Credit: The Eastern Cooperative Oncology Group, Robert Comis, MD, Group Chair Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 83 of 95 APPENDIX 2: GRADING SCALE FOR INJ ECTION SITE REACTION S Local Reaction to Injectable Product Grade 1 Mild Grade 2 Moderate Grade 3 Severe Grade 4 Potentially Life Threatening Pain Does not interfere with activity Repeated use of non -narcotic pain reliever > 24 hours or interferes with activity Any use of narcotic pain reliever or prevents daily activity Emergency room visit or hospitalization Tenderness Mild discomfort to touch Discomfort with movement Significant discomfort at rest Emergency room visit or hospitalization Erythema/Redness 0.5-5 cm 5.1-10 cm > 10 cm Necrosis or exfoliative dermatitis Induration/Swelling* 0.5-5 cm and does not interfere with activity 5.1-10 cm or interferes with activity > 10 cm or prevents daily activity Necrosis * Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 84 of 95 APPENDIX 3: THE RESPONSE EVALUAT ION CRITERIA IN SOLI D TUMORS (RECIST 1.1) GUIDELINES AND GUIDLELINES FOR RESPONSE CRITERIA FO R USE IN TRIALS TEST ING IMMUNOTHERAPEUTICS ( IRECIST) RECIST 1.1 The objective response according to RECIST 1.1 is derived from time -point response assessments based on tumor burden as follows below. Evaluation of target lesions: • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non -target) must have reduction in short axis to < 10 mm. • Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. • Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 1 or more new lesions is also considered progression). • Stable Disease (SD): Neither sufficient sh rinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Evaluation of non -target lesions: • Complete Response (CR): Disappearance of all non -target lesions and normalization of tumor marker level. All lymph nodes must be non -pathological in size ( < 10mm short axis). • Non-CR/Non -PD: Persistence of one or more non -target lesion(s) and/or maintenance of tumor marker level above the normal limits. • Progressive Disease (PD): Unequivocal progression of existing non -target lesions. (Note: the appearance of 1 or more new lesions is also considered progression). Evaluation of Overall Time Point Response for Patients with Measurable Disease at Baseline Target Lesions Non-target Les ions New Lesions Overall Response CR CR No CR CR Non-CR/Non -PD No PR CR NE No PR Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 85 of 95 Target Lesions Non-target Les ions New Lesions Overall Response PR Non-PD or NE No PR SD Non-PD or NE No SD Not all evaluated Non-PD No NE PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD CR = C omplete Response, P R = Partial Response, S D = Stable Disease, P D = Progressive Disease, N E = Not Evaluable When target lesions show SD/PR and some subset of non -target lesions are considered not evaluable , a careful decision must be made whether to call the overall response at this time point SD/PR or NE. This is based on whether the lesions that are not evaluable , if they showed growth, could cause an overall response of PD in the context of the other lesion responses seen. If the non-target lesions that are not eva luable comprise a significant proportion of the overall disease burden, the appropriate time point response is NE. * Please refer to the complete New response evaluation criteria in solid tumours: Revised RECIST guidelines – version 1.1 for further details23. iRECIST The guidelines continue to recommend use of RECIST 1.1 to define whether tumo r lesions are measurable or non -measurable and the principles used to determine objective tumor response are largely unchanged from RECIST 1.1. The concept change for iRECIST is the resetting the bar if RECIST 1.1 progression is followed at the next assess ment by tumor shrinkage. iRECIST defines unconfirmed progress (iUPD) on the basis of RECIST 1.1 principles; however, iUPD requires confirmation on repeat imaging no less than 4 weeks later , which is done on the basis of observing either a further increase in size (or in the number of new lesions) in the lesion category in which progression was first identified in ( i.e., target or non -target disease), or progression (defined by RECIST 1.1) in lesion categories that had not previously met RECIST 1.1 progression criteria. However, if progression is not confirmed, but instead tumor shrinkage occurs (compared with baseline), which meets the criteria of iCR, iPR, or iSD, then the bar is reset so that iUPD needs to occur again (compared with nadir values) and then be confirmed (by further growth) at the next assessment for iCPD to be assigned. If no change in tumor size or extent from iUPD occurs, then the time point response would again be iUPD. This approach allows atypical responses, such as delayed resp onses that occur after pseudoprogression, to be identified, further understood, and better characterized. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 86 of 95 However, many aspects of new lesion assessment are unique to iRECIST. If a new lesion is identified (thus meeting the criteria for iUPD) and the pati ent is clinically stable, treatment should be continued. New lesions should be assessed and categorized as measurable or non -measurable using RECIST 1.1 principles. The algorithm for patients with no previous iUPD is identical to RECIST 1.1. For patients with iUPD at the last time point response, the next time point response is dependent on the status of all lesions, including target, non -target, new lesion target, and new lesion non -target; on whether any increase in size has occurred (either a further i ncrease in size or a sufficient increase to assign a new iUPD if the criteria were not previously met); or the appearance of additional new lesions. Assignment of time point response using iRECIST Time point response with no previous iUPD in any category Time point response with previous iUPD in any category * Target lesions: iCR; non -target lesions: iCR; new lesions: no iCR iCR Target lesions: iCR; non -target lesions: non -iCR/non -iUPD; new lesions: no iPR iPR Target lesions: iPR; non -target lesions: non -iCR/non -iUPD; new lesions: no iPR iPR Target lesions: iSD; non -target lesions: non -iCR/non -iUPD; new lesions: no iSD iSD Target lesions: iUPD with no change, or with a decrease from last time point ; non -target lesions: iUPD with no change, or decrease from last time point ; new lesions: yes Not Applicable New lesions confirm iCPD if new lesions were previously identified and they have increased in size (≥5 mm in sum of measures for new lesion target or any increase for new lesion non -target) or number; if no change is seen in new lesions (size or number) from last time point , assignment remains iUPD Target lesions: iSD, iPR, iCR; non - target lesions: iUPD; new lesions: no iUPD Remains iUPD unless iCPD is confirmed on the basis of a further increase in the size of non -target disease (does not need to meet RECIST 1.1 criteria for unequivocal progression ) Target lesions: iUPD; non -target lesions: non -iCR/non -iUPD, or iCR; new lesions: no iUPD Remains iUPD unless iCPD is confirmed on the basis of a further increase in sum of measures ≥5 mm; otherwise, assignment remains iUPD Target lesions: iUPD; non -target lesions: iUPD; new lesions: no iUPD Remains iUPD unless iCPD is confirmed based on a further increase in previously identified target lesion iUPD in sum of measures ≥5 mm or non -target lesion iUPD (previous assessment need not have shown unequivo cal progression) Target lesions: iUPD; non -target lesions: iUPD; new lesions: yes iUPD Remains iUPD unless iCPD is confirmed on the basis of a further increase in previously identified target lesion iUPD sum of measures ≥5 mm, previously identified non -target lesion iUPD (does not need to be Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 87 of 95 Time point response with no previous iUPD in any category Time point response with previous iUPD in any category * unequivocal), or an increase in the size or number of new lesions previously identified Target lesions: non -iUPD or progression; non -target lesions: non - iUPD or progression; new lesions: yes iUPD Remains iUPD unless iCPD is confirmed on the basis of an increase in the size or number of new lesions previously identified Target lesions, non -target lesions, and new lesions defined according to RECIST 1.1 principles; if no pseudoprogression occurs, R ECIST 1.1 and iRECIST categories for complete response, partial response, and stable disease would be the same. *Previously identified in assessment immediately before this time point . “i” indicates immune responses assigned using iRECIST. iCR=complete res ponse. iPR=partial response. iSD=stable disease. iUPD=unconfirmed progression. non -iCR/non -iUPD=criteria for neither CR nor PD have been met. iCPD=confirmed progression. RECIST=Response Evaluation Criteria in Solid Tumors. Please refer to the complete Guidelines for iRECIST24. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 88 of 95 APPENDIX 4: AMENDMENT JUSTIFICATION AND CHANGE LOG Amendment 6 Justification Amendment 6 is designed to provide clarification and improve ease of operationalization of Amendment 5 across multiple sites with differing practices of front -line patient management. In general, the timing to initiate additive HS -110 to front line maintenance will be restricted by weeks and/or cycles rather than be tethered to the timing of imaging scans. Amendment 6 also clarifies that the primary endpoint of PFS added in Amendment 5 only applies to the newly added Arm 6 cohorts in front -line maintenance; original Arm 5 patients (Cohorts A & B) will retain the same primary endpoint (ORR) which has been in place since the inception of the trial. Additionally, Amendment 6 modifies the allocation of patients to Cohorts B, C, and D due to operational considerations but does not affect the total sample siz e for the trial. Lastly, Amendment 6 offers clarification around frequently asked questions with regard to eligibility criteria , allows for retro - active collection of TMB samples for Cohort B patients enrolled prior to Amendment 5 , as well as modifies the Arm 6 PE schedule to better align with physician visits. Amendment 5 Justification : Amendment 5 expands the patient population to include patient s receiving front line pembrolizumab ± pemetrexed , as well as relaxes the eligibility criteria for CPI Progres sors. Per Investigator feedback, the minimum CPI treatment duration requirement for Arm 5 CPI progressor patients is lowered from 6 months to 4 months. Additionally, the term CPI relapsed is being corrected to CPI progressor, which is more clinically relev ant. To enhance compliance with protocol procedures, the Week 10 tumor biopsy may be waived with written authorization from the Sponsor. To further characterize the patient population, Tumor Mutation Burden (TMB) testing will be performed for exploratory analysis. TMB is a biomarker which has been associated with response to immunotherapy in multiple disease types. TMB measures the number of mutations within a tumor genome, and tumors which harbor more mutations have been shown to have a greater likelihood of response to immunotherapy. Amendment 4 Justification : Amendment 4 corrects the study design by taking the current 4 -arm trial and combin ing the 3 TIL classified arms into one treatment arm receiving HS-110 and nivolumab. This design contains treatment arm cohorts based on previous immune checkpoint inhibitor exposure. The TIL status and response to treatment will still be analyzed as an exploratory endpoint and the statistical plan was amended to support the change in trial design. This amendm ent also broadens the histological type of NSCLC to include squamous cell in addition to adenocarcinoma . While the AD -100 line selected for HS -110 was derived from adenocarcinoma, an evaluation of upregulated gene expression between NSCLC a deno carcinoma a nd squamous cell carcinoma have multiple shared antigens between HS -110 and squamous cell carcinoma , thus support ing the rationale for inclusion of squamous cell carcinoma patients in this clinical trial. In addition, the long -term follow -up scans were def ined to every 8 weeks and iRECIST evaluation criteria was added. Visit windows were expanded to allow for weekends and holidays, and the text throughout has been streamlined and rearranged for compliance with the ICH E6 guidelines and NIH -FDA protocol temp late. Amendment 3 Justification : Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 89 of 95 Amendment 3 addresses the exclusion criteria and safety monitoring secondary to the recent publication of myocarditis with combination immunotherapy treatment.25 It also realigns the physical exam schedule for consistency with nivolumab dosing days. Amendment 2 Justification : Amendment 2 changes address the issue of biopsies that are not evaluable in the on going cohorts. Recent e xperience suggests 25-40% of biopsies will not be evaluable. Patients without an evaluable pre-treatment biopsy are currently being balanced between the two arms in a “next man up” fashion without knowing their TIL status. Arm 4 will allow these patients to continue to receive while maintain ing the appropriate sample size of Arms 2 and 3. This Arm also acts as an overflow for patients who consent to study participation and meet the eligibility criteria for a cohort that is filled. Fin ally, Amendment 2 will allow prospective revision of the expansion cohort selection criteria based on emerging response data from the trial. Amendment 1 Justification: In the period since the HS110 -102 protocol was initiated, the treatment paradigm for thi s population has undergone a