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Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 18 of 86 LIST OF ABBREVIATIONS AE Adverse event AJCC American Joint Committee on Cancer ALT Alanine transaminase AST Aspartate transaminase AT As treated BCG Bacillus Calmette –Guérin cGMP current Good Manufacturing Practices CIS Carcinoma in situ CTCAE Common toxicity criteria for adverse events DMC Data Monitoring Committee DMSO Dimethyl sulfoxide ECG Electrocardiogram ECRF Electronic case report form ELISA Enzyme -linked immunosorbent assay EX Excluded subject EOT End of treatment ESR Erythrocyte sedimentation rate FACS Fluorescent -activated cell sorter FFPE Formalin -fixed, paraffin -embedded FDA Food and Drug Administration GCP Good Clinical Practice gzB Granzyme B HIV Human immunodeficiency virus IEC Independent ethics committee IHC Immunohistochemistry IBC Institutional biosafety committee IBCG International Bladder Cancer Group ICS Intracellular cytokine staining IFNγ Interferon gamma IHC Immunohistochemistry IND Investigational New Drug (application) IRB Institutional Review Board ISR Injection site reaction ITT Intent to treat (population) MedDRA Medical dictionary for regulatory activities MHC Major histocompatibility complex NCI National Cancer Institute NED No evidence of diseas e NMIBC Non-muscle invasive bladder cancer NSCLC Non-small cell lung cancer NYHA New York Heart Association OS Overall survival PBMC Peripheral blood mononuclear cell Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 19 of 86 PCR Polymerase chain reaction PFS Progression free survival POC Proof of concept PP Per Protocol PT Preferred term RECIST Response Evaluation Criteria in Solid Tumors SAE Serious adverse event SAR Suspected adverse reaction SD Standard deviation SOE Schedule of events SOC Standard of care TCR T-cell receptor TURBT Transurethral resection of bladder tumor ULN Upper limits of normal WBC White blood cell Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 20 of 86 1.0 BACKGROUND 1.1 Bladder Cancer Bladder cancer is the 6th most common cancer in the United States with an estimated 74,690 patients diagnosed in 2014 and 15,580 deaths . 1,2 Worldwide, 2.7 million people are living with a history of bladder cancer .2 Bladder cancer is estimated to be the most costly cancer in the US , and treatment -related complications are estimated to account for one -third of total costs.3,4 Approximately 70 -80% of patients have non -muscle invasive bladder cancer (NMIBC) at the time of diagnosis.5,6 Transurethral resection of bladder tumor (TURBT) is the standard treatment for NMIBC and aids in the proper diagnosis and staging of disease. Patients with low -risk disease ( solitary, primary , low-grade, Ta tumor s) have high recurrence -free and progres sion-free rates and an overall favorable prognosis.6,7 In contrast , patients with high-risk disease (T1 and/or high grade and/ or carcinoma in situ (CIS) ) determi ned at the time of initial resection have a one year recurrence -free rate as low as 39% , and by five years, th is rate has dropped even further to 20%.6 Between these two extremes is a large group of patients classified as having intermediate -risk disease, which is defined as multiple or recurrent , low-grade , Ta tumors.7 Because this is a very broad spectrum of patients, the intermediate -risk category can be further stratified. Intermediate -risk patients with at least three of the following four risk factors – multiple tumors, tumor size > 3cm, early recurrence (< 1 year from previous TURBT), or frequent recurrences (i.e. recurrence with a frequency of more than once in any 12 - month period ) – have treatment regimens and outcomes similar to high -risk patients, with recurrence -free rates of 62% at one year and 38% at five years.6,8 Patients with either high -risk disease or intermediate -risk disease with three or more risk factors will make up the patient population for this p rotocol. Adjuvant t reatment options for patients with urinary bladder cancer are limited , as systemic chemotherapy appears largely ineffective in this setting .9,10 Adjuvant intravesical mitomycin -C, often given as a single dose within 24 hours of surgery, and intravesical bacillus Calmette -Guérin ( BCG ), which cannot be initiated until several weeks after surgery to reduce the risk of sepsis, have been used successfully to reduce local recurrence of NMIBC for over 30 years , but nearly a quarter of high -risk patients have evidence of disease 6 months after induction BCG .11 Patients with intermediate - or high -risk disease benefit most when induction BCG is combined with a maintenance phase lasting at least one year.12,13,14,15 However, nearly 15% of these patient s will still go on to experience a recurrence after three years.15 Reasons f or failure are not well defined but may be related to toxicities associated with these agents resulting in utilization of intravesical