............... 35 Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 19 of 95 4.3. Abbreviations and Acronyms Abbreviation Definition 12mOS 12-month overall survival 6mOS 6-month overall survival A2AR A2A adenosine receptor ADP Adenosine diphosphate AE Adverse event ALK Anaplastic lymphoma kinase ALT Alanine aminotransferase AMP Adenosine monophosphate ANA Antinuclear antibodies APC Antigen presenting cell AST Aspartate aminotransferase cAMP Cyclic adenosine monophosphate CBC Complete blood count CFR Code of Federal Regulations cGMP Current good manufacturing practices CI Confidence interval CNS Central nervous system CR Complete response CRF Case report form CT Computed tomography CTCAE Common Terminology Criteria for Adverse Events CTL Cytotoxic T -lymphocyte CTLA -4 Cytotoxic T -lymphocyte associated antigen 4 CPI Checkpoint Inhibitor DC Dendritic cell DCR Disease control rate DLT Dose -limiting toxicity DMC Data monitoring committee DMSO Dimethyl sulfoxide DRR Durable Response Rate Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 20 of 95 Abbreviation Definition EC Ethics committee ECG Electrocardiogram ECHO Echocardiogram ECOG Eastern Cooperative Oncology Group EGFR Epidermal growth factor receptor ELISA Enzyme -linked immunosorbent assay ELISPOT Enzyme -linked immunosorbent spot EOT End of treatment ER Endoplasmic reticulum ESR Erythrocyte sedimentation rate FDA Food and Drug Administration FFPE Formalin -fixed paraffin embedded GCP Good Clinical Practice G-CSF Granulocyte colony -stimulating factor GLP Good Laboratory Practice gzB Granzyme B HIV Human immunodeficiency virus HLA Human leukocyte antigen HSA Human serum albumin IBC Institutional Biosafety Committee ICF Informed consent form IO Immuno -oncology i.v. Intravenous ICH International Conference on Harmonis ation ICS Intracellular cytokine staining IDMC Independent data monitoring committee IDO Indoleamine -2,3-dioxygenase IEC Independent Ethics Committee IFNγ Interferon -γ IHC Immunohistochemistry IR Immunologic response IRB Institutional Review Board Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 21 of 95 Abbreviation Definition iCPD Confirmed Disease Progression based on immune responses assigned using iRECIST iCR Complete Response based on immune responses assigned using iRECIST iUPD Unconfirmed Disease Progression based on immune responses assigned using iRECIST iPR Partial Response based on immune responses assigned using iRECIST iRECIST Response Evaluation Criteria in Solid Tumors for use in trials testing immunotherapeutics iSD Stable Disease based on immune responses assigned using iRECIST ISR Injection site reaction IST Investigator -sponsored trial LTFU Long -term follow -up LVEF Left ventricular ejection fraction mAbs Monoclonal antibodies MAGE -A1 Melanoma -associated antigen 1 Mcg Microgram MedDRA Medical Dictionary for Regulatory A ctivities MHC Major histocompatibility complex MRI Magnetic resonance imaging mRNA Messenger ribonucleic acid MSDS Material safety data sheet MUC1 Mucin -1 (tumor associated antigen) MUGA Multigated acquisition scan NCCN National Comprehensive Cancer Network NCI National Cancer Institute NK Natural killer Non-iCR/non -iUPD Neither criteria for iCR or iPD have been met NOS Not otherwise specified NSCLC Non-small cell lung cancer ORR Objective response rate OS Overall survival PBMC Peripheral blood mononuclear cells PCR Polymerase chain reaction Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 22 of 95 Abbreviation Definition PD Progressive disease PD-1 Programmed death receptor 1 PD-L1 Programmed death ligand 1 PET Positron emission tomography PFS Progression -free survival PI Principal Investigator PP Protocol population PR Partial response PS Performance status QoL Quality of Life RBC Red blood cell RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1 RR Response rate SAE Serious adverse event SAP Statistical Analysis Plan SAR Serious adverse reaction SD Stable disease SOA Schedule of a ctivities SOC Standard -of-care TCR T-cell receptor TEAE Treatment -emergent adverse event TGF Transforming growth factor TIL Tumor infiltrating lymphocytes TKI Tyrosine kinase inhibitor TLR Toll-like receptor T-reg Regulatory T -cell TrPAL Triple positive activated lymphocytes (CD1 6 + CD56 + CD69+) ULN Upper limit of normal VEGF Vascular endothelial growth factor WBC White blood cell Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 23 of 95 4.4. Statement of Compliance This trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) and the following the United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 1 1, 50, 54, 56, and Part 312). The protocol, informed consent form (ICF), recruitment materials, and all participant materials will be submitted to the Institutional Review Board (IRB)/ Ethics Committee (EC) for review and approval. Approval of both the p rotocol and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol and ICF will require review and approval by the IRB/EC prior to implementation. In addition, a determination will be made regarding whether a new ICF needs to be obtained from participants who already provided consent using a previously approved ICF. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 24 of 95 5. INTRODUCTION 5.1. Non-Small Cell Lung Cancer The annual incidence of non -small cell lung cancer (NSCLC) in the United States is estimated at ~222,500 cases in 2017 and remains the deadliest malignancy worldwide . Most NSCLC patients have local or distal metastatic le sions upon diagnosis (stage IV) and the disease has a poor 5-year survival rate of 5.2%.1 Despite a number of therapeutic advances in the last decade, response to first-line and subsequent therapy for advanced NSCLC remains sub -optimal. Treatment strateg ies include consideration regarding tumor histology, molecular pathology, age, and comorbidities. In patients without mutations of epidermal growth factor receptor (EGFR ), anaplastic lymphoma kinase (ALK ) or c-ros oncogene 1 ( ROS1 ) rearrangements , first-line therapy generally includes platinum -based doublet chemotherapy, with or without the anti -vascular endothelial growth factor ( VEGF ) antibody, bevacizumab . Patients with mutations can significantly delay disease progression by treatment with molecularly targeted agents, therefore treatment with tyrosine kinase inhibitor s (TKIs ) should be considered a first line treatment in this patient population2. The programmed death -1 (PD-1) inhibitor pembrolizumab (KEYTRUDA) has recently been approved by the FDA as a first line single agent therapy in patients with programmed cell death ligand -1 (PD-L1) expression more than 50% with negative or unknown results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements. In addition, pembrolizumab is now used in combination with carboplatin/pemetrexed (PARAPLATIN® among others /ALIMTA®) as first -line therapy for patients with advanced non -squamous NSCLC or NSCLC not otherwise specified (NOS) based on the Keynote -021 results.3 The current standard of care (SOC) for second line therapy of NSCLC includes treatment with monoclonal antibody (mAB) immune check point inhibitors (CPI) such as nivolumab (OPDIVO®), pembrolizumab and atezolizumab . These checkpoint inhibitors have delivered objective responses of ~20% in an unselected NSCLC population, with impressive clinical results in a subset of programmed death ligand 1 ( PD-L1) positive patients . Specific subgroup analysis of single agent nivolu mab found response rates in previously treated (second line) non -squamous patients to be 17 to 20%, and in squamous patients to be 14.5 to 20%4,5. PD-L1 expression is often associated