Other tests (e.g. RF, T3, T4, thyroid antibodies) will be performed only as clinically indicated . 9 All patients will have a cystoscopy/cytology performed at Week 7 and at Week 21 . If clinically indicated, a repeat biopsy will be performed. 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 SOC ). Upon discontinuation of study treatment , additional treatment will be at the discretion of the treating physician , and patients will continue in long -term follow -up on the study . 10 Vesigenurtacel -L is administered weekly x 6 weeks to all patients. Patients continuing on trial will receive 6 additional weekly vaccinations then monthly x 3 months . Each dose will be divided into the number of intradermal injections required to reach 1x106 cells per dose with no more than 0.1 mL per injection (approximately 4 -6 injections) . Patients should remain on site for 30 minutes following each vaccination for observation of adverse events. 11 Includes e ye exam for dry eyes , lymph node and joint asses sment , and skin exam for vitiligo and rashes . 12 AEs should be recorded from first dose through four weeks following the last dose of study medication regardless of the causal relationship to the study medication. AEs considered related to study medicati on should be recorded at any time regardless of when they occurred. 13 Cystoscopy/Cytology for disease recurrence per SOC (approximately every 3 months for 2 years then every 6 months for up to a year). Patients who are determined to have evidence of disease will have SOC treatment per the discretion of the investigator and will continue in long -term follow -up on the stud y. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 35 of 86 6.1.2 Phase 1 Screening Procedures The following procedures must be conducted ≤ 4 weeks prior to the first dose of vesigenurtacel -L:  Written informed consent  Verify eligibility criteria  Patient demographics  Pathology Review o Verification of Bladder Cancer Staging at the time of the most recent staging procedure (refer to Appendix 1.) High -risk or intermediate -risk non -muscle invasive disease must be histologically/cytologically confirmed. There will be no central pathology review. In the event that multiple procedures are performed for this occurrence of disease, dates of all procedu res will be captured. o Verification of d ocumentation of cancer sub -type ( transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma or undifferentiated carcinoma)  Physical examination (including weight, vital signs [heart rate, temperature, respir atory rate and blood pressure] )  12-lead electrocardiogram (ECG) The following procedures must be conducted ≤2 weeks prior to the first dose of vesigenurtacel -L:  Medical history , including concomitant medications within 14 days of first dose  Hematology , chemistry with LDH , and dipstick urinalysis  Urine or serum pregnancy test for female patients of childbearing potential 6.1.3 Phase 1 On -Study Procedures Study -related procedures and assessments performed during treatment on study are detailed as follows and in the Schedule of Event s table (see Section 6.1.1 ). 6.1.3.1 Phase 1 Baseline Assessments (Day -3 to Day 1) The following activities may be performed within three days of enrollment or on Day 1 pri or to dosing :  Update of medical history , including concomitant medications  Blood draw for immune monitoring  Physical exam ination (symptoms, weight, vital signs only if screening exam performed more than three days pr ior to first dose)  Hematology , serum chemistry, urinalysis (unless screening labs obtained within three days of first dose)  Urine or serum pregnancy test for female patients of childbearing potential (unless screening labs obtained within three days of first dose)  Autoimmune Labs (ANA, TSH, ESR, and C -reactive protein are required ; RF, T3, T4, and thyroid antibodies if clinically indicated )  Assessment of adult autoimmune system disorders (including: eye exam for dry eyes , lymph node and joint assessment for swelling, and skin exam for vitiligo and rash) Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 36 of 86 Once the patient has met all of the eligibility requirements for the study, the patient will receive the treatme nt assignment from IWRS . Each patient will be considered enrolled in the study a t the time of treatment assignment . 6.1.3.2 Phase 1 Assessments at W eek 1 (Day 1 ) The following procedures will be performed after all the previous baseline procedures have been completed.  Study product administration o Initiate series of weekly vesigenurtacel -L dosing  Monitor patients on site for potential acute reactions for 30 minutes after vesigenurtacel -L administration  Record adverse events  Send at least 4, non -stained, 10 micron sections from most recent staging procedure for evaluation of antigen expression . If slides are not available, f ormalin -fixed paraffin embedded (FFPE) tissue (50 microns) is also acceptable. 6.1.3.3 Phase 1 Assessments at Week 2 (Day 8) through Week 6 (Day 36) The following procedures will be performed at each of the weekly visits for Week 2 (Day 8 ±1) , Week 3 (Day 15±1) , Week 4 (Day 22±1) , Week 5 (Day 29±1), and Week 6 (Day 36±1):  Study product administration o Weekly vesigenurtacel -L dosing  Monitor patients on site for potential acute reactions for 30 minutes after vesigenurtacel -L administ ration  Record adverse events  Record concomitant medications 6.1.3.4 Phase 1 Assessments at Week 7 (Day 43±1) The following procedures will be performed at this visit:  Physical exam ( symptoms, weight and vital signs only)  12-lead ECG  Blood draw for immune monitori ng  Hematology , serum chemistry, urinalysis  Cystoscopy/Cytology and if indicated, a repeat biopsy – per SOC to evaluate for evidence of disease. Note: Patients with evidence of disease may continue on treatment if judged by the investigator to be in the pa tient’s best interest. Patients who discontinue study treatment will continue in long -term follow -up. If biopsy was performed; provide at least 4, non -stained, 10 micron sections for TCR sequencing and analysis of infiltrating T -cells. If slides are not available, FFPE tissue (50 microns) is also acceptable .  Record adverse events  Record concomitant medications Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 37 of 86 6.1.3.5 Phase 1 Assessments at Week 8 (Day 50) through Week 13 (Day 85) The following procedures will be performed at each of the weekly visits for Week 8 (Day 50 ±1), Week 9 (Day 57 ±1), Week 10 (Day 64 ±1), Week 11 (Day 71 ±1), Week 12 (Day 78 ±1), and Week 13 (Day 85 ±1):  Study product administration o Weekly vesigenurtacel -L dosing  Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel -L administration  Record adverse events  Record concomitant medications 6.1.3.6 Phase 1 Assessments at Week 14 (Day 92 ±1) The following procedures will be performed at this visit:  Physical examination ( symptoms, weight, vital signs only)  Blood draw for immune monitoring  12-lead ECG  Hematology , serum chemistry, urinalysis  Autoimmune Labs (ANA, TSH, ESR, and C -reactive protein ; RF, T3, T4, and thyroid antibodies if clinically indicated )  Assessment of adult autoimmune system disorders (including: eye exam for dry eyes , lymph node and joints assessment for swelling, and skin exam for vitiligo and rash)  Record adverse events  Record concomitant medications 6.1.3.7 Phase 1 Assessments at Week 17 (Day 113 ±3) The following procedures will be performed at this visit :  Study product administration o Start series of monthly vesigenurtacel -L dosing  Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel -L administration  Record adverse events  Record concomitant medications 6.1.3.8 Phase 1 Assessments at Week 21 (Day 141 ±3) The following procedures will be performed at this visit:  Cystoscopy/Cytology and if indicated, a repeat biopsy – per SOC to evaluate for recurrent disease . Note: Patients with evidence of disease may continue on treatment if judged by the investigator to be in the patient’s best interest. Patients who discontinue study treatment will continue in long - term follow -up. If biopsy was performed; provide at least 4, non -stained, 10 micron sections for Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 38 of 86 TCR sequencing and analysis of infiltrating T -cells. If slides are not available, FFPE tissue (50 microns) is also acceptable .  Hematology , serum chemistry, urinalysis  Study product administration o Monthly vesigenurtacel -L dosing  Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel -L administration  Record adverse events  Record concomitant medications 6.1.3.9 Phase 1 Assessments at Week 25 (Day 169 ±3) The following procedures will be performed at this visit:  Study product administration o Final monthly vesigenurtacel -L dosing  Monitor patient on site for potential acute reactions for 30 minutes after vesigenurtacel -L administration  Record adverse events  Record concomitant medications 6.1.3.10 Phase 1 Week 29 (Day 197 ±3) – End of Treatment Visit (4 weeks post last dose) The following procedures should be completed approximately four weeks following last dose of vesigenurtacel -L, including patients who discontinue vesigenurtacel -L dosing prematurely.  