a 1:1:1 randomization to a 1:1 randomization, with one arm being briefly suspended. During the period of revised randomization, each patient will maintain at least a 50% chance of receiving vaccine versus placebo. Randomization strata will remain unchanged. Upon batch release of the vaccine the randomization will return to the original 1:1:1 ratio. In order to maintain the study blinding, temporary closure of certain arms will not be disclosed outside of the DMC except as needed for Informed Consent documents . Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 65 of 86 12.3 Accountability, Demographics, and Baseline Characteristics Accountability inf ormation will be summarized for each phase , including the number of enrolled patients , dosed patients , and patients who terminated at the first disease assessment , and the number of patients withdrawn by reason. Also, separately, the number of patients with recurrence events, dropping out, or continuing in the study will be summarized in order to show the percent of subjects without an event still being followed. Descriptive information on demographics and baseline data including age, sex, weight, height, body mass index, physical examination , and medical history will be provided in a summary table. Summaries will be provided by treatment group and overall for the ITT and Per -Protocol population classifications. 12.4 Safety Analysis Safety analysis will be performed for the Safety Population in each phase of the study . 12.4.1 Adverse Events Treatment emergent adverse events (TEAEs) will be defined as events that occur on or after the first dose of study medication . The Medical Dictionary for Regulatory Act ivities (MedDRA) coding dictionary will be used for the coding of AEs. TEAEs, serious or CTC Grade 3 or 4 TEAEs, and TEAEs related to therapy will be summarized overall and by system organ class and preferred term by treatment group. These will summarize the number of events and the number and percent of patients with a given event. A Fisher’s exact test will be provided to evaluate if the number of patients with an event within a specific system organ class is homogeneous across the treatment groups. I n addition, the number and percent of patients with TEAEs will be provided by maximum severity. A summary of all TEAEs by system organ class and preferred term occurring in at least 5% of subjects in either treatment group will be provided by quarter . 12.4.2 Laboratory Assessments All laboratory -based data will be presented as listings of all values as well as abnormal results judged to be clinically significant, which will a lso be reported as AE s. Numeric summaries of all observed and change from baseline labor atory evaluations will be provided by visit and treatment group , including chemistry, hematology, and urinalysis results. No inferential comparisons are planned. 12.4.3 Vital Signs Numeric summaries of all observed and change from baseline vital signs will be pr ovided by time point and treatment group, including blood pressure, heart rate , and temperature. No inferential analyses are planned for vital signs. 12.4.4 ECGs and Physical Examination Physical examination data and changes will be presented as listings. ECG re sults will be presented as listings and summarized by treatment group and visit based on incidence of clinically significant abnormalities. No inferential comparisons across treatment groups are planned. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 66 of 86 12.4.5 Other Assessments Other collected data not specific ally mentioned, including physical examinations and protocol deviations , will be presented in subject listings. 12.4.6 Safet y of Vesigenurtacel -L (Phase 1 and Arm 4 of Phase 2 Only) Safety is defined as the number of adverse events (AE)/serious adverse events (SAE) in patients receiving vesigenurtacel -L. 12.4.7 Safety of the Combination of Vesigenurtacel -L and BCG ( Arms 1, 2 , and 3 of Phase 2 O nly) Safety is defined as the proportion of AE/SAE in patients receiving the co mbination of vesigenurtacel -L and BCG compared to the proportion of AE/SAE in patients receiving the combination of placebo and BCG. 12.5 Efficacy Analy sis (Phase 2) All efficacy analyses will be based on the ITT population unless otherwise specified. 12.5.1 Primary E fficacy Analysis 12.5.1.1 1-year Disease -Free Survival (1 -yr DFS) One-year disease -free survival will be defined as the proportion of patients who are free from recurrent disease, progressive disease , and alive one year after the date of randomization /treatment assignment (Arm 4). For the primary efficacy evaluation, disease -free survival at one year between the experimental groups and the control will be presented as the absolute difference in proportions, as well as the OR, with the associated 95% CI. 12.5.2 Analysis of Secondary Efficacy Parameters The Secondary Efficacy Parameters will be analyzed using Kaplan -Meier time -to-event methodology. 