substantial change with the approval of checkpoint inhibitors for treatment of NSCLC. The main change in Amendment 1 is in response to that changing landscape: addition of study arms to assess the combination of viagenpumatucel with nivolumab (administered per current, approved labeling). Because nivolumab is an approved therapy for this indication and theophylline is not, the option for combination with theophylline is being discontinued (no patients were enrolle d in the theophylline arm of the study.) Amendment 1 also introduces mandatory biopsies for the study arms prescribing the 2-drug combination of viagenpumatucel with nivolumab; this requirement is implemented to define the characteristics of the enrolled p opulation and to allow comparison to emerging literature on patients who typically respond to checkpoint inhibitors (see Section 2.3 for more information). Finally, Amendment 1 allows for expansion (of up to 30 patients) for any combination treatments that show efficacy signals. DURGA Amendment Change Log Protocol Change Affected Section (s) Numbers Section Titles Amendment 2 Updated protocol template ; moved information to a new template; moved sections to fit content of new template All Sections Closed oxygen + HS-110 arm 6.1 Overall Study Design Converted expa nsion cohorts to official Phase 2 study 6.1 6 .3 and 14 Overall Study Design, Treatment Assignment, and Statistics Updated background information. Excluded discussion of hypoxia and adenosine pathway 3 Synopsis Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 90 of 95 Protocol Change Affected Section (s) Numbers Section Titles Removed oxygen as a combination drug; removed oxygen -related assessments 4.1,4.2.2, 5.3, 6, 8.2, 9.4, 10.2, 10.4, 11.3, 12.8, and 14.8 Study Specific Rati onale, Oxygen (former), Exploratory Objectives, Investigational Plan, Subject Exclusion Criteria; Dose Modifications (former); Oxygen (former), Study Drug Storage, ABG Panel (former), Antigen Screening of Baseline or Archival Tumor Biopsy (former) , Explora tory Endpoints (former) and Analyses (former) Updated schedule of assessments to reflect removal of oxygen endpoints and change in frequency of CT/MRI scans 7 Study Procedures Added Cohort C for patients who cannot be entered in to Cohort A or B 6.1 Overall Study Design Added rationale for Cohort C 4.4 Rationale for Arm 4 Added the possibility of using archival tissue for the pre-treatment biopsy 6.1 and8.1 Overall Study Design and Subject Inclusion Criteria Added TCR repertoire characteriz ation by sequencing as an exploratory endpoint 5.3, 6.1, 12.1.2, and 14.7 Exploratory Objectives, Overall Study Design, Characterization of TCR Repertoire, and Exploratory Endpoints and Analyses Added correlation of pre - and post - treatment TIL levels with clinical outcomes to exploratory objectives 5.3, 6.1, and 14.7 Exploratory Objectives, Overall Study Design, and Exploratory Endpoints and Analyses Removed references to irRC for tumor assessments 12.1, 12.2, 14.7.2, and Appendix 2 (former) Tumor Assessments, Immune Criteria for Tumor Assessment (former) , and Progression Free Survival (former), Added references for RECIST 1.1 for tumor assessments 12.1, 12.1.1, 14.6.5, 14.7, and Appendix 3 Tumor Assessments; RECIST 1.1 for Tumor Assessment; Progression -Free Survival, and Exploratory Endpoints Updated amendment change log Appendix 4 Revised language to allow prospective revision of the expansion cohort selection criteria 6.3 Treatment Assignment Updated study drug information 9.1 and 10.1 Description of Study Drug and HS-110 (HS- 110) Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 91 of 95 Protocol Change Affected Section (s) Numbers Section Titles Updated information for study drug storage 10.2 Study Drug Storage Added objective response rate as the primary endpoint for Phase 2 5.1 and 14.5.2 Primary Objective and Phase 2: Objective Response Rate Updated statistical considerations relative to planned analyses 14 Statistics Periodic editorial changes, including, updating Synopsis Multiple sections Throughout document Amendment 3 Revised cardiac exclusion criteria secondary to recent publications of myocarditis with combination immunotherapy treatment 8.2 Subject Exclusion Criteria Added cardiac safety monitoring secondary to recent publications of myocarditis with combination immunotherapy treatment 7.2, 7.4, and 11.5 On-study Procedures, Schedule of Assessments, and Cardiac Monitoring Revised Physical Exam schedule to be consistent with nivolumab dosing days. 7.2, 7.4, and 11.1 On-study Procedures, Schedule of Assessments, and Physical Examination Amendment 4 Corrected study design with the correct use of ‘treatment arms’ by combining the previous TIL -defined treatment arms (#2, 3, and 4) into one single treatment arm of nivolumab plus HS -110 (arm #5), and correlating TIL status to clinical outcomes by statistical analysis. 