Physical exam (full examination as well as weight and vital signs)  12-lead ECG  Blood draw for immune monitoring  Hematology , serum chemistry, urinalysis  Urine or serum pregnancy test for female patients of childbearing potential  Autoimmune Labs (ANA, TSH, ES R, and C -reactive protein are required ; RF, T3, T4, and thyroid antibodies if clinically indicated )  Assessment of adult autoimmune system disorders (including: eye exam for dry eyes , lymph node and joint assessment for swelling, and skin exam for vitiligo and rash)  Record concomitant medications  Record adverse events 6.2 Phase 2 Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 39 of 86 6.2.1 Phase 2 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 dose of study product should occur within 6 weeks of baseline staging procedure. 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 product or early discontinuation of study treatment. Procedure Screen Baseline Week 13 Weeks 2-64 Week 7 Week s 8-124 Week 13 Weeks 14-164 Week 25 Week s 26-2716 Week 28 Week 37 Week 49 Weeks 50-5216 Week 56 (EOT)5 Long -term Follow -up Study Day ≤ -4 wks. -3 to 1 1 43 (±1) 85 (±1) 169 (±3) 190 (±3) 253 (±3) 337 (±3) 386 (±3) Q3mos. 2yrs; Q6mos. 3rd yr Baseline Documentation Informed Consent X Verify All Eligibility Criteria X Enrollment/ Randomization X Medical History X1 X Physical Exam6 X X2 X X Pathology Review X 12-lead ECG X X Laboratory Studies Immunologic Response7 X X14 X X14 X Hematology , Chemistry and LDH , Dipstick Urinalysis X1 X2 X X X X X Pregnancy Test (urine or serum) X1 X2 X Autoimmune Labs8 X X Tumor Assessments Cystoscopy/Cytology for disease recurrence per SOC9 X X X X X15 Tumor collection for antigen screen X Dosing Study Product Administration10 X X X X X X X X BCG Administration11 X X X X X X Other Clinical Assessments Autoimmune Phenomena12 X X X Adverse Events13 X X X X X X X X X X X X X Concomitant Medications X1 X X X X 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 40 of 86 6 PE at screening and Week 56 (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. 7 70mL of heparinized blood, 10mL of non -heparinized blood, and 24mL urine will be collected at the indicated visits. 8 ANA, TSH, ESR, C -reactive protein are required . Other tests (e.g. RF, T3, T4, thyroid antibodies) will be performed only as clinically indicated . 9 All patients will have a cystoscopy/cytology performed at Week 13. If clinically indicated, a repeat biopsy will be performed. 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 SOC ). Upon discontinuation of study treatment, additional treatment will be at the discretion of the treating physician , and patients will continue in long -term follow -up on the study. 10 For Arms 1 -4: Patients will receive study product as the number of intradermal injections required to reach the number of cells per dose with no more than 0.1 mL per injection (approximately 4 -6 inject ions) . Patients should remain on site for 30 minutes following each vaccination for observation of adverse events. 11 For Arms 1 -3 only. 12 Includes e ye exam for dry eyes , lymph node and joint assessment and skin exam for vitiligo and rashes . 13 AEs should be recorded from first dose through four weeks following the last dose of study medication regardless of the causal relationship to the study medication. AEs considered related to study medication should be recorded at any time regardless of wh en they occurred. 14 Samples to be collected prior to dosing 15 Cystoscopy/Cytology for disease recurrence per SOC (approximately every 3 months for 2 years then every 6 months for up to a year). Patients who are determined to have evidence of disease wi ll have SOC treatment per the discretion of the investigator and will continue in long -term follow -up on the stud y. 16 Weekly study evaluations should be completed within ±3 days of the target visit date. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 41 of 86 6.2.2 Phase 2 Screening Procedures The following procedures must be conducted ≤ 4 weeks prior to the first dose of study product :  Written informed consent  Verify eligibility criteria  Patient demographics  Pathology Review o Verification of Bladder Cancer Staging at the time of the baseline staging procedure (refer to Appendix 1) High -risk or intermediate -risk non-muscle invasive disease must be histologically/cytologically confirmed. There will be no central pathology review. In the event that multiple diagnostic procedures are performed for this occurrence of disease, dates of all procedures will be captured. o Verification of cancer sub -type ( transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma or undifferentiated carcinoma) o Verification of the date of baseli ne staging procedure (must be within 6 weeks )  Physical examination (including weight, vital signs [heart rate, temperature, respiratory rate and blood pressure] )  12-lead electrocardiogram (ECG) The following procedures must be conducted ≤2 weeks prior to the first dose of study product :  Medical history , including concomitant medications within 14 days of first dose  Hematology , chemistry with LDH , and dipstick urinalysis  Urine or serum pregnancy test for female patients of childbearing potential 6.2.3 Phase 2 On -Study Procedures Study -related procedures and assessments performed during treatment on study are detailed as follows and in the Schedule of Event s table (see Section 6.2.1 ). 6.2.3.1 Phase 2 Baseline Assessments (Day -3 to Day 1) The following activities may be performed within three days of enrollment/ randomization or on Day 1 prior to enrollment/ randomization:  Update of medical history including concomitant medications  Blood and urine collection for immune monitoring  Physical exam ination (symptoms, weight, vital signs only if screening exam performed more than three days prior to first dose)  Hematology , chemistr y with LDH , and dipstick urinalysis (unless screening labs obtained within three days of first dose)  Urine or serum pregnancy test for female patients of childbearing potential (unless screening labs obtained within three days of first dose) Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 42 of 86  Autoimmune Labs (ANA, TSH, ESR, and C -reactive protein are required ; RF, T3, T4, and thyroid antibodies if clinically indicated )  Autoimmune Phenomena – Assessment of adult autoimmune system disorders (including: eye exam for dry eyes , lymph node and joint assessment for swelling, and skin exam for vitiligo and rash) Once the patient has met all of the eligibility requirements for the study, patient s who will receive BCG will be randomized (treatment assigned within IWRS) . Each patient will be considered enrolled in t he study at the time of first dose . 6.2.3.2 Phase 2 Assessments at Week 1 (Day 1) The following procedures will be performed after all the previous baseline procedures have been completed:  Study product administration o Initiate series of weekly study product dosin g (dosing should begin within 6 weeks of baseline staging procedure) o Initiate series of weekly BCG dosing (Arms 1 -3 only) o Monitor patient on site for potential acute reactions for 30 minutes after study product administration  Record adverse events  Record concomitant medications  Send at least 4, non -stained, 10 micron sections from baseline staging procedure for evaluation of antigen expression . If slides are not available, formalin -fixed , paraffin -embedded (FFPE ) tissue (50 microns) is also acceptable . 