therapy well be low recommended dose intensitie s.16,17 More recently, access to BCG, itself, has become a significant treatment barrier due to production problems with manufacture rs of the drug. Because of the limited long term disease control possible with currently available adjuvant s trategies in patients with high -risk NMIBC , the shortage of BCG, and the progressively less effective and more debilitating outcomes of subsequent rounds of surgical resection, there is a pressing need for a lternate or complementary adjuvant strategies , such as vaccine -based immunotherapy, to reduce recurr ence and improve tolerability of treatments in this patient group . Immunologic surveillance is the mechanism by which cells undergoing malignant transformation are eliminated from the body through recognition by innate an d adaptive immune cells . Immunotherapeutic Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 21 of 86 approaches de signed to exogenously stimulate innate immune surveillance can be classified broadly under active immunotherapy/therapeutic vaccines, adoptive cellular immunotherapy , and passive immunotherapy.18 Although most clinically advanced cancers have escape d immunological control mechanisms, the possibility that autologous cellular immunity can be restimulated to target cancer cells has led to a number of therapeutic trials of a variety of immunotherapy ap proaches .19 These studies have demonstrate d that improved overall survival can be achieved even in generally chemo resistant malignancies , such as advanced renal cancer , prostate cancer , and melanoma.19,20,21,22 Immunomodulation is particularly appropriate in the context of minimal residual disease , such as immediately after TURBT, since it is believed that it may be the setting in which this approach is most effective .23 Recent advances in the immunotherapy field have led to the understanding that destruction of a tumor involves multiple coordinated immune mechanisms , including activation of antigen presenting cells and effector T cells, blockade of immune regulatory mo lecules , including CTLA -4 and PD -1, and reduction of suppressor T cells.24 Additionally, it is now recognized that immunotherapeutic agents are frequently characterized by a period of latency between administration and subsequent clinical response , which i s in contra st to traditional chemotherapeutic or small molecule regimens wherein the clinical response is predicted by and associated with the peak concentration of drug achieved shortly after administration. Furthermore, s hortly after initiating immunotherapy treatment, patients may appear to experience disease progression as assessed by conventional imaging techniques, before the onset of biological activity and clinical effect .25 Greater understanding of the methodological complexity of assessi ng immunotherapeutic agents are now resulting in more appropriate clinical trial designs , which have significantly improved the probability of detecting the anti -cancer clinical utility of immunotherapeutic approaches in early stage clinical trials , such as the one described in this protocol . 1.2 Rationale for Vesigenurtacel -L Development The hypotheses behind the development of vesigenurtacel -L (HS-410), a therapeutic vaccine, to treat urothelial cancer of the bladder are as follows: (1) A range of tumor -associated antigens ( survivin , LAGE -1, MAGE -A3, MAGE -A11, and PRAME ) have been identified in bladder cancer , and it is postulated that treatment with BCG therapy provides the innate immune system with a warning signal to induce and direct an acquired immune response against such antigens.26 However, BCG therapy is accompanied by a high fa ilure rate and significa nt side effects , which limit its clinical application. The clinical response to BCG might be improved through concurrent enhancement of tumor immunogenicity by concomitant administration of a vaccine , such as vesigenurtacel -L, during standard BCG therapy . (2) Secreted gp96 -Ig from vesigenurtacel -L combines adjuvant activity with polyvalent peptide specificity. Vesigenurtacel -L activates dendritic cells (DC), natural killer ( NK) cells, and cytotoxic T lymphocytes ( CTL ). Tumor cells can be killed by NK cell-specific mechanisms, by promiscuous killing by CD8 + CTL through NKG2D, and by major histocompatibility complex (MHC) -restricted CD8 + CTL activity. The activation of DC and NK cells by vesigenurtacel -L may also counteract the generation of immunosuppressive CD4 + regulatory cells. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 22 of 86 (3) Vesigenurtacel -L also stimulates antigen cross presentation via the CD91 receptor, Toll-like receptor (TLR) 2 and TLR4 on DC and macrophages. Allogeneic tumor cells are li kely to share public tumor antigens in analogy to melanoma. Therefore , allogeneic, gp96 -secreting tumor cells used as a vaccine (such as vesigenurtacel -L) are expected to generate NK cell and CTL activity to the patient’s autologous tumor. (4) BCG activat es innate immune receptors, primarily TLR, within the endothelial lining of the bladder following intravesic al administration. Activation of these innate receptors contributes to the local production of inflammatory cytokines, including IL -1β and TNFα , which provide an inflammatory signal leading to upregulation of the local microvascular endothelium within the bladder wall, including expression of selectin ligands and int egrins, such as ICAM -1 and VCAM -1. Vesigenurtacel -L is administered intradermally and leads to the activation of antigen -specific CD8+ T cells that circulate through the systemic vasculature. Extravasation of T cells into tissues requires activation of endothelial cells , and trafficking through inflamed v essels is mediated by selectins, integrins , and chemokines. Thus, the systemic activation of T cells by vesigenurtacel -L is proposed to synergize with BCG through the combined increase in bladder -tumor antigen - specific T cells that may traffic more effici ently into the bladder due to endothelial activation by locally administered BCG. Similarly, inflammation generated in response to the TURBT surgical procedure may drive CD8+ T cells into the bladder tissue, even in the absence of BCG, mediating CD8+ T cel l trafficking to the bladder in a BCG -independent fashion. Initiating vaccination during the perioperative period immediately after TURBT potentially capitalizes on this period of post-operative immunoactivity . (5) In current clinical practice , no treatme nt is typically administered during the 6 week period following completion of BCG induction therapy and prior to the next cystoscopy . Continued treatment with a vaccine , such as vesigenurtacel -L, during this time may provide an additional important window for continued immune stimulation , which could result in improved treatment response. (6) Although it is postulated that concurrent administration of intravesical BCG and intradermal vesigenurtacel -L might result in optimally synergistic immunoactivation , it is also possible that intradermal vesigenurtacel -L monotherapy will result in a significant degree of immune modulation, independently of concomitant BCG. The current study will , therefore , examine vesigenurtacel monotherapy in patients who will not r eceive BCG . 1.3 Description of Investigational Agent Vesigenurtacel -L Vesigenurtacel -L is a whole cell vaccine that has been irradiated to render cell replication incompetent while maintaining biological activity, i.e., expression of certain tumor -associated a ntigens as described above. Vesigenurtacel -L is derived from a human prostate cancer cell line , PC3. This cell line was evaluated amongst others and was selected based on the overlap of its nativ e antigenic profile with that of tumor Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 23 of 86 samples from patients with NMIBC . The chosen PC3 tumor cells were modified to express HLA -A1 protein and secrete gp96 -Ig fusion protein by stable transfection. Clones with a high level of expression were obtained by G418 (Geneticin) selection and flow cyt ometry cell sorting. Preparat ion of the drug product includes expansion of batches of cells using current good manufacturing practices (cGMP) manufacturing methods. The cells are tested for presence of expression of HLA -A1 by fluorescent -activated cell so rter (FACS) and gp96 -Ig expression by enzyme -linked immunosorbent assay (ELISA ). Cells are harvested, washed , resuspended in buffer ed saline, irradiated , washed and vialed. The vialed cells are frozen and then stored at ≤ -120C in the vapor phase of a liquid nitrogen freezer . 1.4 Prior Human Experience This is the first trial to dose patients with vesigenurtacel -L. A first -in-human Phase 1 study of HS -110, a lung cancer vaccine using the same technology platform , was conducted in 18 patients with advanced non- small cell lung cancer ( NSCLC ).27 Patients received one of three dosing regimens. Safety was evaluated as a primary endpoint and tumor response and survival were secondary endpoints. Immune response in peripheral blood was characterized in 15 patient s who received at least one course (6 weeks) of vaccination by measuring produ ction of IFN -γ by patient CD8+ T cells as compared to baseline. The majority of adverse events were mild injection site reactions, consisting mainly of rash, induration, pruritu s, and pain. Six serious adverse events were reported for five patients: respiratory disorder for a patient who was enrolled but not treated with HS -110, disease progression ( two patients), chest pain, and dyspnea and rectal hemorrhage. None of these eve nts was considered by the investigator to be treatment - related. None of the 18 patients had an objective tumor response by the Response Evaluation Criteria i n Solid Tumors (RECIST) . Fourteen patients