Section 5.2.1 Version 2.0, Amendment 1 Modify trial stopping rules such that enrollment is stopped and a full safety review is conducted if a death occurs within 24 -hrs of vaccination if it is not clearly attributed to another cause. (Previously was only if it's definitely related). Section 5 .2.2 Version 2.0, Amendment 1 Modify statement that sites will be provided with optical discs as we will only do this upon request Section 10.2 Version 2.0, Amendment 1 Outline definitions of Protocol Deviations that will be collected in the CRF and that need to be reported to the Sponsor Section 12.75 and new section 13.3 Version 2.0, Amendment 1 Add section for definitions of ECG parameters as a listed procedure Between former sections 11.3 and 11.4 - new section becomes Section 11.4 Version 2.0, Amendment 1 Fix formatting of bullet points around relatedness of AEs Former section 11.7.5 - new numbering Section 11.8.5 Version 2.0, Amendment 1 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 76 of 86 Protocol Change Section Affected Version where implemented Add "recovered / resolved" to AE event outcomes Former section 11.7.5 - new numbering Section 11.8.5 Version 2.0, Amendment 1 Change definition of time to recurrence to be relative to the date of randomization rather than the date of dosing Section 12.5.2 Version 2.0, Amendment 1 Remove immune re sponse lab at Screening SOE and Section 6.1 Version 2.0, Amendment 1 Remove requirement in footnote 1 of the SOA that requires screening labs to be done within 2 weeks of dose, since these labs will be redone at BL if the screening labs were taken more than 3 days prior to first dose SOE Version 2.0, Amendment 1 Update Week 7 and schedule of events window should be +/ - 1 Section 6.2.3 Version 2.0, Amendment 1 Modify language from "pulse" to "heart rate" in the section on vital signs to be consistent with the rest of the protocol Section 12.7.3 Version 2.0, Amendment 1 Combine "persistent disease" and "recurrent disease" and "progressive disease" into "evidence of disease" rather than separate categories since we can't tell them apart. Synopsis, sections 3.1, 3.4, 6.2.3 , 7.2.2, 12.2, 12.3, 12.6.3, SOE Version 2.0, Amendment 1 Revise language in "dosing regimen" and "route" section to avoid duplication between the two and include clearer dosing for each cohort. Synopsis Version 2.0, Amendment 1 Add study schema to visually represent the overall design Section 3.1 Version 2.0, Amendment 1 Add Sponsor protocol approval page Front Version 2.0, Amendment 1 Allow tumor curls or slides or fresh frozen tissue instead of FFPE and if necessary Synopsis and Sections 6.2.1, 6.2.3, 6.2.7, 6.3, 10.1.5 Version 2.0, Amendment 1 Clarify that proteomics and recurrence rate comparison to placebo will only be done in the Phase 2 portion Synopsis and Section 2.2 Version 2.0, Amendment 1 Clarify number of patients that will be enrolled Synopsis and Section 3.4 Versio n 2.0, Amendment 1 Clarify that patients who discontinue vaccine at Week 7 due to evidence of disease will continue in long -term follow - up Section 6.2.3 and SOE Version 2.0, Amendment 1 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 77 of 86 Protocol Change Section Affected Version where implemented Switch ordering of Appendix 2 and 3 and update references to each Synopsis, section 4.1, Appendix 2 and 3 Version 2.0, Amendment 1 Correct "possible" to "possibly" in section defining dose limiting toxicities Section 5.2.1 Version 3.0, Amendment 2 Add DLT escalation rules (eg if 1 of 9 patients get DLT we'll escalate, if 2/9 do, we'll stop). Section 