6 and 14 Investigational Plan and Statistics Modified the eligibility criteria by removing exclusion criteria #12 which prohibited the entry of patients who received prior treatment with immune checkpoint inhibitors, and replacing with criteria to exclude patients who are refractory to checkpoint inhibitors . 8.2 Subject Exclusion Criteria Modified the eligibility criteria by amending inclusion criteria #1 to allow squamous cell histology in addition to adenocarcinoma. 8.1 Subject Inclusion Criteria Corrected study design by removing references to ‘cycles’. Multiple Sections Throughout document Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 92 of 95 Protocol Change Affected Section (s) Numbers Section Titles Updated cardiac m onitoring testing to allow Troponin T in lieu of Troponin I as per facility standard of care. 7.2, 7.4, and 11.5 On-study Procedures, Schedule of Assessments, and Cardiac Monitoring Updated the frequency of follow -up assessments and post -HS-110 radiologi cal scans to every 8 weeks rather than every 9 to 12 weeks. Multiple sections including 7.2 and 7.4 On-study Procedures and Schedule of Assessments Clarified the difference in follow up between ‘post -HS-110’ as off -treatment follow up, and ‘post -nivol umab’ as survival follow up. Multiple sections including 7.2 and 7.4 On-study Procedures and Schedule of Assessments Updated study endpoints to include Duration of Response and updated statistical plan based on amended study design. 5, 14, and 16 Trial Objectives and Purpose and Statistics iRECIST analysis criteria added . Multiple sections and Appendix 3 Throughout the document iRECIST was added in addition to RECIST 1.1 evaluations. Defined criteria for RECIST and iRECIST were added to Appendix 3. Streamlining of text throughout document for clarity and adding/re - arranging text for compliance with ICH E6 guideline and NIH -FDA protocol template . Multiple sections Throughout the document Expansion of visit windows , including EOT, to allow for w eekends and holidays. Added text/assessments to ensure completeness and consistency between SOA and other sections of protocol. 10 and Table 2 Study Procedures and Schedule of Activities Removal of option to conduct study visits at home with qualified home health personnel. 10 and 12.1 Study Procedures and HS-110 Removal of intradermal testing . 10 and Table 2 Study Procedures and Schedule of Activities Removal of immune response lab draw at Week 4 and replacement at Week 1 prior to dosing . 10 and Table 2 Study Procedures and Schedule of Activities Removal of pregnancy test at EOT visit and replacement at Baseline visit . 10 and Table 2 Study Procedures and Schedule of Activities Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 93 of 95 Protocol Change Affected Section (s) Numbers Section Titles Addition of enrollment flowsheet Appendix 5 Appendix 5 Amendment 5 Expansion of patient population to include front line patients who have received immunotherapy with or without chemotherapy, who did not progress at the first imaging assessment and who will begin maintenance immunotherapy with pembrolizumab ± pemetrexed (Arm 6). Synopsis, 7.1, Figure 3, 7.2, 9, 9.1, 9.2 Trial Design, Overall Study Design, Study Treatments, Selection and Withdrawal of Patients, Subject Inclusion Criteria, Subject Exclusion Criteria Addition of study procedures (including treatment) and follow -up for Arm 6. 9.3.1, 10.5, 10.6, 10.7, 11.5, 12, 12.4, 13.4, 14.1, 14.1.1, 15.6, Table 3 Patient Completion, Arm 6: Treatment and Follow -up Procedures, Dose Adjustment Criteria, Study Drug Materials and Management, Labeling, Tumor Assessments, RECIST 1.1 and iRECIST for Tumor Assessment, Stopping Rules, Schedule of Activities (Arm 6: HS -110 + Pembrolizumab ±Pemetrexed), Changed the primary endpoint to PFS, and assigned ORR as a secondary endpoint. Synopsis, 7.1, 8.1, 8.2, 16.5, 16.6 Trial Design, Overall Study Design, Primary Objectives, Secondary Objectives, Primary Efficacy Endpoints and Analysis, Secondary Efficacy Endpoints and Analysis Addition of option for Sponsor waiver for collection of Week 10 biopsy. Synopsis, 6.3, 7.1, 9.1, 10.2.8, 14.6, 16.7, Table 2 Trial Design, Rationale for Obtaining Archival Tissue and Perfo rming Tumor Biopsies, Overall Study Design, Inclusion