6.2.3.3 Phase 2 Assessments at Week 2 (Day 8) through Week 6 (Day 36) The following procedures will be performed at each of the weekly visits for Week 2 (Day 8 ±1) , Week 3 (Day 15±1) , Week 4 (Day 22±1) , Week 5 (Day 29±1), and Week 6 (Day 36±1):  Study product administration o Weekly study product dosing o Weekly BCG dosing (Arms 1 -3 only) o Monitor patient on site for potential acute reactions for 30 minutes after study product administration  Record adverse events  Record concomitant medications 6.2.3.4 Phase 2 Assessments at Week 7 (Day 43±1) The following procedures will be performed at this visit:  Blood and urine collection for immune monitoring collected prior to dosing  Study product administration o Weekly study product dosing Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 43 of 86 o Monitor patient on site for potential acute reactions for 30 minutes after study product administration  Record adverse events  Record concomitant medications 6.2.3.5 Phase 2 Assessments at Week 8 (Day 50) through Week 12 (Day 78 ) The following procedures will be performed at each of the weekly visits for Week 8 (Day 50 ±1), Week 9 (Day 57 ±1), Week 10 (Day 64 ±1), Week 11 (Day 71 ±1), and Week 12 (Day 78 ±1):  Study product administration o Weekly study product dosing o Monitor patient on site for potential acute reactions for 30 minutes after study product administration  Record adverse events  Record concomitant medications 6.2.3.6 Phase 2 Assessments at Week 13 (Day 85 ±1) The following procedures will be performed at this visit:  Physical exam ( symptoms, weight and vital signs only)  Blood and urine collection for immune monitoring  Hematology , chemistry with LDH , and dipstick urinalysis  Cystoscopy/Cytology and , if indicated, a repeat biopsy – per SOC to evaluate for evidence of disease. Note: Patients with evidence of disease may continue on treatment if judge d by the investigator to be in the patient’s best interest. Patients who discontinue study treatment will continue in long -term follow -up. If biopsy was performed , provide at least 4, non -stained, 10 micron sections for TCR sequencing and analysis of inf iltrating T -cells. If slides are not available, FFPE tissue (50 microns) is also acceptable .  Autoimmune Phenomena – Assessment of adult autoimmune system disorders (including: eye exam for dry eyes , lymph node and joints assessment for swelling, and skin exam for vitiligo and rash)  Record adverse events  Record concomitant medications 6.2.3.7 Phase 2 Assessments at Week 1 4 (Day 9 2) through Week 16 (Day 106) The following procedures will be performed at each of the weekly visits for Week 14 (Day 92 ±1), Week 15 (Day 99 ±1), and Week 16 (Day 106 ±1):  Study product administration o Weekly study product dosing o Weekly BCG dosing (Arms 1 -3 only) o Monitor patient on site for potential acute reactions for 30 minutes after study product administration Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 44 of 86  Record adv erse events  Record concomitant medications 6.2.3.8 Phase 2 Assessments at Week 25 (Day 169 ) The following procedures will be performed at the visit for Week 25 (Day169 ±3):  Hematology , chemistry with LDH , and dipstick urinalysis  Cystoscopy/Cytology and , if indicated, a repeat biopsy – per SOC to evaluate for recurrent disease . Note: Patients with evidence of disease may continue on treatment if judged by the investigator to be in the patient’s best interest. Patients who discontinue study treatment will continue in long -term follow -up. If biopsy was performed , provide at least 4, non -stained, 10 micron sections for TCR sequencing and analysis of infiltrating T -cells. If slides are not available, FFPE tissue (50 microns) is also acceptable .  Record adverse events  Record concomitant medications 6.2.3.9 Phase 2 Assessments at Week 26 (Day 176 ) and Week 27 (Day 183) The following procedures will be performed at each of the weekly visits for Week 26 (Day 176 ±3) and Week 27 (Day 183 ±3):  Study product administration o Weekly study product dosing o Weekly BCG dosing (Arms 1 -3 only) o Monitor patient on site for potential acute reactions for 30 minutes after study product administration  Record adverse events  Record concomitant medications 6.2.3.10 Phase 2 Assessments at Week 28 (Day 190±3) The following procedures will be performed at this visit:  Blood and urine collection for immune monitoring collected prior to dosing  Study product administration o Weekly study product dosing o Weekly BCG dosing (Arms 1 -3 only) o Monitor patient on site for potential acute reactions for 30 minutes after study product administration  Record adverse events  Record concomitant medications Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 45 of 86 6.2.3.11 Phase 2 Assessments at Week 37 (Day 253) The following procedures will be performed at the visit f or Week 37 (Day 253±3):  Hematology , chemistry with LDH , and dipstick urinalysis  Cystoscopy/Cytology and , if indicated, a repeat biopsy – per SOC to evaluate for recurrent disease. Note: Patients with evidence of disease may continue on treatment if judged by the investigator to be in the patient’s best interest. Patients who discontinue study treatment will continue in long -term follow -up. If biopsy was performed , provide at least 4, non -stained , 10 micron sections for TCR sequencing and analysis of infiltrating T -cells. If slides or curls or fresh frozen specimens are not available, FFPE tissue (50 microns) is also acceptable .  Record adverse events  Record concomitant medications 6.2.3.12 Phase 2 Assessm ents at Week 49 (Day 337) The following procedures will be performed at the visit for Week 49 (Day 337±3 ):  Hematology , chemistry with LDH , and dipstick urinalysis  Cystoscopy/Cytology and , if indicated, a repeat biopsy – per SOC to evaluate for recurrent disease. Note: Patients with evidence of disease may continue on treatment if judged by the investigator to be in the patient’s best interest. Patients who discontinue study treatment will continue in long -term follow -up. If biopsy was performed , provide at least 4, non -stained, 10 micron sections for TCR sequencing and analysis of infiltrating T -cells. If slides or curls or fresh frozen specimens are not available, FFPE tissue (50 microns) is also acceptable .  Record adverse events  Record concomitant medica tions 6.2.3.13 Phase 2 Assessments at Week 50 (Day 344) through Week 52 (Day 358) The following procedures will be performed at each of the weekly visits for Week 50 (Day 344 ±3), Week 51 (Day 351 ±3), and Week 52 (Day 358 ±3):  Study product administration o Weekly study product dosing o Weekly BCG dosing (Arms 1 -3 only) o Monitor patient on site for potential acute reactions for 30 minutes after study product administration  Record adverse events  Record concomitant medications 6.2.3.14 Phase 2 Week 56 (Day 386 ±3) – End of Treat ment Visit (4 weeks post last dose) The following procedures should be completed approximately four weeks following last dose of study product including patients who discontinue study product dosing prematurely.  Physical exam (full examination as well as weight and vital signs)  12-lead ECG Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 46 of 86  Blood and urine collection for immune monitoring  Hematology , chemistry with LDH , and dipstick urinalysis  Urine or serum pregnancy test for female patients of childbearing potential  Autoimmune Labs (ANA, TSH, ESR, and C-reactive protein are required ; RF, T3, T4, and thyroid antibodies if clinically indicated )  Autoimmune Phenomena – Assessment of adult autoimmune system disorders (including: eye exam for dry eyes , lymph node and joint assessment for swelling, and skin ex am for vitiligo and rash)  Record concomitant medications  Record adverse events 6.3 Long -term Follow -up Visits All patients wil l be followed for the procedures listed below every 3 months from the date of the previous visit for 2 years then every 6 months from the date of the previous visit for a year or until study termination, whichever occurs first:  Survival  New anticancer treatments initiated after disease recurrence  TURBT or fulguration procedures  Cystectomy In addition p atients who have comple ted all study treatment s or have discontinued study product dosing due to reason other than disease recurrence /progression will have the following procedures performed at each long -term follow -up visit:  Cystoscopy /Cytology ; biopsy if area suspicious for disease recurrence is identified at discretion of investigator ( Note: patients who have a biopsy performed will provide at least 4, non -stained, 10 micron sections for TCR sequencing and analysis of infiltrat ing T -cells. ) If slides are not available, FFPE tissue (50 microns) is also acceptable . If a patient has recurrent/progressive disease and discontinues study treatment , the above disease assessment procedures will be discontinued, and subsequent long -term follow -up visits may be conducted via phone vi sit. 6.4 Blinding and Minimization of Bias The Phase 1 portion of the trial will be open label. Ten patients will be enrolled in a single cohort that will receive low dose vesigenurtacel -L vaccine (1 x 106 cells) monotherapy. If well -tolerated, the low dose as well as a higher dose (1 x 107 cells) will be advanced to Phase 2. The Phase 2 portion of the trial will have three blinded (physician -patient) , placebo -controlled arms and one open label arm . The placebo has been formulated with a n intralipid suspen sion to visually resemble the vesigenurtacel -L vaccine. Seventy -five patients who will receive BCG will be randomized to low dose vesigenurtacel -L in combination with BCG, high dose vesigenurtacel -L in combination with BCG, or Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 47 of 86 placebo in combination with BCG ; 25 patients who will not receive BCG will be enrolled i n an arm that will receive high dose vesigenurtacel -L vaccine monotherapy . Blinding in Phase 2 was indicated in order to be able to better facilitate ongoing evaluation of safety. 