5.2.1 Version 3.0, Amendment 2 Remove reference on bottom of page 30 to additional backup sample for immune response timepoint (lingering error from previous version of protocol) Section 6.1 Version 3.0, Amendment 2 Clarify that eye exam involves evaluation for dry eyes Section 11.5 Version 3.0, Amendment 2 Remove risk assessment tool Synopsis, Section 4.1, Section 6.2.1, SOE, Appendix 3, Version 3.0, Amendment 2 Remove requirement that all injections occur with sa me needle. Section 8.3.1 Version 3.0, Amendment 2 Rearrange synopsis content for clarity Synopsis Version 3.0, Amendment 2 Update product description to allow for revised formulation to be implemented without additional protocol amendment Synopsis, Section 8.1 Version 3.0, Amendment 2 Clarify language in dosing administration around injection site rotation Synopsis, Section 8.3.1 Version 3.0, Amendment 2 Note that missed doses will not be made up Section 8.3.1 Version 3.0, Amendment 2 Combine DEC and DSMB into a single entity List of Abbreviations, Synopsis, Section 5.1.2 Version 3.0, Amendment 2 Switch to single blinding (physician - patient) Synopsis, Sections 3.1, 5.3, 6.4 Version 3.0, Amendment 2 Clarify definition of primary endpoint in Phase 1 as an increase of 2 -fold over baseline in IFN -secreting CD8+ T cells Synopsis, Section 3.5.1 Version 3.0, Amendment 2 Switch primary endpoint in Phase 2 from Time to Recurrence to Disease Free Survival to eliminate death as a competing risk and to inclu de disease progression as well as disease recurrence; remove PFS as a secondary endpoint since DFS replaces it Synopsis, Sections 2.1, 2.2, 3.5.1, 3.5.2, Version 3.0, Amendment 2 Replace blood sampling for proteomic analysis with blood banking for future analyses Synopsis, Sections 2.2, 3.5.2, 6.2.1, 6.2.5, 6.2.9, SOE, 12.4.1, 12.4.2, Version 3.0, Amendment 2 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 78 of 86 Protocol Change Section Affected Version where implemented Delete section 12.4 due to duplicity with section 3.5 Sections 12.4, 12.4.1, 12.4.2 Version 3.0, Amendment 2 Clarify that an overage of patients has been included in the sample size and that patients will not be replaced Sections 3.1, 3.4, 7.2.2, 12.2 Version 3.0, Amendment 2 Remove reference to temperature monitoring device due to detailed description in pharmacy manual Section 8.4.3 Version 3.0, Amendment 2 Remove batch number from the label Section 8.4.2 Version 3.0, Amendment 2 Revisions to the statistical sections (analysis populations, sample size justification) etc. Synopsis, Sections 12.X Version 3.0, Amendment 2 Revise the dose escalation process such that the DEC will convene after at least one patient has received 6 vaccine doses and at least three patients have received two doses. Synopsis, Sections 3.1, 5.1.1 Version 3.0, Amendment 2 Extend window of beginn ing of treatment from 8 -10 weeks post -TURBT to 8 -12 week post -TURBT. Synopsis, SOE, Section 3.1 Version 3.0, Amendment 2 Change "enrollment" to "dosing" in description of dose escalation for clarity Synopsis, Section 3.1, 5.2.2 Version 3.0, Amendment 2 Add detail in Appendix 2 to provide additional clarity about staging requirement Appendix 2 Version 3.0, Amendment 2 Remove section 3.3 as duplicative to section 3.1 Section 3.3 Version 3.0, Amendment 2 Change regimen in Phase 1 and Phase 2 Synopsis, Section 3.1 , Section 6.0, Section 8.5 , Section 12.1 Version 4.0, Amendment 3 Define a BCG maintenance schedule Synopsis, Section 3.1 , Section 8.5.1, Section 8.5.2 Version 4.0, Amendment 3 Allow a single post -TURBT instillation of intravesical chemotherapy Section 9.1 Version 4.0, Amendment 3 Analyze recurrence separately from progression Section 10. 