had died, and four surviving patients were followed for a median of 10.6 months (range 2.6 to 16.6). The Kaplan -Meier estimate of median survival was 8.0 months (95% confidence interval [CI]: 6.7 to 18.2), and the 6, 12, and 24 -month overall survival (OS) rates were 77.8% (95% CI: 51.1 to 91.0%), 41.9% (95% CI: 19.1 to 63.3%), and 11.2% (95% CI: 0.8 to 37.3%), respectively. All patients have now died. 2.0 OBJECTIVES 2.1 Primary Objective Phase 1 To characterize the safety and tolerability of low dose monotherapy vaccination with vesigenurtacel -L in patients with non -muscle invasive bladder cancer Phase 2  Arms 1, 2, and 3: To evaluate 1 -year disease -free survival in patients with non -muscle invasive bladder cancer treated with BCG in combination with blinded study product (one of two doses of vesigenurtacel -L or placebo )  Arm 4: To evaluate 1-year disease -free survival in patients with non -muscle invasive bladder cancer treated with high dose vesigenurtacel -L monotherapy Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 24 of 86 2.2 Secondary Objectives  To evaluate the safety of the combination of vesigenurtacel -L and BCG (Phase 2 only)  To evaluate the safety of high dose vesigenurtacel -L monotherapy (Phase 2 only)  To evaluate the proportion of patients with recurrence at 3, 6, 12, 18, and 24 months  To evaluate the proportion of patients with progressive disease at 3, 6, 12, 18 , and 24 months  To evaluate disease -free survival at 3, 6, 18, and 24 months  To evaluate overall disease -free survival  To evaluate overall survival (OS)  To evaluate the proporti on of patients undergoing post-treatment TURBT or fulguration by 12 and 24 months  To evaluate the proportion of patients undergoing cystectomy by 12 and 24 months  To evaluate the proportion of patients with immunologic response of PBMCs via intracellular cytokine staining (ICS) by flow cytometry and/or ELISPOT on CD8+ cells following vesigenurtacel -L vaccination 2.3 Exploratory Objectives  Immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD8, CD19, CD25, CD45, CD56, FoxP3, and degranulation) and stimulation analysis via ICS of IFNγ and granzyme B (gzB)  Total PBMC counts by flow cytometry, including lymphocyte subsets (B cells, helper T -cells, cytotoxic T -cells, NK cells and T -reg)  Evaluation of tumor tissue obtained prior to treatment for antigen expression , expression of major histocompatibility complex (MHC) class I, and expression of immunosuppressive molecules  Evaluation of tumor tissue obtained from repeat biopsy, if clinically indicated, for presence of tumor infiltrating T -lymphocytes (TILs)  T cell receptor sequencing of PBMCs and tumor tissue to determine correlation between clonally expanded T cell populations and other endpoints  Immune cell infiltration and inflammatory cytokine level s in urine (Phase 2 only) 3.0 TRIAL DESIGN 3.1 Study Design Overview This is a multi -center, randomized, placebo -controlled study consisting of two phases as shown in Figure 1 below . Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 25 of 86 Figure 1. Study Design Patients with non -muscle invasive bladder cancer who have either undergone TURBT or fulguration for the removal of papillary disease or who have carcinoma in situ (CIS) only, are candidates for BCG treatment, and are judged to be at an increased risk for r ecurrence are eligible if they are BCG naive or have completed previous BCG treatment >12 months prior to the baseline staging procedure . Phase 2 also allows patients who will not otherwise receive BCG. The Phase 1 portion is an open -label, safety study c onsisting of one cohort with 10 patients. Patients will have previously received 3 -6 instillations of weekly intravesical BCG induction therapy (as standard of care) followed by low dose intradermal (1 x 106 cells) vesigenurtacel -L monotherapy. In Phase 2, patients will be assigned to treatment gr oups based on whether they will receive induction BCG in the typical post -TURBT window. If the investigator plans to administer BCG, patients will be randomized to one of three blind ed (physician -patient) , place bo-controlled groups and receiv e either intradermal placebo or low dose or high dose (1 x 107 cells) vesigenurtacel -L in combination with induction and maintenance intravesical BCG. If patients will not receive BCG, they will be enroll ed into an open - label, non -randomized group an d receive high dose intradermal vesigenurtacel -L monotherapy . Phase 1 : Patients enrolled in the first cohort within 8 -10 weeks of TURBT or fulguration for patients with papillary disease and staging procedure for patients with CIS only and after induction BCG will be treated with vesigenurtacel -L weekly for 6 weeks . After a one-week vaccine holiday for disease assessment, patients will receive vesigenurtacel -L for an additional 6 weeks followed by three once monthly treatments for a total of 15 vaccinations. Patients will be observed weekly to assess the safety of vesigenurtacel -L. Dosing of the first three patients will be staggered by two-week intervals to allow for safety evaluation before treating additional patients. If vesigenurtacel -L appears safe and well -tolerated in the 3 lead -in patients, dosing will be continued to 10 patients. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 26 of 86 Phase 2 : Dosing in Phase 2 will begin when all 10 patients have been dosed in the Phase 1 cohort, at least 6 patients in that cohort have completed the Week 7 safety assessments, and the Data Monitoring Committee (DMC) has met to review this data and agree d it is safe to advance to Phase 2. A total of 100 patients will be assign ed to four groups: 75 who will receive BCG will be randomized to arms combining either low dose vesigenurtacel -L, high dose vesigenurtacel -L, or placebo , respectively, with induction a nd maintenance BCG; 25 who will not receive BCG will be enrolled in the high dose vesigenurtacel -L monotherapy arm . In the randomized arms, t reatment will commence within 6 weeks of the most -recent TURBT or fulguration for patients with papillary disease and staging procedure for patients with CIS only . Patients will be treated during an induction phase with weekly intravesical BCG and intradermal blinded study product (vesigenurtacel -L or placebo) for 6 weeks followed by 6 weekly injections of blinded study product alone. During a subsequent maintenance phase, patients will receive an additional three courses of three once - weekly blinded study product injections in combination with intravesical BCG approximately 3, 6, and 12 months after initiating induction BCG. Patients may receive additional courses of maintenance BCG in long-term follow -up at the investigator ’s discretion but should not receive any other cancer therapy prior to disease recurrence /progression . In the monothera py arm, treatment will commence within 6 weeks of the most -recent TURBT or fulguration for patients with papillary disease and staging procedure for patien ts with CIS only . Patients will be treated during an induction phase with weekly intradermal vesigenurtacel -L for 12 weeks. During a subsequent maintenance phase, patients will receive an additional three courses of three once -weekly vesigenurtacel -L injections approximately 3 , 6, and 12 months after initiating induction vesigenurtacel -L. All patients in both the Phase 1 and Phase 2 portions of the study will have a cystoscopy and cytology and , if clinically indicated, a biopsy performed approximately e very 3 months for 2 years then every 6 months for up to a year, study termination, disease progression, or recurrence requiring treatment discontinuation , whichever occurs first. Patients with evidence of disease at an assessment may continue on treatment if judged by the investigator to be in the patient’s best interest (e.g. would normally receive another course of BCG therapy as standard of care (SOC)). Upon discontinuation of study treatment, additional treatment will be at the discretion of the treati ng physician per SOC. While treatment may continue in the presence of evidence of disease, statistical analysis of disease -free status will still follow strict definitions as defined in section 10.1 Evaluation of Disease . 3.2 Justification of Study Product Adm inistration Strategy A clinical trial of a similar vaccine for lung cancer derived from the same proprietary technology as the vaccine for this study examined three dosing schedules: twice weekly, weekly , and once every two weeks. The twice weekly and week ly dosing schedule s were determined to produce the most desirable immune response in peripheral blood (at least a doubling of CD8 from baseline). The weekly dosing schedule was selected for this trial as it was determined to provide reasonable patient acceptability for frequency of treatment visits and concordance with the standard BCG dosing schedule . Two doses were selected (1 x 106 cells and 1 x 107 cells) for this study. The 1 x 107 cell dose was selected based on the number of cells needed to produce an equivalent amount of gp96 -Ig to that used in the lung cancer vaccine. Additionally, m urine data suggest that lower doses may produce a sufficient immune Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 27 of 86 response and may even result in superior clinical effects , and therefore, the lower dose of 1 x 106 cells was included as one of the two doses for evaluation in this trial . Study product will be admi nistered weekly as the number of intradermal injections required to reach the number of cells per dose with no more than 0.1mL per injection (see Section 8.3). The selection of the route of administration is based on the hypothesis that split doses stimulate stronger immune responses by allowing vaccine antigens to reach more regional lymph nodes (where immune responses are generated). Vesigenurtacel -L will be administered intradermally to enhance stimulation of cellular immune res ponses as compared to subcutaneous or intramuscular immunization. 