7.0 SUBJECT COMPLETI ON AND WITHDRAWAL 7.1 Subject Completion Patients may continue to receive study treatment until they complete the dosing phase of the study or meet the criteria for treatment discontinuation described in Section 7.2.1 . 7.2 Subject Withdrawal from Study In accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines, a patient has the right to withdraw from the study at any time for any reason without prejudice to his/her future medical care by the physician or a t the institution. The investigator and sponsor also have the right to withdraw patients from the study treatment, as describe d below or for safety, behavioral , or administrative reasons. 7.2.1 Discontinuation from Study Treatment Every effort must be made by study personnel to keep patients on study treatment . However, a patient will be discontinued prior to completion of the study treatment for any of the following reasons:  Grade 4 adverse event related to study product (or Grade 3 adverse event at the Princ ipal Investigator’s discretion ).  Suspected Unexpected Adverse Drug Reaction , which requires patient unblinding  Grade 3 or greater allergic reaction or autoimmune reaction  Progressive disease  Pregnancy  Termination of the study by Heat Biologics  Concurrent illness that prevents further administration of treatment Patients may also be discontinued prior to completion of the study treatment for any of the following reasons:  Recurrent disease (Patients with recurrent disease at an assessment may continue on treatment if judged by the investigator to be in the patient’s best interest.)  Significant deviation from protocol on the part of the patient (includes lack of compliance)  Significant protocol violation on the part of the investigator The explanation of why the patient is discontinuing study treatment should be documented in the ECRF . If the patient discontinues study treatment due to toxicity, “Adverse Event” will be recorded as the primary reason for withdrawal. If a patient is prem aturely discontinued from the study at any time due to an AE or Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 48 of 86 SAE, the patient must be followed until resolution to Grade 2 or less, unless it is unlikely to improve because of underlying disease . 7.2.2 Discontinuation from Study Follow -Up If a patient prematu rely discontinues study treatment for any reason, the patient will continue to be followed for study endpoints, unless consent for this is specifically withdrawn. If the patient withdraws consent for continued follow up, the investigator must make every e ffort to perform the EOT assessments four weeks following the last dose of study product , even if the patient has initiated other anticancer treatment . 7.2.3 Lost to Follow -Up If a patient fails to return for the necessary visits or discontinues prematurely from treatment, a genuine effort should be made to determine the reason why. For a patient lost to follow -up there should be at least two documented attempts to contact the patient . 7.2.4 Replacement of Subjects Patients will not be replaced. A 10% overage of patients has been included in the sample size to allow for patients who discontinue for reasons other than evidence of disease or toxicity or who are missing data. 8.0 INVESTIGATIONAL PRODUCT All production, formulation, and packaging of the investigational ag ent will be in accordance with applicable current Good Manufacturing Practice (cGMP) and meet applicable criteria for use in humans. 8.1 Description of Investigational Product, Vesigenurtacel -L Vesigenurtacel -L is a cell line derived from a human cancer cell line, designated as PC3 . The cell line was transfected with the plasmid cDNA ‘B45 -neo-gp96Ig -HLA A1’. Vesigenurtacel -L has been irradiated to render cells replication incompetent while maintaining biological activity; i.e., expression of certain proteins. Manufacturing of vesigenurtacel -L includes expansion of batches of cells with testing for presence of expression of HLA -A1 by fluorescen ce-activated cell sorter and gp96 -Ig by enzyme -linked immunosorbent assay (ELISA). Cells are harvested, washed, resusp ended in buffer, and irradiated at 12,000 rad. The vesigenurtacel -L vaccine to be injected will contain irradiated cells expressing HLA -A1 on at least 70% of the cells and produce ≥60ng gp96 -Ig/24h x 1 million cells; the cells will have ≥70% viability by trypan blue exclusion. Vesigenurtacel -L is provided as frozen, single -dose vials either 1) as concentrated frozen liquid, which will require dilution by the pharmacist with sterile saline , or 2) as fully -diluted frozen liquid not requiring additional dilution. In either case the final drug product will consist of cells resuspended in buffered saline containing human serum albumin (HSA) , dimethyl sulfoxide ( DMSO ), and pentastarch and will be delivered at doses of either 1 x 106 cells or 1 x 107 cells. Overfill is factored into each vial to allow extraction of the full dose for patient administration. Refer to the Pharmacy Manual for instructions for preparation and labeling. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 49 of 86 8.2 Description of Placebo A challenge for cell -based immunotherapy is the devel opment of a placebo control that is safe for use in patients and which mimics the appearance and biophysical properties of intact cells in solution. Toward this end, we will utilize a diluted suspension of Intralipid (Baxter), which is FDA approved for us e in humans. This Intralipid solution will be diluted to a final concentration of 0.15% in a buffered saline solution also containing HSA , DMSO , and pentastarch , but lacking vesigenurtacel -L cells. This solution closely resembles the appearance and viscos ity of the vesigenurtacel -L vials used in the experimental arms of the study. Intralipid solution is contraindicated in patients with a soy, egg, or peanut allergy. 8.3 Dosage and Administration of Vesigenurtacel -L and Placebo At each dosing visit for Phase 2 , the site must contact the IWRS for assignment of the dose vial. Study product will be administered intradermally . Each dose will be divided into the number of injections required to reach the number of cells per dose with no more than 0.1 mL per injection (approximately 4 -6 injections), and administered as spatially divided intradermal injections separated by approximately 4-5 cm in the same extremity to increase volume distribution and enhance antigen presentation to lymph node regions shared wit h the urinary bladder . Dosing will rotate injection site extremities every four timepoints: antero -lateral left thigh, antero -lateral right thigh , left buttock , and right buttock . Injection sites will be recorded and retained in the patient records. If injection site reactions are reported as an AE, an alternative injection site may be used upon discussion with the sponsor . Missed doses may be made up depending on the timing of the dosing, after discussion with the sponsor . 8.4 Dosage and Administration of BCG (Phase 2) A full dose of BCG according to the investigator’s standard practice should be administered intravesically , unless dose reductions are deemed appropriate by the investigator to manage toxicity . The induction phase consists of 6 weekly doses, and the maintenance phase includes three once -weekly doses at 3, 6, and 12 months since the start of induction BCG . Patients who receive 5 of 6 induction doses may continue to receive study product and maintenance BCG. Additio nal information can be f ound in the package insert s: (http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProd ucts/ApprovedProdu cts/UCM310364.pdf and http://www.merck.com/product/usa/pi_circulars/t/tice_bcg/ticebcg_pi.pdf ). Dose reductions will follow those as defined in Secti on 8.5.2. 8.5 Treatment Assignment The definitions of the randomized arms relative to the intended intervention to be used in those arms will be as follows: Phase 1: Vesigenurtacel -L Low Dose: 1 x106 cells per dose Phase 2:  Arm 1: Vesigenurtacel -L consisting of 1 x 106 cells per dose + BCG Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 50 of 86  Arm 2: Vesigenurtacel -L consisting of 1 x 107 cells per dose + BCG  Arm 3: Placebo (containing intralipid for blinding, but no cells) + BCG  Arm 4: Vesigenurtacel -L consisting of 1 x 107 cells per dose In Phase 2, patients who w ill receive BCG will be randomized centrally to Arm 1, 2, or 3 using a stratified block design according to risk of recurrence (strata: high vs. intermediate risk ) and CIS (strata: yes vs. no). Patients who will not receive BCG will be enrolled in Arm 4. 