with T -cell activation and patients with a low level of existing tumor -infiltrating lymphocytes (TIL) appear to be less likely to respond to checkpoint inhibition. In fact, 60 -70% of NCSLC patients are TIL -negative, whi ch may be a contributing factor in the low overall response rate to checkpoint therapy in this unselected patient population. These observations support the hypothesis that tumor -specific T -cell activation enhances the clinical activity of checkpoint ther apy. HS-110 represents a novel way to stimulate a CD8+ T -cell response toward tumor associated antigens to enhance checkpoint therapy in treating NSCLC. This trial will include both CPI naïve and CPI progressor patients. The relatively poor responses seen with second -line and subsequent treatments are due to a combination of progressive biological resistance of the underlying tumor arising from successive regimens of chemotherapy and a decline in the performance status of patients, due to treatment - and di sease -related morbidities. The large and increasing population of patients being delivered checkpoint inhibitor therapy to the post-first-line setting , open s an opportunity to combine an immunostimulatory vaccine, HS-110, Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 25 of 95 to create a potential synergist t reatment. Since the historical objective response rate ( ORR ) for nivolumab as second line agent in NSCLC is 20%, this is a population that could derive benefit from the immunostimulating ability of HS-110 in combination with nivolumab. Immune CPI progressor patients have an unknown response rate to nivolumab as a s ingle agent in the second - line setting. It is currently recommended for second -line therapy per National Comprehensive Cancer Network (NCCN ) Clinical Practice Guidelines in Oncology™ , but there is an insufficient quantity of data stating the exact ORR of n ivolumab after a patient has progressed on first-line pembrolizumab. It can be understood logically to be a lower response, as the patient previously progressed while on the CPI in the first -line setting. HS-110 in previous human trials in NSCLC was found to be safe and immunogenic. This mechanistically novel technology and inherent low toxicity profile in combination with nivolumab in the second -line setting has potential to fill an unmet need in this population. 5.2. Vaccine Monotherapy Approaches for NSCLC Vaccines have the potential to trigger a durable antitumor response with minimal toxicity, thus presenting an attractive alternative for NSCLC treatments. Vaccine -based therapy utilizing an autologous or allogeneic antigenic stimulus to promote endogenous a ntitumor immun e activation is currently being heavily investigated in the clinic. Melanoma -associated antigen 3 (MAGE -A3) and mucin 1 glycoprotein (MUC1) are antigen s specifically associated with various solid tumors, including NSCLC . 6,7 Two vaccines , designed to target these antigens , have been unsuccessful in treating potentially curable, earlier stage NSCLC in recent phase 3 trials. The MAGE -A3 vaccine failed to extend disease -free survival i n pati ents with MAGE -A3-positive tumors , and no gene- signature -defined patient subsets could be identified that may have experienced clinical benefit.8,9 The L-BLP25 vaccine administered in combination with cyclophosphamide , failed to show an overal l survival (OS) advantage against placebo in unresectable stage IIIB NSCLC after definitive chemoradiation.7,10 Although up to 50% of patient tumors may exp ress either MAGE -A3 and/or MUC1, the expression of these antigens within an individual tumor is rarely uniform , reflecti ng the underlying genetic heterogeneity of tumors , and suggests that patients who may be positive for a particular molecular signature and/or antigen may also have a significant tumor burden that is neg ative for those same molecular targets, thus leading to ineffective treatment for single -agent therapies. Following treatment with a single -antigen vaccine, even in the presence of a robust immune response, MAGE -A3 or MUC1 negative tumor cells may be resis tant to a tumor -specific immune response. Furthermore, these trials did not enrich their patient population through selection for specific biomarkers that may exist in certain patients who may have benefitted from either of these therapies. 5.3. Vaccine Combi nation Approaches to NSCLC Tumor heterogeneity, as evidenced by the recurrence of tumors after single -agent chemotherapeutic interventions, strongly suggests that a multi -targeted approach may be more successful; however, combinations with traditional chem otherapeutic agents alone remains difficult due to the overt toxicity caused by those agents. Due to the lack of such toxicity with vaccine therapies, this is an attractive therapeutic option being investigated. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 26 of 95 Recent phase 3 results of tumor cell vaccine, belagenpuma tucel -L, showed that while the vaccine failed to improve OS across the entire study population, an additional subset analysis suggested that there was a survival benefit for belagenpumatucel -L treated patients who had recently complet ed front -line chemotherapy and in those who received front -line combination radiation chemotherapy .11,12 Additionally, TG4010 (a recombinant viral vector genetically modified to express MUC1 and interleukin -2 [IL -2]), added to first-line chemotherapy , resulted in an increase in OS in NSCLC patients.13 Furthermore, a better clinical outcome was observed in TG4010 -treated patients with a normal percentage of triple positive activated lymphocytes (CD1 6 + CD56 + CD69+ [TrPAL]) when compared to patients with a high percentage of TrPAL . The vaccine combination approaches of the current trial are predicated on an assumption that significant localized immunosuppression exists within the tumor microenvironment, mediate d mainly by regulatory T -cells (T-regs), predominately driven by checkpoint pathway dysregulation, intra-tumor hypoxia, and extracellular adenosine. The consequent dow n-regulation of the CD4 + CD8 + T-cell population results in a formidable degree of tumor immunodefense against tumor -directed vaccine strategies. A number of studies have consistently suggested elevated T -reg levels in NSCLC and a direct association with both an adverse prognostic outcome and response to therapy, findings of direct relevance to the currently proposed therapeutic strategy, predicated as it is on T-cell targeting.14,15 T-regs in NSCLC also appear to exhibit particularly high levels of PD-L1 and CTLA -4, supporting their pivotal role in the c ontrol of the neoplastic immune milieu and further implicating them as suitable targets for therapeutic immuno -intervention.15,16 5.4. Description of Investi gational Agent, HS-110 HS-110 (v iagenpumatucel -L) is an allogeneic, cell -based immunotherapy containing a broad range of NSCLC tumor antigens (up to 66 known cancer testis antigens) combined with a specific mechanism for the transport of these antigens to patient a ntigen -presenting cells that results in a specific CD8+ cytotoxic T-cell response. Gp96 is a member of the heat -shock protein family and has evolved specific characteristics that are advantageous for a therapeutic cancer vaccine. Similar to other heat sho ck proteins, gp96 is an intracellular protein that functions as a protein chaperone to facilitate the proper folding of other cellular proteins. In contrast to other heat -shock proteins, endogenous gp96 is restricted to the endoplasmic reticulum (ER) via expression of a KDEL (target peptide sequence) ER