Criteria, Week 10 and 16 Assessments, Analysis of Infiltrating T Cells (Optional Post Treatment Tumor Biopsy), Exploratory Endpoints and Analyses, Schedule of Activities (Arm 5: Treatment and Follow -up Procedures) Tumor Mutation Burden (TMB) testing added as exploratory analysis. Synopsis, 14.9, 16.7 Exploratory Endpoints, Tumor Mutation Burden Testing, Exploratory Endpoints and Analysis Modified and streamlined statistical methodology without formal h ypothesis testing. Synopsis, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8 Overall Study Design, General Statistical Considerations, Sample Size, Analysis Populations, Disposition, Demography and Baseline Characteristics, Primary Efficacy Endpoints and An alysis, Secondary Efficacy Endpoints and Analysis, Exploratory Endpoints and Analysis, Safety Analysis Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 94 of 95 Protocol Change Affected Section (s) Numbers Section Titles Separation of efficacy endpoints between RECIST 1.1 and iRECIST. Synopsis, 8.1, 8.2, 16.5, 16.6 Trial Design, Primary Objectives, Secondary Objectives, Primary Efficacy and Endpoints and Analysis, Secondary Efficacy Endpoints and Analysis Removal of Appendix 5. Appendix 5 Level 2 Flowchart / Minimum Enrollment Requirements for the Initial Examination of Response by the DMC (version 1.0) Removal of histology -based cohorts in Arm 5 , and addition of enrollment caps for Treatment Arm 5 cohorts and Arm 6. Synopsis, 7.1, 16.1 Trial Design, Overall Study Design, General Statistical Considerations Change in terminology from ‘subjects’ to ‘patients’. N/A Various throughout document Change in terminology from ‘relapsed’ to ‘progressor’. N/A Various throughout document Modification of existing eligibility criteria from a 6 -month CPI requirement to a 4 month CPI requirement. Synopsis, 9.1 Subject Inclusion Cr iteria Removal of Week 19 visit for Arm 5. 10.2, SOA Arm 5: On Study Treatment Procedures Removal of exploratory testing involving TCR repertoire, major histocompatibility (MHC) class I expression, and characterization of neo - antigens. Synopsis, 7.1, 8.3, 14.4, 16.7 Trial Design, Overall Study design, Exploratory Endpoints, Exploratory Endpoints and Analysis , Phenotyping Phenotypic Analysis of Blood Lymphocyte Subsets by FACS Reference to Investigational Product as ‘HS-110’ from ‘Viagenpumatucel -L’ N/A Various throughout document Change in terminology from ‘Off - Treatment Follow -Up’ to ‘Post -HS-110 Follow -Up’ period. N/A Various throughout document Revised nivolumab dosing schedule in Arm 5 Post -HS-110 Follow -Up period. 7.1, 7.2, 9.3.1, Overall Study design , Study Treatments, Patient Completion, Removal of immune response lab draw at Week 1 prior to dosing and replacement with TMB. 10.2.1, Table 2 Week 1 Assessments (Day 1), Schedule of Activities (Arm 5: Treatment and Follow -up Procedures) Amendment 6 Clarification of timing for addition of HS-110 to front -line maintenance treatment. 9.0, 9.1.9, 10.1, 10.5.1 Synopsis, Selection and Withdraw of Patients, Subject Inclusion Criteria, Screening Procedures and Baseline , Week 1 Assessments Clarification that original primary endpoint of ORR will still apply to Arm 5 Cohorts A & B, and the recently 8.1, 16.5.2, 16.6 Synopsis, Primary Objectives, Primary Efficacy Endpoints; Secondary Efficacy Endpoints Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 95 of 95 Protocol Change Affected Section (s) Numbers Section Titles added PFS will only the primary endpoint for the new Arm 6 Cohorts C & D. Also corrected the omission of 6 and 12 month PFS endpoints . Increase in Cohort B Sample Size from 40 to 60 with option for over -enrollment based on patient availability ; Decrease in Cohort C/D Sample Size fro m 40 to up to 20 based on patient availability . Total trial sample size remains unchanged. 7.1, Figure 3, Synopsis, Overall Study Design, Study Design Clarifying remarks inserted to eligibility criteria. 9.1, 9.2 Synopsis, Subject Inclusion Criteria, Subject Exclusion Criteria Modified Injection Site Reaction Grading Scale to capture more ISRs. Appendix 2 Injection Site Reaction Grading Scale Added exclusion criteria for patients who have received more than 3 lines of treatment for metastat ic NSCLC. 9.2 Synopsis, Subject Exclusion Criteria Clarification on TMB collection when not obtained at Week 1. 10.2.1, Table 2, 14.6 Week 1 Assessments, Arm 5 Schedule of Assessments, Tumor Mutation Burden Alignment of Arm 6 PE with physician visits. 10.5.5, 10.5.8, Table 3 Week 5 & 11 Assessments, Week 10 Assessments; Arm 6 Schedule of Assessments