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. Dur ing 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. 8.5.1 Schedule and Duration of Treatment The dose administration will fol low the regi men outlined in Figure 2 below. Figure 2. Dosing Schedule In Phase 1, each patient will receive intradermal injections of vesigenurtacel -L weekly for 12 doses (doses administered on Weeks 1 -6 with a vaccine holiday on Week 7 to allow for disease assessment, followed by Weeks 8 -13), then monthly for 3 doses for up to a total of 15 doses, unless the criteria for treatment discontinuation are met. Vesigenurtacel -L should be administered within the allowable windows of the Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 51 of 86 scheduled dose. In Phase 2, each patient in Arms 1 -3 will receive weekly intradermal injections of blinded study product in combination with intravesical induction BCG for 6 weeks followed by 6 weeks of blinded study product monotherapy with a vaccine holiday on Week 13 to allow for disease assessment , followed by three courses of three once -weekly injections in combination with intravesical maintenance BCG for a total of 21 doses , unless the criteria for treatment discontinuation are met . Patients in Arm 4 will receive weekly intradermal injections of vesigenurta cel-L for 12 doses , followed by three courses of three once -weekly injections for a total of 21 doses, unless the criteria for treatment discontinuation are met. 8.5.2 Dose Modifications Dose modifications of vesigenur tacel -L will not be permitted during the trial. BCG should be given at full strength with dose reductions as needed for management of toxicity according to the investigator’s standard of care . 8.6 Study Product Handling and Accountability 8.6.1 Preparation Vesigenurtacel -L and placebo must be thawed and labeled prior to injection. In addition, certain batches will require dilution with sterile saline. Preparation of the product and labeling procedures will be described in the Pharmacy Manual. 8.6.2 Labeling Study product will be labeled with the product name /placebo , the vial number, storage conditions , and other local regulatory requirements. 8.6.3 Storage Vesigenurtacel -L and placebo must be stored at ≤ -120C in the vapor phase of a liquid nitrogen dewar . If liquid nitrogen storage is not available at the investigative site, a unit will be supplied by the study sponsor. The sponsor will also arrange for replacement of the liquid nitrogen at regular intervals to ensure that the proper storage temperature is maintained throughout the study. 8.6.4 Product Accountability The investigator or designee (where applicable) will be responsible for study product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements , the investigator or designated site staff (e.g., investigational drug pharmacist) must maintain current investigational product accountability records throughout the course of the study. These records will contain the following information:  Patient Study ID number  Date, quantity, and vial number of agent received, dispensed , administered , lost, and destroyed  Documentation of storage conditions These inventories must be made available for inspection by the study monitor. The investigator will be responsible for ensuring that all used and unused trial supplies are accounted for. At the end of the trial the Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 52 of 86 study monitor will also collect the investigational agent dispensing record. A copy of the dispensing record should be kept at the site and maint ained with the study records. 8.7 Treatment of Investigational Product Overdose As this is the first patient trial with vesigenurtacel -L, there have been no cases of overdose. Treatment of any suspected or confirmed overdose with vesigenurtacel -L should be s ymptomatic , and supportive care is recommended in cases where overdose is suspected. As described in the Investigator’s Brochure for vesigenurtacel -L, Heat Biologics does not recommend specific treatment for overdose or toxicity; however, the investigator should use appropriate clinical judgment in treating the overdose. For the purposes of this study, an overdose of vesigenurtacel -L is defined as any dose 50% greater than the intended dose for that patient. Appropriate supportive care measures would nee d to be provided to address these potential toxicities in the event of an overdose. 8.8 Occupational Safety Precautions should be taken to avoid direct contact with the investigational product. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling precautions will be available to the investigator. 9.0 CONCOMITANT MEDICATIONS AND NON -DRUG THERAPIES 9.1 Permitted Medications and Non -Drug Therapies A single dose of mitomycin C or other standard intravesical treatment administer ed immediately post - TURBT (for the current occurrence of non -muscle invasive bladder cancer) is permitted according to the investigative center’s standard practice. Maintenance BCG per the institution’s standard of care may be administered to patients in P hase 1 at any time. Additional courses of maintenance BCG may be administered to patients in Phase 2 after the completion of study treatment per the protocol. All concomitant medications , including prescription and over -the-counter medications , taken duri ng the 14 days before the date of first dose, during the study treatment, and through 4 weeks post the last dose of study product will be documented. Any concomitant medication(s), including herbal or vitamin preparations, taken during the study will be r ecorded in the ECRF. At a minimum, the drug name, dose, and the dates of administration will be recorded. Caffeine consumption will also be collected. Local and/or systemic injection reactions may be treated with anti -allergics, antipyretic s, and/or anal gesics in accordance with standard local practice and investigator’s clinical judgment. Pre-treatment of the vaccine injection site with anesthetic cream is allowed only after the Week 1 vaccine administration has been performed without it and injection pa in has been documented as an AE. Repeat TURBT or fulguration procedures will be permitted only in the setting of persistent, recurrent, or progressive disease according to an investigator’s standard practice. 9.2 Prohibited Medications and Non -Drug Therapies Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 53 of 86 Prohibited concomitant medications include chronic use of systemic corticosteroids or other immunosuppressant medications. Topical and inhalation steroids will be permitted. No concomitant chemotherapy , immunotherapy (other than BCG according to the protocol schedule ), immunosuppressive or other anti -cancer therapy will be permitted prior to progression/ recurrence or study withdrawal for other reasons . Administration of other concomitant investigational agents for any indication, other than the vesigenurtacel -L vaccine , is not permitted in the treatment phase of this study and for 30 days prior to first dose. During long-term follow -up there are no prohibited medications, and patients may enroll in any investigational study for which they are elig ible. 9.3 Supportive Care Patients should receive full supportive care during the study, including transfusions of blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, and other care as deemed appropriate, and in accordance with their institutional guidelines. Please see Section 9.2 for prohibited medications. 10.0 ASSESSMENT OF EFFICACY 10.1 Evaluation of Disease Monitoring for disease status via cystoscopy, cytology, and biopsy if indicated, will be conducted every 3 months during treatment and follow up for 2 years then every 6 months for up to a year per SOC . Disease - free status is defined as no evidence of disease, which in turn is defined as negative cytology, negative cystoscopy, and negative biopsy if cl inically indicated. Recurrence is defined as disease that has recurred to the same extent of disease (i.e. same stage/severity) or to a lower stage/severity of disease compared to screening . Persistent disease is defined as evidence of CIS disease by 6 mo nths for patients with CIS at screening . Progression is defined as an increase in T stage from CIS or Ta (at screening) to T1 (lamina propria invasion), development of T2 or greater or lym ph node (N +) disease or distant metastasis (M1), or an increase in g rade from low to high per the IBCG recommendations . The stage of disease at the time of recurrence or progression will be captured to distinguish between recurrence to the same extent of disease as at screening (i.e. the same stage/severity) versus recurre nce to a lower stage/severity of disease at screening versus persistent disease for CIS versus progression. The date of confirmation of recurrence or progression is defined as the earliest date on which the diagnosis had been made based on the findings of cystoscopy, urinary cytology , or some other diagnostic imaging technique regardless of whether the patient continues treatment . For the purpose of clarity, in the situation where a patient with CIS documented at screening has evidence of CIS at the 3 -mont h assessment, continues treatment, and still has evidence of CIS at 6 months, that patient will be assumed to have persistent disease from the date of randomization. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 54 of 86 For i ntermediate -risk patients (i.e. without CIS) who have evidence of disease at the 3 -month assessment, continue treatment, and still ha ve evidence of disease at 6 months, the date of recurrence would be the date of the 3 -month assessment. If requested, the cystoscopy and cytology reports and images may be appended to the ECRF with all patien t identifier information removed and the study site and patient study number written on the report, which is to be signed and dated by the investigator. 10.2 Immunologic Response Peripheral blood samples and urine specimens will be obtained at time points according to the Schedule of Events . All samples will be shipped to and processed by one or more central laborator ies. Seventy (70) mL heparinized blood and 10 mL of non -heparinized blood will be drawn at each time point and used for analysis as ou tlined below. Peripheral blood mononuclear cells (PBMC s) will be isolated from heparinized blood samples by Ficoll separation. Isolated PBMC s will be utilized for immunophenotyping analysis using flow cytometry , DNA isolation and subsequent T cell recept or sequencing, intracellular cytokine analysis, and ELISPOT assays as described below. Serum will be collected from non -heparinized blood samples and stored for batch analysis of antibody titers and serum cytokines/chemokines . Twenty -four (24) mL of urine will be collected at each time point. Part of each sample will be centrifuged and cell counts determined. If there are sufficient numbers of cells , samples may be analyzed by multicolor flow cytometry using standard procedures to examine lymphocyte subs ets. The remainder of each sample will be frozen for batch analysis of inflammatory cytokines. In addition to the analyses specified below, subsequent exploratory mechanistic analyses, the nature of which will be determined by emerging PBMC and tumor biop sy data on the immunological environment pre- and post -vaccine, may also be performed. 10.2.1 Production of Interferon -gamma from CD8+ T Cells (ICS Assay) The immune response will be evaluated by antigen -specific flow cytometry and/or ELISPOT analysis for IFNγ production by patient T cells. These ICS assays will be done under Good Laboratory Practice (GLP) - like conditions using standard operating procedures and validating assays with standardized negative and positive controls. Processing of all patient samp les by a single facility in large batches will be performed to minimize assay variability between samples. Thawed and i solated PBMCs will be challenged or restimulated with specific tumor vaccine antigens as follows:  PBMCs alone (negative control)  PBMCs + PMA + Ionomycin (positive control)  PBMCs + vesigenurtacel -L whole cell lysates (vaccine)  PBMC + a cocktail of known shared antigens, including survivin, LAGE -1s, MAGE -A1, and MAGE -A3 A maximum of four stimulation conditions at each time point per blood sam ple will be set up . Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 55 of 86 For the flow cytometry assay , following in vitro stimulation, cells will be harvested and labeled with antibodies to cell surface markers, including CD4 and CD8, and then fixed , permeabilized , and stained for the indicated intracellula r markers, including IFNγ and gzB. Samples will be analyzed by flow cytometry immediately after staining. For the ELISPOT assay, the frozen PBMCs will be thawed, antigen challenged, plated for analysis of IFN and gzB production by ELISPOT assay , and analyzed in triplicate for each time point for each patient. If cells are limiting, IFNγ analysis will be prioritized. Following incubation, samples will be quantitated in an automated ELISPOT reader. The frequency of IFN  producing CD8 + cells is th ought to mirror the frequency of cytotoxic CD8 + cells. However , cytotoxicity is primarily mediated by perforin and granzymes following granule exocytosis. In some instances IFN γ secretion and granule exocytosis are uncoupled. Therefore , the direct measur ement of gzB secretion by ICS may provide a more direct readout for antigen -specific granule exocytosis and cytotoxicity. For clinical efficiency it may be important to detect both IFN  secretion and gzB exocytosis. Antigen specificity of the ICS respons e will be evaluable by comparing responses generated using the various stimulator cell populations and specific shared bladder cancer antigens as indicated. This will also enable separation of the ‘allo -antigen’ specific response with the potential parent cell line tumor -antigen - specific response. Positive responses will be defined as a greater than two -fold increase in the number of IFNγ positive CD8+ T cells compared to baseline . 10.2.2 PBMC Counts Total PBMC counts will be obtained from each patient from two sources. First, blood hematology will be performed for each patient at Baseline and the treatment weeks indicated in the Schedule of Events at the clinical centers. Second, the peripheral blood phenotyping analysis (described below) will be performed quantitatively for each of the markers indicated, providing a secondary measure of PBMC subsets defined by expression of the individual markers indicated. Total PBMC counts may be utilized as a surro gate endpoint for the overall health of a patient’s immune system. 10.2.3 Phenotyping of Blood Lymphocyte Subsets Following alkaline lysis of red blood cells using standard procedures, peripheral blood samples will be stained using antibodies specific for the fo llowing cell markers: CD3, CD4, CD8, CD 19, CD25, CD45, CD56 , and FoxP3 . Samples will be analyzed by multicolor flow cytometry using standard procedures. Flow cytometric analysis of patient peripheral blood samples will quantitatively determine the frequency and number of lymphocytes (CD45+), B cells (CD45+CD3 -CD19+), helper T cells (CD45+CD3+CD4+), cytotoxic T cells (CD45+CD3+CD8+), regulatory T cells (CD3+CD4+CD25+FoxP3+), and natural killer cells (CD45+CD56+) at baseline and over the course of the rapy. In addition a T cell activation panel (CD4, CD8, Ki67, perforin, IFNγ) will be performed before and after in vitro stimulation with PMA/ionomycin, a regulatory T cell panel (CD4, CD25, FoxP3, CD127, CD45 -RA), a myeloid suppressor cell panel (CD39, CD11b, CD124, CD45, HLA -DR, CXCR4), and T cell suppression panel (CD4, CD8, CTLA -4, PD -1, Tim-3) will be performed on freshly isolated PBMC. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 56 of 86 10.2.4 TCR Sequencing ELISPOT and intracellular cytokine assays are frequently used to monitor patient immune response to immunotherapy, despite the knowledge that th ese assay s have not previously been strongly predictive of clinical response. Thus, prognostic immune monitoring assays are highly desired. If T cell receptor ( TCR ) clones are present that recognize antigens int roduced by vesigenurtacel -L, clonal expansion of these cells is indicative of effective vaccination and potentially predictive for the presence of patient -tumor antigen specific T cells. TCR genomic DNA extracted from tumor tissue and PBMCs will be amplifi ed and sequenced . The Phase 2 study is designed to explore the feasibility of application of this approach to later phase studies. In addition, data generated using this approach during Phase 2 may later be compiled with a larger data set to investigate the prognostic significance of individual TCR sequences before and during treatment with vesigenurtacel -L. Although this assay is potentially predictive of a clinical response, it remains an expl oratory endpoint in this trial because this analysis can only be confirmed once expansion of individual T cell clones is found to correlate (or not) with improved patient survival. Thus, the TCR sequencing data will be analyzed both before the survival da ta has matured in order to ascertain whether there are conserved sequences expanded for patients with similar HLA types but also to determine whether a clonal TCR signature emerges that has the potential to be used as a predictive biomarker for response in subsequent trials. 