12.5.2.1 Time to Recurrence Defined as the time from randomization to recurrence of disease to the same extent (stage and gra de) as screening. 12.5.2.2 Time to Progression Defined as the time from randomization to progression of disease to a greater stage. 12.5.2.3 Disease -Free Survival Defined as time from randomization to recurrence or progression 12.5.2.4 Overall disease -free survival Overall DFS is defined as the interval between the date of disease recurrence , progression , or death (whichever occurs first) and the date of randomization /treatment assignment (Arm 4) for patients without CIS. For patients with CIS at screening who have persisten t disease at 6 months, the date of disease persiste nce will be defined as the date of randomization /treatment assignment (Arm 4) (i.e. DFS = zero). Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 67 of 86 Patients with CIS at screening who are disease -free by 6 months will have their overall DFS interval calcu lated between the date of disease recurrence , progression , or death (whichever occurs first) and the earliest date that the patient was determined to be disease -free. Patients will be censored at the last time of contact if recurrence , progression , or deat h has not been confirmed at the time of the analysis. Overall DFS will be analyzed using a log -rank test with a term for treatment assignment. In addition, Kaplan -Meier curves will be produced separately for each treatment group. The weighted log rank t est will also be applied in an exploratory manner. In a supporting analysis, a simple Cox proportional hazards model with treatment group as the sole independent variable will be built in order to estimate the hazard rate (HR) and 95%CI for overall DFS between the low and high dose vesigenurtacel -L groups relative to the control. A HR of less than one will provide initial evidence of a favor able outcome with vesigenurtacel -L. These analyses will be completed for the ITT and Per-Protocol populations. 12.5.2.5 Overa ll survival OS is defined as the interval between the date of death and the date of randomization /treatment assignment (Arm 4) . Patients will be censored at the last time of contact if death has not been confirmed at the time of the analysis. OS will be analyzed using a log-rank test with a term for treatment assignment. In addition, Kaplan -Meier curves will be produced separately for each treatment group. The analysis will be completed for the ITT and Per-Protocol populations. 12.5.2.6 Burden of Repeat TURBT Defined as the proportion of patients with no repeat TURBT vs 1 TURBT vs 2 TURBT vs 3 TURBT etc within 12 months since rando mization , within 18 months since randomization , and within 24 months since randomization. 12.5.2.7 Time to Cystectomy Defined as the t ime from randomization to cystectomy. 12.5.2.8 Immune Response Section 10. 2.1 details how samples are run in duplicate or triplicate using ICS via flow cytometry or ELISPOT . The first step in the analysis of immunologic response will be to form the subject average across the duplicate or triplicate measurements recorded at each time point. In situations where only one measurement is obtained, the single value will be used in the analysis. If any values are in the range (0,1) inclusive, a value of 0.5 will be used in the analysis of count information on the log10 scale. The observed and log10 transformed values will be summarized for each visit. In addition, the change fro m baseline will also be summarized descriptively. At each visit and for the last available visit, a sign -rank test will be used to evaluate the null hypothesis that the change from baseline is centered at zero separately for each of the dosing groups. Si milarly, a Wilcoxon rank -sum test will be used to evaluate the null hypothesis that the observed and change from baseline values have a similar location ((i.e. median) between the low and high dose groups.) A 95% CI for the ratio of the differences geomet ric mean will be obtained by back -transforming the 95% non -parametric CI for the difference in log10 analysis. For the purposes of identifying the most important comparison, the analysis of the last assessment will be considered the primary analysis with other time points considered secondary analyses. Additionally, a repeated measures analysis will be completed modeling log10 transformed values as a function of visit, treatment, and a visit Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 68 of 86 by treatment interaction. Model results may not be reported if convergence is unattainable because of the small sample size. These analyses will be completed using the ITT and Per -Protocol populations. 