3.3 Number of Subjects Approximately 110 patients will be enrolled from up to 20 clinical trial centers. In Phase 1, 10 patients will be enrolled in a single cohort given treatment with monothe rapy low dose vesigenurtacel -L. In Phase 2, 25 patients will be enrolled in each of four arms: low dose vesigenurtacel -L in combination with BCG, high dose vesigenurtacel -L in combination with BCG, placebo in combination with BCG , and high dose vesigenurt acel-L monotherapy (100 patients total). 3.4 Study Endpoints 3.4.1 Primary Efficacy Endpoint Phase 1 : Safety and tolerability Phase 2 : 1-year Disease -Free S urvival (1-yr DFS) 3.4.2 Secondary Endpoints  Safety of the combination of vesigenurtacel -L and BCG (Phase 2 only)  Safety of high dose vesigenurtacel -L monotherapy (Phase 2 only)  Proportion of patients with recurrence at 3, 6, 12, 18, and 24 months  Proportion of patients with progressive disease at 3, 6, 12, 18 and 24 months  Disease -free survival (DFS) at 3, 6, 18, and 24 months  Overall DFS  Overall Survival (OS)  Proportion of patients undergoing post-treatment TURBT or fulguration by 12 and 24 months  Proportion of patients undergoing cystectomy by 12 and 24 months  Proportion of patients with immunologic response of PBMCs via intracellular cytokine staining (ICS) by flow cytometry and/or ELISPOT on CD8+ cells after receiving vesigenurtacel -L treatment as compared to baseline 3.4.3 Exploratory Endpoints  Immunologic response of PBMCs (analysis of surface markers, CD3, CD4, CD 8, CD19, CD25, CD45, CD56, FoxP3, and degranulation) and stimulation analysis via ICS of IFNγ and gzB  Total PBMC counts by flow cytometry, including lymphocyte subsets (B cells, helper T -cells, cytotox ic T-cells, NK cells and T -reg) Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 28 of 86  Evaluation of tumor tis sue obtained prior to treatment for antigen expression , expression of major histocompatibility complex (MHC) class I, and expression of immunosuppressive molecules by mRNA expression and/or immunohistochemical analysis  Evaluation of tumor tissue obtained f rom repeat biopsy, if clinically indicated, for presence of infiltrating T -lymphocytes (TILs)  T cell receptor sequencing of PBMCs and tumor tissue to determine correlation between clonally expanded T cell populations and other endpoints  Immune cell infiltration and inflammatory cytokine levels in urine (Phase 2 only) 3.5 Study Termination Criteria The sponsor may terminate the study at any time on the basis of safety considerations or other factors that may be deemed to affect the scientific validity or ethical viability of the protocol. 4.0 PARTICIPANT SELECTION 4.1 Inclusion Criteria Patients must meet all of the following inclusion criteria to be enrolled into the study: 1. Willing and able to sign informed consent and comply with the protocol, including clinic v isits to receive weekly vesigenurtacel -L injections for 12 doses followed by either monthly vesigenurtacel - L injections for three months in Phase 1 or three courses of three once -weekly injections in Phase 2. 2. Histologically or cytologically confirmed non -muscle invasive bladder cancer [Ta, T1 or Tis (CIS)] . Papillary disease must have been removed by transurethral resection or fulgu ration . 3. Either i. High -risk disease, defined as T1 and/or high -grade and/or CIS, or ii. Intermediate -risk disease defined as Ta low -grade with at least three of the following four risk factors: multiple tumors, tumor size > 3cm, early recurrence (<1 year from previous staging procedure ), or recurrence with a frequency of more than once in any 12 month period . 4. Patients must be BCG naive or have completed previous BCG treatment >12 months prior to the baseline staging procedure . 5. For Phase 2 only: Arms 1, 2 , and 3: Suitable , in the opinion of the investigator, to receive a 6 -week course of induction intravesical BCG in the adjuvant setting within 6 weeks following the baseline staging procedure for the current occurrence of non -muscle invasive bladder cancer. Arm 4: Suitable for monotherapy vaccine administrat ion post -TURBT. For Phase 1 only: Has previously received 3 -6 weekly doses of BCG . 6. Age ≥18 years 7. Lab parameters: Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 29 of 86  Albumin ≥2.5 mg/dL  Total bilirubin <1.5 mg/dL  Alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5 × upper limit of normal (ULN )  Serum creatinine ≤2.2 mg/dL or calculated creatinine clearance > 35 mL/minute per the Cockcroft -Gault formula  White blood cell (WBC) count ≥4,000/mm3 with an absolute neutrophil count ≥1,500/mm3  Hemoglobin ≥9 g/dL  Platelet count ≥ 75,000/mm3 8. Women of childbearing potential or men of fathering potential must use adequate birth control measures (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) during the study and for 6 months after receiving the last administration of study medication. Female patients of childbearing potential must test negative for pregnancy prior to enrolling in the trial. 