10.2.5 Analysis of Infiltrating T Cells (Post -Treatment Tumor Biopsy) If a biopsy is performed at any time post -treatment , the tissue will also be examined for presence of infiltrating T -cells (TILs). Two-color fluorescence immunohistochemist ry (IHC) and multicolor fluorescence -activated cell sorting analysis will be used for quantification of CD8 + T cells and measurement of their activation status (CD69 -expression) and cytotoxic activity (CD107a -expression) in situ. These data will be correl ated with clinical response. 10.2.6 Antigen Screening of Resected Tumor Tissue A sample containing at least 4, non -stained, 10 micron sections will be collected for the purpose of screening the tissue for representative antigen expression (LAGE -1, NY -ESO -1, MAGE -[A1-10], CT7, CT10, GAGE, etc.), expression of MHC class I, and expression of immunosuppressive molecules, including, for example, CTLA -4, PD -L1 and PD -1, by mRNA expression and/or IHC analysis . If slides are not available, FFPE tissue (50 microns) is also acceptable . These data will be retrospectively correlated with immune response to determine if a particular antigen expression profile may predict response to treatment. The tumor arrays will be processed by IHC and PCR according to standard method s. Bound antibodies will be visualized by using the avidin -biotin complex method according to the recommendations of the supplier (Vectastatin Elite ABC Kit; Vector Laboratories Inc., Burlingame, CA). Diaminobenzidine will be used as chromogen. 57B stain ing will be classified as follows: no staining; “weak,” indicating low -intensity staining regardless of positive cell percentages or medium intensity staining of no more than 20% of cells; “moderate,” indicating medium -intensity staining of more than 20% o f cells or high -intensity staining of no more than 20% of cells; “strong,” indicating high -intensity staining of more than 20% of cells. Only Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 57 of 86 moderately and strongly positive cases will be considered positive. For PCR based analysis, total RNA will be is olated from collected tissue samples and reverse transcribed to cDNA using standard methods. The expression of tumor antigens from cDNA samples will then be interrogated using real -time PCR and a variety of specific tumor antigen probes. 11.0 SAFETY ASSESSMENT S Safety will be assessed throughout the study by a qualified physician, physician assistant , or nursing staff. Measurements used to evaluate safety will include history, physical examination, vital signs, clinical laboratory tests, urinalysis, 12 -lead EC G, and monitoring for AEs. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI -CTCAE v4.03) NCI, 20 10. Laboratory measurements that deviate significantly (as determined by the investigator) from previous measurements may be repeated. If warranted, additional or more frequent testing than is specified in the protocol should be done to provide adequate documentation of AEs and the resolution of AEs. 11.1 Physical Examination Medical a nd physical examinations must be performed by a qualified physician, nurse practitioner, or physician assistant and should include a thorough review of all body systems at Screening, Baseline , and End of Treatment . Examinations should be performed as list ed on the schedule of events . Physical examinations will include vital signs (heart rate, temperature, respiratory rate , and blood pressure) . Blood pressure, heart rate, and respiration rate will be measured after resting in a semi -supine or supine posit ion, and patients must be in the same position at each assessment for at least 5 minutes before and during the assessment. Physical examinations at Week s 7 and 14 in Phase 1 and Week 13 in Phase 2 are limited to vital signs and symptoms. 11.2 Clinical Laborato ry Tests Patients will have blood samples collected for routine clinical laboratory testing. The clinical laboratory parameters will be analyzed at the site’s local laboratory. Laboratory assessments to be co mpleted will include hematology , chemistry, and urine or serum pregnancy test (females of childbearing potential). Laboratory assessments will be defined as follow s:  Chemistry: To include sodium, calcium, total protein, albumin, creatinine, blood urea nitrogen, total bilirubin, alkaline phosphatase, AST, ALT, potassium, c hloride, bicarbonate, lactate dehydrogenase, and glucose.  Hematology : To include white blood cell (WBC) with differential, platelet count, hemoglobin, and red blood cell (RBC) count.  Urine or serum preganancy test – See section 11.7 below for further details . Additional laboratory assessments may be conducted throughout the study as medically necessary. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 58 of 86 11.3 Urinalysis Patients will have urine samples collected for routine urinalysis. The urinalysis will include color, appearance, and dipstick for specific gravity, protein, white blood cell -esterase, glucose, ketones, urobilinogen, nitrite, WBC, RBC, and pH. Microscopic analysis of urine will be performed if indicated based on macroscopic examination and urine dipstick results. 11.4 ECG The following parameters from 12-lead ele ctrocardiograms (ECG) will be evaluated: heart rate, PR interval, QRS duration, QT interval, and QTcF interval. 11.5 Autoimmune Monitoring Autoimmune monitoring will occur through laboratory measurements of ANA , TSH, erythrocyte sedimentation rate (ESR) , and C -reactive protein. Other tests, such as rheumatoid factor (RF), T3 , T4, and thyroid antibodies may be performed as clinically indicated. Furthermore, periodic physical examinations, including eye exam for dry eyes , lymph node and joint assessment, and skin exam for vitiligo and rashes , will be performed. 11.6 Injection Site Reactions The grading scale for injection site reactions (ISRs) used in this trial can be found in Appendix 3. Grade 1 ISRs consisting of mild redness, erythema , and swelling around the injection site are anticipated. Grade 1 reactions should dissipate over several days to a week with no special treatment. All ISRs should be recorded on the Injection Site Reaction CRF page. Attempts t o obtain photographs at the peak of severity and at follow -up visits which show resolution over time are encouraged. A ruler should be in the field of view to allow measurement of the size of the reaction. If the patient consents, the de -identified photo graph(s) should be appended to the ECRF . 11.7 Pregnancy All female patients of childbearing potential will have a urine or serum pregnancy test performed at Screening , Baseline , and End of T reatment. Female patients who become pregnant during the study should d iscontinue study medication immediately. The patient will receive counseling from the investigator or designee regarding the nature of the study medication and the potential risk on fetal development. 11.7.1 Time Period for Collecting Pregnancy Information The time period for collecting information on whether a pregnancy occurs i s from the Screening visit to four weeks after the last dose of study medication. Information on pregnancies identified prior to study product administration does not need to be reporte d to Heat Biologics. 11.7.2 Action to Be Taken if Pregnancy Occurs The investigator will notify Heat Biologics , or designee, within one week of learning of a patient’s pregnancy. The patient will also be followed to determine the outcome of the pregnancy. Infor mation on Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 59 of 86 the status of the mother and child will be forwarded to Heat Biologics , or designee . Generally, follow -up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported . While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE (see AE/SAE section of the protocol). A spontaneous abortion is always conside red to be an SAE and will be reported as such. Furthermore, any SAE occurring as a result of a post -study pregnancy and that is considered reasonably related to the investigational product by the investigator will be reported to Heat Biologics. While the investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting. 11.7.3 Action to be Taken if Pregnancy Occurs in a Female Partner of a Male Study Subject The investigator will attempt to collect pregnancy information on any female partner of a male study patient who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to Heat Biologics , or designee, within one week of learning of the partner’s pregnancy. The partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to Heat Biologics , or designee . Genera lly, follow -up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported. 11.8 Adverse Events (AE) and Serious Adverse Events (SAE) The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety evaluation, the investigator or site staff will be responsible for detecting, documenting , and reporting AEs and SAEs, as detailed in both this section of the protocol and in the AE/SAE section of the study procedures manual . AEs should only be recorded for up to four weeks following the last dose of study medication, unless the AE is considered related to the study medication , which requires that the AE be reported regardless of the amount of time that has passed since receiving the last dose of study medication. 