retention sequence on its C -terminus. Within the ER, gp96 is exposed to a majority of proteins and antigens that eventually are displayed on MHC I. This property is likely to have influenced the evolution of a secondary role for gp96 as a molecular warning system for necrotic cell death.17 Endogenous gp96 is typically released from cells only upon physical destruction or necrotic cell death. Upon release from a dying cell, extracellular gp96 is able to interact with a series of receptors, including Toll -like receptors (TLR) -2 and TLR -4 on the surface of antigen presenti ng cells, and engagement of TLR -2 and -4 provides an adjuvant signal. Simultaneously, gp96 is able to bind to the endocytic scavenger receptor (CD91 ) to facilitate internalization of gp96 together with whatever protein cargo it bound within the dying cell. Any antigens brought into an antigen presenting cell by gp96 are then transferred to MHC I, through the cross -presentation pathway, fo r induction of a CD 8 + T-cell-mediated cytotoxic T-cell response.18 Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 27 of 95 Heat Biologics’ ImPACT techn ology seeks to replicate this natural mechanism by engineering gp96 to become a secretable molecule through the replacement of the KDEL retention signal with a secretory sequence from an immunoglobulin molecule. The resulting gp96 -Ig fusion protein can then be transfected into a tumor cell line that contains a profile of antigens that are specific for a given tumor type and used to stimulate a CD8 + T-cell response toward those antigens. In the case of HS-110, Heat Biologics has screened a series of NSCLC cell lines to prioritize antigens that are known to be shared amongst a high proportion of patients with NSCLC (including MAGE -A3, NY-ESO -1, etc.) and selected the AD100 cell line based on these shared antigen expression characteristics. Figure 1 illustrates th at structure of HS-110. Figure 1: Structure of ImPACTTM Vaccine, HS-110 Figure 1: Schematic diagram showing the structure of HS-110. This vaccine has a cellular backbone (AD100 cell line) which has been modified with a gp96 -Ig expression plasmid. Tumor cell antigen -gp96 -Ig complexes are secreted by the cell in order to deliver a pan -antigenic antitumor response 5.5. Prior Human Experience with HS-110 A first -in-human P hase 1 investigator -initiated, single -center, open -label study to examine the safety and im munogenicity of HS-110 was conducted in patients with stage IV or recurrent NSCLC who failed at least one line of standard chemotherapy. The primary objective of th is study was to evaluate the safety o f HS-110 vaccine in patients with advanced NSCLC , and secondary objectives were to study the immune response to vaccination, monitor clinical responses, and recommend a dose-schedule ( DS) combination for further testing in an initial clinical trial of vaccine efficacy. A total of 36 patients were to be assig ned to receive HS-110 administered as an intradermal injection following one of 3 DS regimens, designed to deliver equivalent numbers of cell s for up to 18 weeks . Patients were treated with one of 3 dose-schedule (DS) combinations, • DS-1: > 4 × 107 cells every other week for 6 weeks with up to 3 courses and 9 vaccinations . • DS-2: > 2 × 107 cells weekly for 6 weeks with up to 3 courses and 18 vaccinations . • DS-3: > 1 × 107 cells twice -weekly for 6 weeks with up to 3 courses and 36 vaccinations . Nineteen (19) of the planned 36 patients enrolled in the study ; 1 patient withdrew prior to receiving treatment and 18 received study treatment (n=11 patients in DS -1, n=4 patients in DS -2, and n=3 patients in DS -3). The first 7 patients were enrolled in th e DS -1 cohort , and those enrolled subsequent were assign ed to each of the DS cohorts in a 1:1:1 ratio. This study was closed to Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 28 of 95 enrollment at the mid -way point following a strategic decision to focus on further development under a commercial Investigational New Drug ( IND) application . Data from this study have been published.19 Four patients died due to disease progression , and 4 patients reported a total of 6 serious adverse events (SAEs), none of which were considered by the Investigator to be treatment -related. Five SAEs were reported by 3 (16.7%) treated patients, which included rectal hemorrhage, dyspnea, chest pain, and lun g infection (pneumonia) , all of which were severe (Grade 3) in nature. One of these patients also reported a Grade 3 event of fatigue. The patient who did not receive treatment experienced a SAE of respiratory disorder , which resulted in study discontinuat ion. The majority of adverse events ( AEs) were Grade 1 or Grade 2 , the most frequent of which were induration (n=18, 100%), rash (n=16, 88.9%), pruritus and pain (n=5 each, 28%). Overall, a total of 14 patients died and the 4 surviving patients have been followed for a median of 10.6 months (range 2.6 to 16.6). The Kaplan -Meier estimate of median survival was 8.0 months (95% confidence interval [ CI]: 6.7 to 18.2), and the 6, 12, and 24 -month OS rates were 77.8% (95% CI: 51.1 to 91.0%), 41.9% (95% CI: 19.1 to 63.3%), and 11.2% (95% CI: 0.8 to 37.3%), respectively. Although comparison is limited due to incomplete accrual, 2 (0.5%) patients who received weekly vaccines (DS-2) and 2 (66.7%) of those receiving vaccine 2 times per wee k (DS- 3) have survived longer than the median survival time of 7.1 months for the 11 patients who were vaccinated every other week (DS -1). Time to progression for DS -2 and DS -3 patients also appears to compare favorably with the median progression -free sur vival (PFS) of 1.3 months for DS -1 patients. Although there were no objective responses by Response Evaluation Criteria in Solid Tumors (RECIST ) 1.1, 7 of 15 evaluable patients exhibited stable disease (SD) after a single course of therapy; 3 of these patients had durable SD of greater than 3 years. Of the 18 patients enrolled in the trial, at least 2 samples (baseline and either week 6, 12 and/or 18) were available for 15 of the 18 patients on the trial. Peripheral blood samples were collected from each patient prior to treatment and at 6 -, 12-, and 18 -week time points . Immune response was characterized by production of Interferon -gamma ( IFNγ ) by patient CD8 + T-cells and assayed by Enzyme -Linked ImmunoSpot (ELISPOT ). Of the 15 evaluable patients, 11 (73.3%) demonstrated a doubling or greater (in some cases upwards of 100 -fold increases) of a CD8 + T-cell-mediated, vaccine -specific immune response. Furthermore, th ere was no increase in CD 4 + T-cell-mediated immunity by ELISPOT, confirming preclinical findings that the effect of the gp96 -Ig approach is limited to CD8 + cytotoxic T -cell responses. When the survival of the immune responders (11/15 patients , 73.3% ) was compared to that of the non -responders (4/15 , 26.7% ), it was observed that the immune responder OS was 16.5 months vs. 4 months in the immune non -responder group. These data provide a possible link between increas ed vaccine -specific cytotoxic T -cell responses and increased survival. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 29 of 95 6. STUDY RATIONALE 6.1. Study Specific Rationale The combination of HS-110 and nivolumab is hypothesized to evoke a synergistic effect, based on the theory that checkpoint inhibitors work best in PD -L1 positive tumors in the presence of TIL. Studies in mice have s hown that the combination of PD -1 blockade and gp96 -Ig vaccination results in a potent increase in the number of CD 8 + cytotoxic T-cells.20 Emerging data f rom the ongoing DURGA trial show s increased TIL after HS-110 vaccine. Th us, combining HS-110 with anti -PD-1 agents may enhance the vaccine’s anti -tumor activity while prolonging or increasing the efficacy of the checkpoint inhibitor. HS-110 is distinct from other competitive vaccine approaches in clinical testing as it is an allogeneic, cell -based immunotherapy containing a broad range of NSCLC tumor antigens combined with a specific mechanism for the transport of these antigens to patient antigen -presenting cells for the generation of a specific CD8 + cytotoxic T-cell response. It is, therefo re, likely that HS-110 will represent a more effective antigenic stimulus than many other existing vaccine constructs. HS-110 is based on Heat Biologic s’ ImPACT™ technology, a gp96 -Ig fusion protein expression construct, which when expressed, leads to the secretion of gp96 -bound cellular specific antigens. The backbon e cell line for HS-110, AD100, was selected based on its antigenic profile which overlap s with the antigenic profiles in a large proportion of NSCLC patient tumor samples. Extracellular gp96 activates a CD8 + T-cell mediated immune response in 2 distinct manners: 1) by functioning as an adjuvant to activate dendritic cells (DC) via TLR -2 and TLR -4 and 2) by functioning as an antigen carrier for antigen cross presentation to CD8 + T-Cells via the endocytic scavenger receptor, CD91. These characteristics make gp96 unique because it can both activate and deliver chaperoned antigens by an antigen presenting cell ( APC ) to MHC I in order to elicit a CD8 + T-cell mediated immune response. A comparison of our ImPACT approach to other vaccine monotherapies is shown in Table 1 below. Table 1: Comparison of ImPACT to Other Immunotherapies Criteria ImPACT Therapy Other Allogeneic Autologous Cell-based Pan-antigen delivery ✓ Some Some Targeted delivery of antigens to APC in vivo ✓  Some Exclusive cytotoxic CD8 + T-cell response ✓  Some Dual antigen carrier/adjuvant ✓   Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 30 of 95 Criteria ImPACT Therapy Other Allogeneic Autologous Cell-based Rapid and efficient new product development ✓ Some  Low manufacturing cost of goods sold ✓ Some  Thus , the rationale for the evaluation of HS-110 in combination with multiple immune modulating strategies is as follows: • Recent and paradigm -changing clinical data support the feasibility of effective NSCLC immunotherapy when NSCLC cells become susceptible to attack by cytotoxic T lymphocytes (CTL). • Secret ed gp96 -Ig from HS-110 combines immune adjuvant activity with polyvalent peptide specificity , activat ing DC, NK cel ls, and CTL s, and result ing in death of tumor cells by NK cell -specific mechanisms and by MHC -restricted CD8 + CTL activity. The activation of DC and NK cells by HS-110 may also counteract the generation of immunosuppressive T -regs. • This master protocol design facilitates t he testing of novel combinations of immunotherapies in a small number of patients in order to characterize the safety profile and immune response to advanc e promising new combination regimens into larger expansion cohorts . • The combination of HS-110 with anti-PD-1 checkpoint inhibitors may enhance the efficacy of the vaccine by accelerating the immune system response with PD-L1, which is expressed on the surface of many tumor cells. Likewise, given that patients require TIL to respond to checkpoint inhibitor therapy , the combination may enhance or prolong the ir activity by inducing TIL presence in patients who do not have TIL at baseline. Though the exact TIL threshold is uncertain, for patients with baseline TIL, HS-110 may drive further activation and clonal expansion of antigen -specific and activated CD8 + T-cells, leading to a higher quality immune response of TIL. 6.2. Justification of HS-110 Dose Selection As indicated in the initial phase 1 investigator -sponsored trial ( IST), the weekly (2 × 107 cells) and twice weekly (1 × 107 cells) dosing schedules were determined to produce the most desirable immune response (at least a doubling of CD8 + numbers from baseline). The weekly dosing regimen was selected for this trial as a starting point, as it represents the schedule with greatest patient acceptability for frequency of treatment visits. Further, the choice of the lower dose is prudent from a safety perspective as this trial is th e first test ing HS-110 in combination with multiple treatment regimens that incorporate additional immunomodulation. Furthermore, murine and simian data suggest that lower doses may produce sufficient immune response with possibly superior clinical effects.21 Speci fically, the murine dose -ranging studies indicated that production Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 31 of 95 of approximately 400 ng gp96 -Ig per million cells (15-20 micrograms [mcg] per kg on a weight basis ) provided the optimal dose. Production of approximately 5 -10 mcg gp96 -Ig per million cells (1-2.5 mcg per kg on a weight basis ) in a macaque dose -ranging study provided the optimal dose. Thus, there is not an expectation of a typical dose -escalation in larger mammals as is anticipated for most antibodies or small molecules where receptor satura tion is predictive of efficacy. In the case of HS-110, no significant difference in immune response was detected between the 3 doses in the phase 1 IST and longer anecdotal survival was observed in 2 of 3 patients who received the 10 million cells per dose, tw ice-weekly treatment schedule. Finally, improvements in the cell-freezing protocol have increased the viability of the frozen c ells. Thus, we concluded that the 10 million cells weekly dosing regimen was most appropriate for this phase 1b combinati on study. The selection of the multi -injection intradermal route of administration for HS-110 is based on the hypothesis that split doses stimulate stronger immune responses by allowing vaccine antigens to reach more regional lymph nodes (where immune resp onses are generated). The vaccine will be administered intradermally to enhance stimulation of cellular immune responses as compared to subcutaneous or intramuscular immunization. 6.3. Rationale for Obtaining Archival Tissue and Performing Tumor Biopsies In ord er for an allogeneic cell -based vaccine to elicit to a clinical response, it must not only stimulate a tumor -antigen -specific immune response as detected by circulating lymphocytes in the peripheral blood, but those lymphocytes must also infiltrate the tumor microenvironment. A respon se to HS-110 is expected in patients whose tumors express antigens that overlap with the antigens contained within the AD100 cell backbone of HS-110. In addition, the response of patients with tumors that express numerous antigens shared with HS-110 is expected to surpass the response of those with tumors that only share 1 or 2 antigens with HS-110. Furthermore, clinical response to HS-110 may be predicted by the presence and extent of tumor infiltration by CD8 + T-cells. Thus, a rchival or fresh biopsy tissue will be obtained for pre -treatment tumor analysis , and a fresh biopsy sample should be collected for post -treatment analysis when feasible (unless written authorization from the Sponsor is obtained) . 6.4. Rationale for Inclusion of Squamous Cell Carcinoma Patients While the AD 100 line selected for HS -110 was deriv ed from adenocarcinoma, an example of evaluating upregulated gene expression between NSCLC a deno carcinoma and s quamous cell carcinoma has been depicted below (Figure 2) showing overlap of 14 antigens between adenocarcinoma tumor bank data and HS -110, and an overlap of 10 antigens between squamous cell carcinoma tumor bank antigen expression and HS -110. Thus, m ultiple shared antigens between HS -110 and squamous cell carc inoma support the rationale for inclusion of squamous cell carcinoma patients in this clinical trial. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 32 of 95 Figure 2: Number of Common Antigens between HS -110, Squamous and Adenocarcinoma in NSCLC Figure 2 : HS-110 was derived from AD100 cell line from adenocarcinoma; HS -110 has 14 antigens in common with adenocarcinoma and HS -110. In addition , HS-110 has 10 antigens in common with squamous NSCLC. 6.5. Rationale for Checkpoint Inhibitor Progressor Patients and First Line Maintenance Patients Currently, pembrolizumab is the only checkpoint inhibitor approved for first -line treatment in NSCLC in patients with ≥ 50% PD -L1 expression. It has shown an improvement in ORR, but there are still patients that have PD. This is an area of unmet need and response rates to additional check point inhibitors in the second and third line , specifically monoclonal antibodies (mAbs) such as nivolumab, pembrolizumab, and atezolizumab are unknown . Combining HS-110 with anti -PD-1 agents may enhance the vaccine’s anti -tumor activity while prolonging or increasing the efficacy of the checkpoint inhibitor. The combination of HS-110 and nivolumab is hypothesized to evoke a synergistic effect, based on the theory that checkpoint inhibit ors work best in PD -L1 positive tumors in the presence of TIL. Studies in mice have s hown that the combination of PD -1 blockade and gp96 -Ig vaccination results in a potent increase in the number of CD 8 + cytotoxic T-cells.20 Emerging data from this ongoing DURGA trial show s increased TIL after HS-110 vaccine and i ncreased tumor expression of P D-L1. Therefore, Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 33 of 95 combining this treatment for CPI progressor patients affords the opportunity to determine if HS- 110 can stimulate PD -L1 expression on the tumor , and improve efficacy of nivolumab. 6.6. Rationale for First Line Maintenance Dosing Patients in first line maintenance phase run the risk of disease progression, some of which can be attributed to the continuous generation of exhausted and inadequate numbers of tumor specific effector T cells. The goal of adding HS-110 along with PD -1/L1 blockade in the maintenance phase is to ensure a higher probability that tumor growth will be controlled by the continuous generation of antigen specific CD8 + T cells, and rescue of this activated CD8 + T cells from exhaustion. Many patients fail to receive second -line therapy due to rapid progression of disease, decrease in their performance status, or increase cancer -related symptoms. By treating patients with HS-110 along with PD -1 blockade in the maintenance phase of first line therapy, the window of opp ortunity for immune driven treatment benefit may be augmented and extended. Exhausted tumor specific T cells maybe refractory or resistant to complete rescue by PD -1 blockade therapy alone and require additional activation and expansion of new tumor specif ic sets of CD8 + T cells. It can therefore be surmised that concomitant dosage of HS-110 along with checkpoint blockade in the first line maintenance phase until progression can ensure an ongoing and expanded adaptive immune response as opposed to CPI treat ment alone. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 34 of 95 7. INVESTIGATIONAL PLAN 7.1. Overall Study Design This is a master protocol, intended to evaluate multiple immune modulation strategies in combination with HS-110; subsequent treatment arms will be added by amendment as supporting data for these combi nation therapies mature. Patients will be assigned to treatment arms based on the fit to eligibility criteria. As of Amendment 4, the Phase 1b portion of the trial (consisting of the first 15 patients to receive HS-110 in combination with nivolumab) is com plete . Subsequent patients and cohorts will be considered Phase 2. Treatment Arm 1 (HS -110 plus oxygen, n=1 patient) has been discontinued. Patients in previously designated Arms 2, 3, and 4 all received HS -110 + nivolumab but had different TIL status. Pa tients from these arms have now been reclassified as Arm 5, and further enrollment into this arm is ongoing. As of Amendment 5, the patient population under study will be expanded to include front line patients who have received immunotherapy (with or wi thout chemotherapy), who have not progressed clinically or radiographically (per RECIST 1.1) at the most recent imaging assessment , and who will begin maintenance immunotherapy with SOC pembrolizumab ± pemetrexed. HS- 110 will be added to their immunotherapy maintenance regimen, and must be initiated on or before maintenance cycle 3 (after completion of platinum chemotherapy ), or no later than week 19 (if receiving front line pembrolizumab monotherapy). Patients who meet all eligibility criteria will be enrolled to the below treatment arm s and cohorts (n=120) : Arm 5 HS-110 plus SOC nivolumab (n=100, to include 15 phase 1b patients and 85 phase 2 patients). Arm 6 HS-110 plus SOC pembrolizumab ± pemetrexed (n=up to 20 phase 2 patients). Arm 5 p atients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a dose of 1 × 1 07 viable cells/ 0.5 mL for 18 weeks and nivolumab infusions administered every two weeks . After 18 weeks of treatment, patients will continue on monotherapy SOC nivolumab until confirmed disease progression or unacceptable toxicity, whichever occurs first. After completion of 18 weeks of combination therapy, patie nts may receive either nivolumab dosing schedule listed in the package insert (every 2 weeks or every 4 weeks) per Investigator discretion . Arm 5 patients will be scanned radiographically at Screening, Week 9, Week 18, and every 8 weeks thereafter until c onfirmed disease progression . Arm 6 patients will receive a combination of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a dose of 1 × 107 viable cells/ 0.5 mL for 1 3 weeks in combination with SOC pembrolizumab ± pemetrexed every 3 weeks. Following the 1 3-week prim ing period, HS-110 injections will be administered for boost ing every 3 weeks in combination with SOC pembrolizumab or SOC pembrolizumab/pemetrexed until con firmed disease progression or unacceptable toxicity, whichever occurs first . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 35 of 95 Arm 6 patients will be scanned radiographically at Screening and every 9 weeks thereafter until confirmed disease progression . For all study patients , the scan schedule will continue until confirmed disease progression (iCPD) as defined by iRECIST , after which they will be followed for OS. Using the principles of iRECIST, patients with unconfirmed disease progression (iUPD) should continue on study treatment until confirmed pr ogression (iCPD) unless clinical progression necessitates otherwise. For all study patients, screening tumor samples (archival or fresh) and on -treatment biopsy tumor samples (when feasible to obtain) will be screened for expression of immune active cell subsets and molecules, expression of PD -L1 on tumor cells and evaluation for the presence of TILs . Pre- and post -treatment TIL and PD-L1 levels with be correlated with clinical outcomes. Peripheral b lood samples will be taken to evaluate tumor mutatio n burden and immune cell subsets for correlation with clinical outcomes. Safety will be assessed by frequency of adverse events (AEs), evaluation of clinical laboratory parameters (hematology, liver function, electrolytes, troponin, and renal function), vi