1 Version 4.0, Amendment 3 Define persistent disease for patients with CIS Section 10.1 Version 4.0, Amendment 3 Define the dose of BCG Section 8.4, Section 8.5.2 Version 4.0, Amendment 3 Modify window between TURBT and start of treatment Synopsis, Section 3.1 , Section 6.2.1 Version 4.0, Amendment 3 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 79 of 86 Protocol Change Section Affected Version where implemented Require 5 of 6 cycles of induction BCG Section 8.4 Version 4.0, Amendment 3 Changed criteria for CrCl, albumi n, and platelet laboratory parameters Synopsis, Section 4.1 Version 4.0, Amendment 3 Adopt the standard definition of high -risk disease (T1 and/or high grade and/or CIS) Synopsis, Section 4.1, Appendix 1 Version 4.0, Amendment 3 Exclude patients with prior prostatic pelvic radiation within the past 12 months Synopsis, Section 4.2 Version 4.0, Amendment 3 Exclude patients with neo -adjuvant therapy prior to the most recent TURBT Synopsis, Section 4.2 Version 4.0, Amendment 3 Exclu de patients with allergy to peanuts Synopsis, Section 4.2 Version 4.0, Amendment 3 Reduce time window for cardiac exclusion from previous 6 months to 3 months Synopsis, Section 4.2, Appendix 2 Version 4.0, Amendment 3 Move directly to Phase 2 after cohort 1 in Phase 1 Synopsis, Section 3.1, Section 5.1, Section 6.2 Version 4.0, Amendment 3 Take immune response off the decision - tree and advance both doses into Phase 2 Synopsis, Section 3.1, Section 5.1, Section 6.2 Version 4.0, Amendment 3 Keep patients without progression or T1 high-grade disease on trial until 6 months even if evidence of disease Synopsis, Section 3.1, Section 6.1, Section 6.2, Section 10. 1 Version 4.0, Amendment 3 Add endpoints for recurrence at 6, 12, 18, and 24 months ; DFS at 6, 18, and 24 months; overall DFS; repeat TURBT by 12 and 24 months; cystectomy by 12 and 24 months . Add 6-mo CR endpoint Synopsis, Section 3.4.2, Section 12. 5.2 Version 4.0, Amendment 3 Change primary endpoint in Phase 1 to safety and tolerability Synopsis, Section 3.4 .1 Version 4.0, Amendment 3 Change primary endpoint in Phase 2 to 1 - yr DFS Synopsis, Section 3.4 .1, Section 12.5.1 .1 Version 4.0, Amendment 3 Change title Cover page, Sponsor Protocol Approval page, Investigator Protocol Agreement page, Synopsis Version 4.0, Amendment 3 Clarify definition of recurrence events Section 10. 1 Version 4.0, Amendment 3 Allow a subset of intermediate risk patients Synopsis , Section 4.1, Appendix 1 Version 4.0, Amendment 3 Add stratification factors for intermediate vs. high risk and presence of CIS Synopsis, Section 8.5 Version 4.0, Amendment 3 Update introduction Section 1.1, Section 1.2 Version 4.0, Amendment 3 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 80 of 86 Protocol Change Section Affected Version where implemented Update Sponsor address and Medical Monitor Contact Page Version 4.0, Amendment 3 Change sample size Synopsis, Section 3.3 , Section 12. 