11.8.1 Definition of an AE An adverse event is any untoward medical occurrence associated with the use of a medicinal product in humans, whether or not considered related to the medicinal product (21 CFR 312.32 (a)). Note: an AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom , or disease (new or exa cerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse, or misuse. A suspected adverse reaction (SAR) is defined as any AE for which there is reasonable possibility that the drug caused the AE (21 CFR 312.32 (a)). An AE or SAR is considered unexpected if it is not listed in the Investigator ’s Brochure or is not listed at the specificity or severity that has been observed or , if an Investigator ’s Brochure is not required or Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 60 of 86 available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application (21 CFR 312.32 (a)). 11.8.2 Definition of an SAE The Code of Federal Re gulations (CFR) Title 21 part 312.32 a nd ICH Guideline for Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, ICH -E2a March 1995, as implemented by the US FDA, defines a SAE or serious adverse drug experience as a ny untoward medical occurrence at any dose that:  Results in death (i.e., the AE actually causes or leads to death)  Is life -threatening (with regards to determining if an AE is serious, “life -threatening” is defined as an AE for which the patient was at risk of death at the time of the event. It does not refer to an event which hypothetically might have caused death if it were more severe. If either the investigator or the sponsor believes that an AE meets the definition of life -threatening, it will be considered life -threatening)  Requires i npatient hospitalization or prolongation of existing hospitalization  Results in p ersistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  Results in a c ongenital an omaly/birth defect  Results in a ny “other” important medical event. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life -threa tening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such eve nts are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. 11.8.3 Disease -Related Events or Outcomes Not Qualifyin g as SAEs An event that is part of the natural course of the disease under study (i.e., disease progression) should not be reported as an SAE. Recurrence or progression of the patient’s neoplasia will be recorded in the clinical assessments in the ECRF . Death due to disease progression is to be recorded on the Death ECRF page and not as a SAE. However, if the progression of the underlying disease is greater than what would normally be expected for the patient, or if the investigator considers that there was a causal relationship between treatment with vesigenurtacel -L or protocol design/procedures and the disease progression, then it must be reported as an SAE. Any new primary cancer must be reported as an SAE. 11.8.4 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs Abnormal laboratory findings ( e.g., clinical chemistry, hematology, and urinalysis ) or other abnormal assessments (e.g., ECGs or vital signs) that are judged by the investigator as clinically significant will be recorded as AEs and SAEs if they meet the definition of an AE or SAE. Cli nically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 61 of 86 However, clinically sig nificant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the patient’s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs. The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant. 11.8.5 Repor ting Adverse Events The investigator will record all directly observed AEs and all AEs spontaneously reported by the study patient on the Adverse Event ECRF . In addition, each study patient will be questioned about AEs. Each AE should be described in detail on the Adverse Event ECRF and SAEs on a Serious Adverse Event form and include the following information: start and stop dates, CTCAE v. 4 .03 grading, relationship to study medication, action taken, and outcome. AEs s hould be recorded from time of first dose up to four weeks following the last dose of study medication regardless of the causal relationship to the study medication. AEs considered related to study medication should be recorded at any time regardless of w hen they occurred. The investigator will also assess the possible relationship between the AE and the study medication as well as any concomitant medications according to the following criteria:  Related: AE and administration of study product are related i n time, and a direct association can be demonstrated .  Not related: AE is clearly explained by another cause not related to study product. Event outcome will be recorded using the f ollowing categories:  Recovered/resolved  Not recovered/not resolved  Recovered /resolved with sequelae  Fatal  Unknown 11.8.6 Prompt Reporting of SAEs All SAEs, whether or not considered related to the investigational product , must be reported within 24 hours of becoming aware of the event to the Med ical Monitor listed on the second page of this protocol. The Medical Monitor will require the following patient information as listed on the SAE form :  Subject identification , including patient study number, initials, and sex  Date of first dose of investigational product  Total dose and number of doses administered  Date and amount of last dose of investigational product Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 62 of 86  Whether the patient was taking investigational product at the time of the AE  Date, duration, and description of AE  Events and/or symptoms leading up to the AE  Action taken , including whether patient was withdrawn from study  Concomitant therapy (including doses, routes, and regimens)  Pertinent laboratory data  Medical history (including time on study prior to AE and history that might be related to the AE)  Dosing s tatus of investigational product (e.g., interrupted, discontinued, dose changed) In addition to the above information, the Medical Monitor will require the investigator's assessment of the following:  Intensity of the AE  Investigator's assessment of the relationship o f the AE to study treatment  Outcome of the AE Any necessary follow -up must be submitted within a reasonable time thereafter. The sponsor will promptly report SAEs to the FDA and other applicable regulatory agencies in accordance with Title 21 of the Code of Federal Reg ulations (CFR), Part 312.32 (21 CFR 312.32) and local regulatory requirements. The investigator should also comply with any applicable requirements related to the reporting of SAEs to the IRB/IEC. The investigator will provide an SAE follow -up report to the sponsor. In this report, the investigator is to assess and record the SAE in detail, including the date and time of onset, description, intensity, duration, outcome, etiology, relationship to study drug, and action taken. Any SAEs that c ontinue at the patient’s last study visit must be followed until the event resolves or follow -up is agreed to be adequate by the investigator, Medical Monitor, and sponsor. The clinical site i nvestigator and the Medical Monitor will review each SAE report and evaluate the relationship of the SAE to study treatment and to underlying disease. Based on the investigator’s and sponsor’s assessment of the SAE, a decision will be made concerning the need for further action. The primary consideration governing fu rther action is whether new findings affect the safety of patients participating in the clinical study. If the discovery of a new SAE related to vesigenurtacel -L raises concern over the safety of continued administration of study drug to patients, the spo nsor will take immediate steps to notify the FDA and all investigators participating in clinical studies of vesigenurtacel -L. Further action that may be required includes the following:  Modification of the protocol  Discontinuation or suspension of the study Heat Biologics, Inc. Investigational Product: Vesigenurtacel -L Protocol HS410 -101 CONFIDENTIAL Version 8.0; 03 Feb 2016 Page 63 of 86  Modification of the existing consent form and informing current study participants of new findings  Addition of any newly identified vesigenurtacel -L-related AEs to the list of expected AEs 12.0 STATISTICAL CONSIDERATIONS 12.1 General Statistical Considerations Phase 1 : Data fr om Phase 1 of the study will be presented descriptively. Standard descriptive statistics will include the sample size, mean and standard deviation (SD), median, minimum, and maximum values for continuous variables.