tal signs, electrocardiogram (ECG), and physical exams (PEs). Efficacy will be assessed by measures of OS, ORR, DOR , DCR, DRR and PFS by RECIST 1.1 . The overall study design is summarized below in Figure 3. Figure 3: Study Design 7.2. Study Treatment s Each patient will be assigned a unique patient identification number at screening ; this unique identifier will be recorded on all CRF s and ancillary documents specific to the patient . Prospective patients will be considered enrolled in the study on the date of their first dose of HS -110. Patients enrolled in Arm 5 will receive HS-110 administered concomitantly with nivolumab . HS- 110 0.5 mL will be administered intradermally as weekly injection s for 18 weeks. Standard of care nivolumab will be given intravenously every 2 weeks until the HS-110 administration period is Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 36 of 95 complete, after which nivolumab may be administered either every 2 weeks or every 4 weeks (per Investigator’s discretion) in accordance with the current approved nivolumab Package Insert . Patients enrolled in Arm 6 will receive HS-110 plus SOC pembrolizumab ± pemetrexed. HS-110 will be administered concomitantly with maintenance pembrolizumab +/ - pemetrexed. HS-110 0.5 mL will be administered intradermally as weekly injection s for 13 weeks , followed by 0.5 mL intradermal injections every 3 weeks . Treatment with HS-110 and pembrolizumab +/ - pemetrexed will continue until confirmed disease progression or unacceptable toxicity, whichever occurs first . Patients’ participation in this study may continue 2 years or longer . The duration of the nivolumab, pembrolizumab, and pembrolizumab/pemetrexed treatments are standard of care (SOC) and will continue along with radiology scans until confirmed disease progr ession or unacceptable toxicity. Following confirmed disease progression , patients will be followed by telephone or office visit for survival approximately every 3 months . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 37 of 95 8. STUDY OBJECTIVES AND PURPOSE 8.1. Primary O bjective s Phase 1b: To characterize the safet y and tolerability of HS-110 in combination with multiple immune modulating strategies in patients with NSCLC . Phase 2, Arm 5 : To evaluate Objective Response Rate (ORR) by RECIST 1.1 in each cohort . Phase 2, Arm 6: To evaluate progression free survival (PFS) by RECIST 1.1 in each cohort . 8.2. Secondary O bjectives • To evaluate overall survival (OS) , objective response rate (ORR ), progression free survival ( PFS), duration of response (DOR) , durable response rate (DRR) and disease control rate (DCR) per RECIST 1.1 . • Arm 5: To characterize the safety and tolerability of HS-110 in combination with nivolumab in patients with NSCLC . • Arm 6: To characterize the safety and tolerability of HS-110 in combination with pembrolizumab ± pemetrexed in patients with NSCLC. 8.3. Exploratory Objectives • Efficacy parameters of ORR, PFS, DOR, DCR, and DRR will be analyzed using the principals of iRECIST to produce iORR, iPFS, iDOR, iDCR, and iDRR. • To characterize the peripheral blood immunologic response (IR) via Enzyme -Linked ImmunoSpot (ELISPOT) analysis. • To determine total peripheral blood mononuclear cell (PBMC) counts, including leukocyte subsets that define NK and T cell subsets of activation, memory and exha ustion . • To evaluate archival and fresh biopsy tissue for presence of tumor -infiltrating lymphocytes (TILs), level of PD -L1 expression, correlation of pre - and post -treatment TIL and PD -L1 measurements on tumor cells with clinical outcomes, and expression of immune active cells and molecules. • To examine tumor mutation burden and other exploratory analysis of peripheral blood and tumor tissue to determine immune changes and response to treatment. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 38 of 95 9. SELECTION AND WITHDRA WAL OF PATIENTS The study population will consist of two distinct patient types. Arm 5 will include meta static NSCLC patients that have failed first line therapy and are undergoing second line therapy or greater . The patients can have adenocarcinoma or squamous cell NSCLC and be checkpoint inhibitor ( CPI) naïve or CPI progressor . Arm 6 will include metastatic NSCLC patients who have received immunotherapy (with or without chemotherapy) in the front line , who have not progressed clinically or radiographically (per RECIST 1. 1) at the most recent imaging assessment , and who will begin initiation of maintenance immunotherapy with standard of care ( SOC ) pembrolizumab ± pemetrexed. [Note: HS -110 dosing to be initiated at/before the start of the 3rd maintenance treatment cycle, or within 1 9 weeks of front -line pembrolizumab monotherapy.] The sections b elow list all of the inclusion and exclusion criteria patients must meet to proceed with enrollment , and they must voluntarily provide written consent to participate in the study. 9.1. Subject Inclusion Criteria Patients must meet all of the following inclusion criteria to be enrolled into the study: 1. Age ≥18 years . 2. Histologically or cytologically confirmed diagnosis of non-small cell lung adenocarcinoma or squamous cell carcinoma . Patients with mixed histology other than adeno -squamous are not eligible. 3. At least one site of measurable disease by CT scan or MRI as defined by RECIST 1.1. [Note: criteria not applicable to Arm 6 patients who have achieved 100% reduction in Target Lesions .] 4. Arm 5: Received at least one prior line of therapy, but no more than three prior lines of therapy, for incurable (i.e. unresectable) or metastatic NSCLC, including cytotoxic chemotherapy, molecularly -targeted agents, or imm unotherapy. One prior line of FDA - approved checkpoint inhibitor (CPI) therapy is permitted, however a treatment period with CPI of at least 4 months is required. OR Arm 6: Received front line immunotherapy (with or without chemotherapy) for incurable or metastatic NSCLC and did not progress clinically or radiographically per RECIST 1.1 at the most recent imaging assessment, and will begin maintenance immunotherapy with SOC p embrolizumab ± pemetrexed. [Note: HS -110 dosing to be initiated at/before the start of the 3rd maintenance treatment cycle, or within 1 9 weeks of front -line pembrolizumab monotherapy.] 5. Life expectancy of at least 18 weeks. 6. Arm 5: Documented disease progression at study entry. OR Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 39 of 95 Arm 6: Documented Stable Disease, Partial Response, Complete Response (SD/PR/CR) per RECIST 1.1 after a minimum of 9 to 12 weeks of front line immunotherapy (with or without chemotherapy). 7. Eastern Cooperative Oncology Group (ECOG ) performance status (PS) of 0 or 1. 8. Central Nervous System ( CNS ) metastases may be permitted after discussion with the Medical Monitor and must meet the following conditions: a. Patient must be treated and radiographically and neurologically stable . Stab le CNS metastases are defined by the return of neurological symptoms to baseline, use of no more than 10 mg of prednisone or equivalent per day, and no evidence of new or active brain lesions in the repeated scan prior to study entry. b. Brain lesions must ha ve been previously irradiated, including whole brain radiation therapy or radiosurgery. c. All radiation treatment (except for localized stereotactic palliative therapy) must be completed at least 4 weeks prior to enrollment . 