6 Version 4.0, Amendment 3 Fix typos, abbreviations, punctuation and spacing Throughout Version 4.0, Amendment 3 Add safety objective for Phase 2 Synopsis, 2.2 Secondary Objectives , 12.5.2 Analysis of Secondary Efficacy Parameters Version 5.0, Amendment 4 Allow patients who have had fulguration or no surgery if they have CIS alone Synopsis, 2.2 Secondary Objectives , 3.1 Study Design Overview, 4.1 Inclusion Criteria Version 5.0, Amendment 4 Update Immu ne Response methodology , objectives, and endpoints Synopsis , 2.2 Secondary Objectives, 3.4.2 Secondary Endpoints , 10.2 Immunolgic Response , 12.5.2.9 Immune Response Version 5.0, Amendment 4 Remove blood sample for banking 6.2 Phase 2 Version 5.0, Amendment 4 Increase blood collected for Immunologic Response 6.2.1 Phase 2 Schedule of Events , 10.2 Immunologic Response Version 5.0, Amendment 4 Remove specific dose information for BCG Synopsis, 8.4 Dosage and Administration of BCG Version 5.0, Amendm ent 4 Update sample size assessment assumptions (removed event and censoring times follow an exponential distribution) 12.6.2 Phase 2 Version 5.0, Amendment 4 Add fulguration at 12 and 24 months to secondary and exploratory objectives /endpoints Synopsis , 2.2 Secondary Objectives , 3.4.2 Secondary Endpoints , 12.5.2.7 Proporti on of patients undergoing post - treatment TURBT or fulguration by 12 and 24 months, 12.5.2.10 Exploratory Endpoints Version 5.0, Amendment 4 Change most -recent TURBT procedure to baseline staging procedure Throughout Version 5.0, Amendment 4 Update creatinine clearance requirement Synopsis , 4.1 Inclusion Criteria Version 5.0, Amendment 4 Combine Removal of Patients from Treatment with Discontinuation from Study Treatment Section 7.2.1 Version 5.0, Amendment 4 Indicate preference for tissue sections rather than FFPE 6.1 Phase 1, 6.2 Phase 2 Version 5.0, Amendment 4 Wrote out assessments for Weeks 37 and 49 in Phase 2 6.2.3.10 and 6.2.3.11 Version 5.0, Amendment 4 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 81 of 86 Protocol Change Section Affected Version where implemented Update Figure 2 8.5.1 Schedule and Duration of Treatment Version 5.0, Amendment 4 Remove frequency of liquid nitrogen replacement 8.6.3 Storage Version 5.0, Amendment 4 Update CTCAE version to 4.03 11.0 Safety Assessments Version 5.0, Amendment 4 Allow anti -allergics, antipyretics, and/or analgesics for local and/or systemic injection reactions 9.1 Permitted Medications and Non - Drug Therapies Version 5.0, Amendment 4 Updated discontinuation language so that patients with evidence of disease may continue to receive tre atment if in the patient’s best interest at the investigator’s discretion Synopsis, 3.1 Study Design Overview, 6.1.1 Phase 1 Schedule of Events , 6.1.3.3 Phase 1 Assessments at Week 7, 6.1.3.7 Phase 1 Assessments at Week 21, 6.2.1 Phase 2 Schedule of Events, 6.2.3.5 Phase 2 Assessments at Week 13, 6.2.3.7 Phase 2 Assessments at Week 25, 6.2.3.10 Phase 2 Assessments at Week 37, 6.2.3.11 Phase 2 Assessments at Week 49, 7.2.1 Discontinuatio n from Study Treatment Version 5.0, Amendment 4 Include exploratory analysis to pool both vaccine groups in Phase 2 Synopsis, 12.1 General Statistical Considerations, 12.5.1.1 1 -year Disease - Free Survival Version 5.0, Amendment 4 Increased non -heparinzed blood sample to 10mL 10.2 Immunologic Response Version 5.0, Amendment 4 Removed magnesium laboratory 11.2 Clinical Laboratory Tests Version 5.0, Amendment 4 Added analysis of urine immunology Synopsis, 2.2 Secondary Objectives, 3.4.2 Secondary Endpoints , 6.2.1 Phase 2 Schedule of Events , 6.2.3.1 Phase 2 Baseline Assessments, 6.2.3.3 Phase 2 Assessments at Week 7, 6.2.3.5 Phase 2 Assessments at Week 13, 6.2.3.9 Phase 2 Assessments at Week 28, 6.2.3.13 Phase 2 Week 56 , 10.2 Immunologic Response Version 5.0 , Amendment 4 Exclude patient with any condition requiring active steroid or other immunosuppressive therapy Synopsis, 4.2 Exclusion Criteria Version 5.0, Amendment 4 Exclude patients with prior treatment with a cancer vaccine Synopsis, 4.2 Exclusion Cri teria Version 5.0 Amendment 