12.5.2.9 Exploratory Efficacy Analyses In an exploratory analysis, patients experiencing an immune response in all four treatm ent arms will be compared to those who did not experience an immune response. The analysis will include a univariate comparison of patient and clinical variables at baseline as well as a comparison of any difference between immune responders and non -respo nders for the follo wing endpoints: proportion with progressive or recurrent disease at selected time points, disease -free survival, proportion undergoing post -treatment TURBT or fulguration or cystectomy , and overall survival. In an additional exploratory analysis, the proportion of patients whose disease has recurred to a lower stage than at screening and the proportion of patients whose disease has recurred to the same extent as at screening will be compared between the experimental and control groups and presented as an OR with 95% CI. 12.6 Sample Size Estimations 12.6.1 Phase 1 Phase 1 is designed to provide some indication of safety and tolerability of the low dose of vesigenurtacel -L as a monotherapy. A sample size of 10 patients in the monotherapy setting is deemed suitable for an assessment of safety . 12.6.2 Phase 2 For the randomized portion, a sample size of 75 subjects in the ITT population was selected for this study. The sample size assessment was based on the following assumptions:  75 patients will be randomized to yield 6 9 evaluable ( 25 patients per arm )  A one year disease -free survival rate of 60% in the control and 90% in the respective experimental groups for an absolute difference of 30% in favor of the experimental treatments  10% drop -out rate  Type I error (alpha) = 0.1 0 and using a one sided test with no adjustment for multiplicity  Power = 80% to detect a 30% difference in one year disease -free survival between the vesigenurtacel -L groups and the control group  Patients are followed for three years after the last patient is enrolled Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 69 of 86 13.0 STUDY CONDUCT CONSIDERATIONS 13.1 Regulatory and Ethical Considerations Heat Biologics will obtain favorable opinion/approval to conduct the study from the appropriate regulatory agency in accordance with applicable country -specific regulatory requirements or local regulations where applicable prior to a site initiating the study in that country. The study will be conducted in accordance with all applicable regulatory re quirements, includin g a US IND. The study will also be conducted in accordance with GCP, all applicable patient privacy requirements, and the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the following:  IRB/IEC /IBC review and favor able opinion/approval to conduct the study and of any subsequent relevant amending documents  Patient informed consent  Investigator reporting requirements The sponsor will provide full details of the above either verbally, in writing , or both. Written informed consent will be obtained for each patient before he or she can participate in the study. 13.2 Quality Control (Study Monitoring) In accordance with applicable regulations, GCP, and Heat Biologics procedures, Heat Biologics monitors , or designee, will c ontact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and Heat Biologics requirements. Heat Biologics will monitor the study consistent wit h the demands of the study and site activity to verify that the:  Data are authentic, accurate and complete.  Safety and rights of patients are being protected.  Study is conducted in accordance with the currently approved protocol and any other study agreeme nts, GCP, and all applicable regulatory requirements.  The investigator agrees to allow the monitor direct access to all relevant documents. 13.3 Protocol Deviations In general, a protocol deviation is an inadvertent excursion to, or non -compliance with, the IRB approved protocol . The investigator is responsible for ensuring the study is conducted in accordance with the procedures described in this protocol and should not implement any changes to the protocol unless it is required to eliminate an immedia te hazard to the patient. For the purposes of the protocol, deviations that fall into the following categories will be captured on the ECRFs. If the deviation affects the safety of the patient, the sponsor must be notified immediately. Other deviations o utside of these categories will be reported to the IRB in accordance with local requirements, as applicable. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 70 of 86  Entered into the study without meeting eligibility criteria  Developed withdrawal criteria during th e study and was not withdrawn  Received wro ng treatment or incorrect dose  Received excluded concomitant treatment  Failed to collect data necessary to interpret primary endpoints 13.4 Quality Assurance To ensure compliance with GCP and all applicable regulatory requirements, Heat Biologics may conduct one o r more quality assurance audits. Regulatory agencies may also conduct regulatory inspection of this study.