4.2 Exclusion Criteria Patients that meet any of the following exclusion criteria are no t eligible to be enrolled into the study: 1. Known human immunodeficiency virus (HIV) infection or other immunodeficiency disorders, either primary or acquired 2. Infections or concurrent illness, requiring active therapy 3. Any condition requiring active steroid or other immunosuppressive therapy 4. Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome 5. Prior prostatic pelvic radiation within the p ast 12 months 6. Known history of clinically significant cardiac impairment, congestive heart failure > New York Heart Association (NYHA) cardiac disease classification Class II, unstable angina, or myocardial infarction during the previous three months 7. Known current alcohol or chemical abuse, or mental or psychiatric condition precluding compliance with the protocol 8. Pregnant or nursing 9. Known allergy to soy, egg , or peanut products 10. Receiving another investigational agent (30 day wash -out required prior to firs t dose ) 11. Neo-adjuvant therapy prior to the baseline staging procedure for the current occurrence of non - muscle invasive bladder cancer 12. Prior treatment with a cancer vaccine for this indication Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 30 of 86 13. Prior vaccination with BCG for tuberculosis disease 14. Prior splenectomy 5.0 SAFETY MONITORING 5.1 Data Monitoring Committee A study specif ic Data Monitoring Committee (DM C) will provide dose expansion recommendations during Phase 1 and will continue safety surveillance in Phase 2. A full description of the membership, rol e, and responsibilities of the DM C will be o utlined in a separate charter. 5.1.1 Phase 1 A lead -in phase will enroll three patients in Phase 1 at the low dose of vesigenurtacel -L (1 x 106 cells). Patients will be observed weekly to assess the safety of vesigenu rtacel -L. Dosing of the first three patients will be staggered by two-week intervals to allow for safety evaluation before treating additional patients. The D MC will convene after the third patient has received at least two doses of vesigenurtacel -L and at least one patient has completed the Week 7 safety assessments. If vesigenurtacel -L appears safe and well - tolerated in the 3 lead -in patients, dosing will be continued to 10 patients . The DM C will reconvene when all 10 patient s in Phase 1 have received vesigenurtacel -L and data is available for the Week 7 safety assessments from at least 6 patients . If th is regimen is determined to be safe by the DM C, Phase 2 will commence . 5.1.2 Phase 2 In order to continually monitor safety during the Phase 2 portion, the DMC will review (unblinded) all available safety data after one patient has been randomized to each of the active arms and ha s completed four weeks of treatment and then after 3, 6, and 12 patients in each randomized treatment group have completed the Week 7 assessment. Subsequently the DMC will review all availab le safety data at regular three -monthly intervals until study completion or should they determine that review is no longer necessary. Additionally, the DMC will convene on an ad -hoc basis sho uld any patient experience a Grade 3 or higher adverse event (considered by the investigator to be related to vesigenurtacel -L) at any time during the study. Depending on emerging data, the DMC will have the authority to suspend allocation to a particular study treatment and require that additional patients are studied in a particular arm or at a particular dose level of vesigenurtacel -L, in order to further characterize the safety profile. 5.2 Dose Limiting Toxicities and Stopping Rules 5.2.1 Dose Limiting Toxiciti es Dose limiting toxicities ( DLT) (i.e. toxicities which would prevent an escalation to a higher dose in Phase 2) will be evaluated by the DM C during Phase 1 of the trial. The period for evaluating DLTs will be from the time of administration of the first dose of vesigenurtacel -L until the time that all 10 patients in Phase 1 have received at least one dose of vesigenurtacel -L and at least 6 patients have received 6 doses . A DLT is Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 31 of 86 defined as any anaphylactic reactions, a full -thickness ulceration/necrosis, or any AE ≥ Grade 3 related to study product with the following exceptions:  Local injection site reactions lasting <72 hours including pain, redness, swelling, induration, or pruritus  Systemic reactions lasting <72 hours of fever, my algia, headache, or fatigue Grading of DLTs will be according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Event (CTCAE) v 4.0 3. If one patient in Phase 1 experience s a DLT prior to the dose expansion decision to move to Phas e 2, escalation may still be considered; if more than one patient experiences a DLT , expansion will not occur. 