4 Current serious cardiac arrhythmia no longer exclusionary Synopsis, 4.2 Exclusion Criteria Version 5.0, Amendment 4 Collect information on caffeine consumption 9.1 Permitted Medications and Non - Drug Therapies Version 5.0, Amendment 4 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 82 of 86 Protocol Change Section Affected Version where implemented Allow patients who had a radical prostatectomy with detectable PSA below the definition of biochemical recurrence per the Phoenix criteria and no radiologic evidence of metastatic disease or with PSA doubling time greater than one year and no evidence of metastases with no active therapy Synopsis, 4.2 Exclusion Criteria Version 5.0, Amendment 4 Added Heat Biologics logo Cover page Version 5.0, Amendment 4 Updated HS -410 to vesigenurtacel -L Throughout Version 5.0, Amendment 4 Updated vesigenurtacel -L or placebo to blinded study product Throughout Version 5.0, Amendment 4 Updated Grade 4 adverse event to probably or definitely related to study product 7.2.1 Discontinuation from Study Treatment Version 5.0, Amendment 4 Added new section on discontinuation from study follow -up with text from 7.2.1 7.2.2 Discontinuation from Study Follow -Up Version 5.0, Amendment 4 Added new section on discontinuation from study follow -up with text from 7.2.1 7.2.3 Lost to Follow -Up Version 5.0 , Amendment 4 Changed preparation of vesigenurtacel -L to manufacturing of vesigenurtacel -L 8.1 Description of Investigational Product, Vesigenurtacel -L Version 5.0, Amendment 4 Indicated that site must contact IWRS for assignment of the dose vial at each dosing 8.3 Dosage and Administration of Vesigenurtacel -L and Placebo Version 5.0, Amendment 4 Indicated that vesigenurtacel -L must be stored at ≤ -120C 8.6.3 Storage Version 5.0, Amendment 4 Clarify that no investigational agents allowed during treatme nt but no prohibited medications during follow -up 9.2 Prohibited Medications and Non - Drug Therapies Version 5.0, Amendment 4 Added IBCG and AJCC List of Abbreviations Version 5.0, Amendment 4 Added ISR Grading Scale New Appendix 3 and 11.6 Injection Site Reactions Version 5.0, Amendment 4 Removed reference to Post -Study AEs and SAEs chapter in the study manual 11.7.2 Action to Be Taken if Pregnancy Occurs Version 5.0, Amendment 4 Added definition of safety for Phase 1 12.4.6 Safety of Vesigenurtacel -L (Phase 1 Only) Version 5.0, Amendment 4 Updated definition of safety for Phase 2 and moved from 12.5.2.1 to 12.4.7 12.4.7 Safety of the Combination of Vesigenurtacel -L and BCG (Phase 2 Only) Version 5.0, Amendment 4 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 83 of 86 Protocol Change Section Affected Version where implemented Stated that staging is based on AJCC Appendix 1 Version 5.0, Amendment 4 Updated serum creatinine to 2.2 mg/dL or calculated creatinine clearance > 35 mL/minute per the Cockcroft -Gault formula Synopsis, 4.1 Inclusion Criteria Version 5.0, Amendment 4 Increased total sample size from 84 to 110, the number of patients in Phase 1 from 9 to 10, and the number of patients in Phase 2 from 75 to 100 Synopsis, 3.3 Number of Subjects , 6.4 Blinding and Minimization of Bias Version 6.0 Amendment 5 Added a fourth treatment arm in Phase 2; patients who will not receive BCG will be enrolled in an open -label a rm and receive 12 weeks of high dose vesigenurtacel -L followed by 3 courses of 3 once -weekly vaccine injections 3, 6, and 12 months after beginnin g vaccine therapy Synopsis, 3.0 Trial Design , 5.3 Emergency Unblinding of Treatment Assignment, 6.0 Study Procedures, 8.5 