9. Lab parameters: • Albumin ≥ 2.5 g/dL. • Total Bilirubin < 3.0 × u pper limit of normal ( ULN ) unless patient has Gilbert’s syndrome. • Alanine transaminase ( ALT ) and aspartate transaminase ( AST ) ≤ 3.0 × ULN or ≤ 5 × ULN in the case of liver metastases. • Calculated or measured creatinine clearance > 35 mL/minute per the Cockcroft -Gault formula. • Absolute neutrophil count ≥ 1,500/mm3. • Hemoglobin ≥ 9 g/dL. • Platelet count ≥ 100,000/mm3. 10. Willing and able to comply with the protocol and sign informed consent, i ncluding office visits for weekly HS-110 injections for 18 weeks (Arm 5) or weekly HS-110 injections for 13 weeks followed by every 3 week boosting injections until disease progression (Arm 6) . 11. Female patients who are of childbearing potential and fertile m ale patients must agree to use an effective form of contraception (e.g., abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) with their sexual partners throughout study participation. Female pati ents of childbearing potential must test negative for pregnancy prior to enrolling in the trial. 12. Willing to provide either archival or fresh biopsy sample at Screening , and fresh tumor biopsy at Week 10 when feasible . Archival tissue used at Screening must be representative of the patient’s current disease state unless written authorization from the Sponsor is obtained . Fresh biopsy at Week 10 may be waived with written authorization from the Sponsor. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 40 of 95 13. Arm 5 : Suitable for treatment with nivolumab per the current approved package insert. OR Arm 6: Suitable for front line maintenance treatment with pembrolizumab ± pemetrexed per the current approved package inserts. 9.2. Subject Exclusion Criteria Patients that meet any of the following exclusion criteria are not eligible to be enrolled into the study: 1. Arm 5: Received systemic anticancer therapy within 21 days prior to first dose of study drug. 2. Human immunodeficiency virus (HIV), hepatitis B or C, o r severe/uncontrolled infections or concurrent illness, unrelated to the tumor, requiring active therapy. Testing is not required in the absence of history. 3. Any condition requiring concurrent systemic immunosuppressive therapy. 4. Known immunodeficiency disor ders, either primary or acquired. 5. Known leptomeningeal disease. 6. Active malignancies within 12 months , with the exception of those with a negligible risk of metastasis or death , and treated with expected curative outcome. 7. Pregnant or breastfeeding. 8. Prior pa rticipation in a cl inical study of HS-110. 9. Active, known, or suspected autoimmune disease. 10. Received a live vaccine within 30 days prior to first dose of study drug. 11. Significant cardiovascular disease: a. Baseline Left Ventricular Ejection Fraction (LVEF ) below lower limit of normal range per institutional standard by ECHO or MUG A within 30 days prior to first dose of study drug . b. History of myocardial infarction within 1 year of enrollment. c. History of heart failure within 2 years of enrollment , or at any time if due to auto - immune causes or prior immunotherapy treatment , unless pre -approved by the medical monitor . d. A clinically significant ECG abnormality, including PR interval of >26 0 ms, any evidence of heart block , or a baseline prolonged QTc interval (e.g., a repeated demonstration of a QTc interval >480 ms) within 30 days prior to first dose of study drug. 12. Refractory to prior immunotherapy ( clinical or radiographic progression after 12 weeks or less of immunother apy). Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 41 of 95 9.3. Patient Completion and Withdrawal Patient Completion Patients in Arm 5 will receive a combination of weekly injections of HS-110 and nivolumab infusions every two weeks for 18 weeks. After 18 weeks of treatment, patients will continue on monotherapy SOC nivolumab until disease progression or unacceptable toxicity, whichever occurs first. After 18 weeks of combination therapy, SOC nivolumab may be administered according to either dosing schedule in the nivolumab package insert (every 2 weeks or every 4 weeks) per Investigator discretion . Arm 5 patients will be scanned radiographically at Screening, Week 9, Week 18, and every 8 weeks thereafter until confirmed disease progression. Patients in Arm 6 will receive we ekly injections of HS-110 for 13 weeks in combination with SOC pembrolizumab ± pemetrexed infusions administered every 3 weeks. Following the 1 3-week prim ing treatment period, HS-110 injections will be administered for boosting every 3 weeks in combination with SOC pembrolizumab ± pemetrexed until confirmed disease progression or unacceptable toxicity, whichever occurs first . Arm 6 patients will be scanned radiographically at Screening and every 9 weeks thereafter until confirmed disease progression. After confirmed disease progression, patients will be followed for collection of subsequent anti - cancer therapies and survival status every 3 months . This may be done via telephone or office visit. Discontinuation from Study Treatment s Every effort must be mad e by study personnel to keep patients on study treatment(s); however, a patient will be discontinued prior to completion of HS-110 treatment for any of the following reasons: • Grade 4 AE(s) considered by the Investigator to be related to study treatment (or Grade 3 AE(s) at the Investigator’s discretion) assessed as related to treatment , except for “expected” AEs with nivolumab or pembrolizumab or pembrolizumab/pemetrexed treatment, as per the package insert s. • Pregnancy. • Termination of the study by the Sponsor. • Intercurrent illness that prevents further administration of treatment. • Patient withdrawal of consent. Patients may also be discontinued prior to completion of the study treatment for any of the following reasons: • Progressive disease, acco rding to iRECIST by a confirmed scan , or significant clinical progression at an earlier time point, if judged by the Investigator to be in the patient’s best interests. If a patient prematurely discontinues study treatment for any reason, the patient will continue to be followed for study endpoints, unless consent for this is specifically withdrawn. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 42 of 95 A reason for discontinuation must be documented in the case report form ( CRF ). If the patient discontinues study treatment due to toxicity, “Adverse Event” wi ll be recorded as the primary reason for withdrawal. If a patient is prematurely discontinued from the study at any time due to an AE or SAE, the patient must be followed until resolution, unless it is unlikely to improve because of underlying disease . Patient Withdrawal from Study 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 2 documented attempts to contact the patient for scheduling a follow -up visit . In accordance with the International Conference on Harmonisation (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 at the institution. The Investigator and Sponsor also have the right to withdraw patients from study treatment, as described above or for safety, behavioral, or administrative reasons. If the patient does not have enough data to be considered evaluable (received at least 6 doses of HS-110 and had a pre -treatment tumor assessment and at least one post -treatment tumor assessment) an additional patient may be enrolled into the study . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 43 of 95 10. STUDY PROCEDURES This study will be conducted in compliance with the protocol, GCP, and applicable regulatory requirements. A current , signed and dated informed consent form (ICF) that has been approved by an IRB/I EC must be obtained from the potential patient before he/she can participate in any study -specific procedures, including study -specific screening procedures. A patient will be considered enrolled on the date of the first dose of HS -110. For Arm 5 patients, t he study will generall y be conducted in 4 periods, as follows: Screening, On Study ( receiving HS -110 treatment ), Post-HS-110 Follow -up ( no longer receiving HS -110 treatment, but not yet progressed ), and Survival Follow -up (after confirmed disease progression) . For Arm 6 patients, the study will generally be conducted in 3 periods, as follows: Screening, On Study ( priming and boosting until progression), and Survival Follow -up (after confirmed disease progression). 10.1. Screeni ng Procedures and Baseline (Day -28 to Day -1) The following procedures and assessments must be conducted within approximately 4 weeks (Day -28 to Day -1) prior to the first dose of study medication . For e ach potential patient , the following procedures and assessments will be performed by qualified study staff. These procedures and assessments may occur on the same day as dosing, as long as the collection of biopsy tissue and blood samples occurs PRIOR to dosing with any stud y drug and recorded appropriately to verify . Qualified study personnel should obtain the following : • A current IRB/IEC -approved ICF must be signed and dated before any study -related procedures are performed. • Complete medical history including prior treatments and surgeries, prior medications , and pre -existing clinical signs and symptoms • Patient demographics (age, sex, race and ethnic ity) • Eastern Cooperative Oncology Group ( ECOG ) performance status (PS) (Appendix 1 ) • Full p hysical examination (PE) including height and weight, and an evaluation of all body systems (Section 13.1) • Vital signs (blood pressure, heart rate , respiratory rate, and temperature) • Draw b lood for hematology , serum chemi stry, and troponin I or T (Section 13.2) • Blood draw for baseline immunological response (Section 14.2) • Serum or urine pregnancy test for fe male patients of childbearing potential (Section 13.2) • Tumor assessment, including CT scan or MRI, to document target and non -target lesions by RECIST 1.1 and iRECIST . (Section 14.1.1 ) Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 44 of 95 • Mandatory archival or fresh tissue collection . Note that sample must be obtained via incis ional, excisional or core needle biopsy. A fine needle aspiration is not acceptable for archival or fresh biopsy. Additional tissue collection and preparation procedures are provided in a separate Biopsy Manual . • Electrocardiogram (ECG) • Echocardiogram (ECHO ) or Multiple -Gated Acquisition ( MUGA ) Scan with left ventricular ejection fraction ( LVEF ) (Section 13.4) • Verify eligibility criteria via inclusion and exclusio n criteria per Section 9.1 and Section 9.2. Baseline Assessments (Day -7 to Day 1) The following procedures will be performed after all the previous screening procedures have been completed and prior to dosing. • Reassessment of ECOG PS (Appendix 1 ) • Record pre -existing symptoms as medical history and prior medications. • Hematology and serum chemistry only if the Screening Visit was performed more than 2 weeks prior to the first dose (Section 13.2) • Serum or urine pregnancy testing for females of child -bearing potential only if the Screening Visit was performed more than 2 weeks prior to the first dose (Section 13.2) • Re-Verify eligibility criteria via inclusion and exclusion criteria per Section 9.1 and Section 9.2 10.2. Arm 5: On Study Treatment Procedures Study -related procedures and assessments performed during treatment on study are detailed as follows and in the Schedule of Activities (SOA ; Table 2). This period of the study is generally considered to be the combination treatment period from Day 1 through Week 18, but could be shorter in duration if HS-110 is prematurely discontinued . Week 1 Assessments (Day 1) The following procedures will be performed after all the previous Screening and Baseline procedures have been completed: • Update of prior medications and p re-existing symptoms as medical history • Reconfirm eligibility prior to dosing • Blood draw for tumor mutation burden (TMB) obtained prior to dosing (Section 14.6). Note that Cohort B patients enrolled prior to Amendment 5 that did not have a week 1 TMB sample collected should have a one -time TMB lab drawn at the next feasible visit (i.e. Week 4, 10, 16 or post -HS110/survival follow -up). • Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 45 of 95 • Administration of HS-110 • Monitor patients on site for potential acute reactions for 30 minutes after HS-110 admini stration (first dosing only) • Administration of SOC nivolumab per package insert • Record any AEs experienced by patient • Record concomitant medications Week 2 Assessments The following procedures wil l be performed at Week 2 (Day 8 ± 3): • Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) • Vital signs, with abbreviated PE (Section 13.1) targeted to signs and symptoms • Administration of HS-110 • Record AEs experienced by patient • Record concomitant medications Week 3 Assessments The following procedures will be performed at Week 3 (Day 15 ± 3): • Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) • ECG conducted prior to dosing • Vital signs, with abbreviated PE targeted to signs and symptoms • Administration of HS-110 • Administration of SOC nivolumab , per package insert • Record AEs experienced by patient • Record concomitant medications Week 4 Assessments The following procedures will be performed at Week 4 (Day 2 2 ± 3): • Blood draw for Troponin I or T levels obtained prior to dosing (Section 13.4) • Vital signs, with abbreviated PE targeted to signs and symptoms • Blood draw for h ematology and serum chemistry (Section 13.2) • Administration of HS-110 • Record AEs experienced by the patient • Record concomitant medications Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 46 of 95 Week 5, 6, 8, and 11 Assessments The following procedures w ill be performed at Week 5 (Day 29 ± 3), Week 6 (Day 3 6 ± 3), Week 8 (Day 5 0 ± 3), and Week 11 (Day 7 1 ± 3). • Vital signs, with abbreviated PE targeted to signs and symptoms (Weeks 5 and 11 only) • Administration of HS-110 • Administration of SOC nivolumab (Weeks 5 and 11 only), per package insert • Record AEs experienced by the patient • Record concomitant medications Week 7 and 13 Assessments The following procedures will be performed at Week 7 (Day 4 3 ± 3), and Week 13 (Day 8 5 ± 3): • Vital signs, with abbreviated PE targeted to signs and symptoms (Week 7 only). • Blood draw for IR prior to dosing (Section 14.2) • Blood draw for hematology and serum chemistry (Section 13.2) • Administration of HS-110 • Administration of SOC nivolumab , per package insert • Record AEs experienced by the patient • Record concomitant medications Week 9 and 18 Assessments The following procedures will be performed at Weeks 9 (Day 5 7 + 3) and Week 18 (Day 12 0 ± 3): • Tumor assessment by CT scan or MRI and evaluation of tumor response using RECIST 1.1 and iRECIST ( Section 14.1.1 ) • Administration of HS-110 • Administration of SOC nivolumab (only on Week 9) , per package insert • Record AEs experienced by the patient • Record concomitant medications Week 10 and 16 Assessments The following procedures will be performed at Week 10 (Day 6 4 ± 3) and Week 16 (Day 10 6 ± 3): • Blood draw for hematology and serum chemistry (Section 13.2) • Tumor biopsy (Week 10 only) to be obtained when feasible unless written authorization from the Sponsor is obtained. Note that sample must be obtained via incisional, excisional or core needl e biopsy.