5.2.2 Trial Stopping Rules In the event of a death within 24 hours of vaccination that cannot be clearly attributed to another cause , or ≥3 related SAE s (in any number of patients) at any time after receiving study product during the treatment period, dosing will halt immediately , and the DM C will be consulted. All data will be reviewed prior to any further dosing, and dosing will not co ntinue until the DM C agrees that it is safe to contin ue. At the discretion of the DM C, the Food and Drug Administration (FDA) or other Health Regulatory Agencies may be consulted. 5.3 Emergency Unblinding of Treatment Assignment Investigational product for this study has been packaged and labeled in a blinded fashion. Although the vial labels will be blinded in Phase 1 of the trial, the patient and the study personnel will know the dose the patient is receiving , since the Phase 1 portion of the trial is not blinded. For the Phase 2 portion of the trial, patients in Arms 1 -3 will be randomized to vesigenurtacel -L (high dose or low dose ) or placebo. The patient and site personnel will not know which treatment the patient is receiving. For Arm 4, however, patients and stu dy personnel will know the treatment the patient is receiving. Unblinding a treatment assignment for adverse events should only be performed in situations where knowledge of the treatment assignment is essential for further medical management of the patien t. Unblinding can only be done by the study medical monitor. When unblinding is necessary, the investigator should contact the study medical monitor to discuss. All unblinding events will be recorded and reported by the IWRS. Specific steps for request ing unblinding will be provided in the Study Procedures Manual . 6.0 STUDY PROCEDURES A signed, written informed consent form that is currently approved by an IRB must be obtained from the potential patient before he/she can participate in any study -specific procedures, including screening procedures. Patients will be enrolled (Phase 1 and Arm 4 of Phase 2 ) and randomized (Arms 1 -3 of Phase 2) once all screening procedures have been completed and it is determined that the patient meets all eligibility criteria . The schedule of assessments is distinct for patients receiving low dose vesigenurtacel -L monotherapy in Phase 1 and for patients receiving blinded study product (vesigenurtacel -L or placebo ) in Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 32 of 86 combination with BCG or high dose vesigenurtacel -L monother apy in Phase 2. These two different schedules are outlined below. 6.1 Phase 1 REST OF PAGE LEFT INTENTIONALLY BLANK Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 33 of 86 6.1.1 Phase 1 Schedule of Events 1 Screening evaluations should be completed ≤ 2 weeks of first dose. 2 PE, hematology, chemistry, LDH, dipstick urinalysis and pregnancy test do not need to be repeated at Baseline if they were performed at Screening within three days prior to first dose. 3 First vesigenurtacel -L dose should occur 8 -12 weeks (56 -84 days) following TURBT or fulguration for patients with papillary disease and staging procedure for patients with CIS only regardless of the number of BCG inst illations. 4 Weekly study evaluations should be completed within ±1 day of the target visit date. 5 EOT evaluations should be completed 4 weeks ±3 days after last dose of study vesigenurtacel -L or early discontinuatio n of study treatment. 6 PE at screening and Week 29 (End of Treatment) will have a full examination of body systems and vital signs. Other PE evaluat ions will be limited to symptoms, weight and vital signs. Procedure Screening Baseline Week 13 Weeks 2-64 Week 7 Weeks 8-134 Week 14 Week 17 Week 21 Week 25 Week 29 (EOT)5 Long -term Follow -up Study Day ≤ -4 wks. -3 to 1 1 43 (±1) 92 (±1) 113 (±3) 141 (±3) 169 (±3) 197 (±3) Q3mos. 2 yrs; Q6mos. 3rd yr Baseline Documentation Informed Consent X Verify All Eligibility Criteria X Enrollment X Medical History X1 X Physical Exam6 X X2 X X X Pathology Review X 12-lead ECG X X X X Laboratory Studies Immunologic Response7 X X X X Hematology , Chemistry and LDH , Dipstick Urinalysis X1 X2 X X X X Pregnancy Test (urine or serum) X1 X2 X Autoimmune Labs8 X X X Tumor Assessments Cystoscopy/Cytology for disease recurrence per SOC9 X X X13 Tumor collection for antigen screen X Dosing Vesigenurtacel -L Administration10 X X X X X X Other Clinical Assessments Autoimmune Phenomena11 X X X Adverse Events12 X X X X X X X X X Concomitant Medications X1 X X X X X X X X X X Survival and subsequent therapy X Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 34 of 86 7 70mL of heparinized blood and 10mL of non -heparinized blood will be collected at the indicated visits. 8 ANA, TSH, ESR, C -reactive protein are required .