Treatment Assignment Version 6.0 Amendment 5 Updated the statistical analysis given the fourth treatment arm in Phase 2 Synopsis, 12.1 General Statistical Considerations, 12.2 Analysis Populations, 12.4 .6 Safety of Vesigenurtacel -L, 12.4.7 Safety of the Combination of Vesigenurtacel -L and BCG , 12.5 Efficacy Analysis, 12.6 Sample Size Estimations Version 6.0 Amendment 5 Cystoscopy /cytology and long -term follow -up will occur every 3 months for the first 2 years of follow up, then every 6 months for up to a year Synopsis, 3.1 Study Design Overview, 6.1 Phase 1, 6.2 Phase 2 Schedule of Events, 6.3 Long -term Follow -up, 10.1 Evaluation of Disease Version 6.0 Amendment 5 Updated the per protocol population definition 12.2 Analysis Populations Version 6.0 Amendment 5 Updated the exclusion criteria on active malignancies in the past 12 months , added an exclusion for prior vaccination with BCG for tuberculosis , and added an exclusion for prior splenectomy Synopsis, 4.2 Exclusion Criteria Version 6.0 Amendment 5 Increased the number of trial centers from up to 17 to up to 20 Synopsis , 3.3 Number of Subjects Version 6.0 Amendment 5 Added background information on BCG timing, the current BCG shortage, and immunotherapy in the setting of minimal residual disease 1.1 Bladder Cancer Version 6.0 Amendment 5 Included possible synergy between inflammat ion from surgery and vesigenurtacel -L 1.2 Rationale for Vesigenurtacel -L Development Version 6.0 Amendment 5 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 84 of 86 Protocol Change Section Affected Version where implemented Updated Figures 1 and 2 3.1 Study Design Overview, 8.5.1 Schedule and Duration of Treatment Version 6.0 Amendment 5 Allow patients with evidence of disease to continue on treatment longer than the next assessment if judged by the investigator to be in the patient’s best interest Synopsis, 3.0 Trial Design, 6.1 Phase 1 , 6.2 Phase 2 , 10.1 Evaluation of Disease Version 6.0 Amendment 5 Replaced AE wording “possibly, probably or definitely related ” with “related” 5.2.1 Dose Limiting Toxicities, 5.2.2 Trial Stopping Rules, 6.1.1 Phase 1 SOA, 6.2.1 Phase 2 SOA, 11.8 AE and SAE, 11.8.5 Reporting AE Version 6.0 Amendment 5 Due to batch release delays of certain doses of vaccine, the randomization schedule has been revised. Synopsis, 3.0 Trial Design, 5.1 Data Monitoring Committee, 6.4 Blinding and Minimization of Bias, 8.5 Treatment Assignment, 12.2 Analysis Populations, 12.6 Sample Size Estimations Version 7.0 Amendment 6 Added abbreviation of DMSO Synopsis, List of Abbreviations Version 7.0 Amendment 6 No longer specify number of injections or dose per vial of product Synopsis; 3.2 Justification of Study Product Admini stration; 6.1.1 Phase 1 Schedule of Events; 6.2.1 Phase 2 Schedule of Events; 8.1 Description of Investigational Product, Vesigenurtacel - L; 8.3 Dosage and Administration of Vesigenurtacel -L and Placebo Version 7.0 Amendment 6 Removed excipient percentages for placebo 8.2 Description of Placebo Version 7.0 Amendment 6 Removed references to UM -UC-3 cell line; added PC3 cell line 1.2 Rationale for Vesigenurtacel -L Development; 1.3 Description of Investigational Agent Vesigenurtacel -L Version 8.0 Amendment 7 Revised Statistical Analysis methods to match Statistical Analysis Plan 12.0 Statistical Considerations Version 8.0 Amendment 7 Removed direct reference to TCR sequencing vendor 10.2.4 TCR Sequencing Version 8.0 Amendment 7 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 85 of 86 REFERENCES 1 American Cancer Society. Cancer Facts & Figures (2014).