except to the extent that disclosure would be required by law and for the purpose of evaluating and/or conducting this clinical study . It is permissible to disclos e informatio n only to your Institutional Review Board or Ethics Committee, study personnel directly involved with conducting this study, or participants in the study to obtain informed consent. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 2 of 95 Persons to whom information is disclosed must be notified tha t the information is confidential and proprietary to Heat Biologics, Inc . Sponsor: Lori McDermott Vice -President, Clinical Development Heat Biologics, Inc. 801 Capitola Drive, Suite 12 Durham, NC 27713 Tel: +1 -919-794-8950 Email: lmcdermott @heatbio.com Medical Monitor: James Balsley, MD ProPharma Group 5205 Indigo Moon Way Raleigh, NC 27613 Tel: +1 -410-708-7609 Fax: +1 -919-844-6948 Email: james.balsley@propharmagroup.com Principal Investigator: Daniel Morgensztern, MD Associa te Professor, Division of Oncology Department of Medical Oncology Washington University School of Medicine in St. Louis St. Louis, MO 63110 Tel: +1 -314-747-7948 Email: danielmorgensztern@wustl.edu Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 3 of 95 1. INVESTIGATOR’S AGREE MENT Protocol Number: HS110 -102 Protocol Title: A Phase 1b/2 Study of Viagenpumatucel -L (HS -110) in Combination with Multiple Treatment Regimens in Patients with Non -Small Cell Lung Cancer (The “DURGA” Trial) Amendment #: 6 Version Date: 24 May 2019 I have read and understood Protocol HS110 -102 Amendment 6 (dated 24 May 2019 ) and agree to conduct the study as outlined and in accordance with the principles of Good Clinical Practice as described in the Internation al Conference on Harmonization G uideline s (ICH E -6) and Form FDA 1572 , including the archiving of essential documents . I agree to maintain the confidentiality of all information received or developed in connection with this protocol . Printed Name of Investigator Signature of Investigator Date Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 5 of 95 3. SYNOPSIS Name of Sponsor/Company: Heat Biologics, Inc. Name of Investigational Product: Viagenpumatucel -L (HS -110) Title of Study: A Phase 1b/2 Study of Viagenpumatucel -L (HS -110) in Combination with Multiple Treatment Regimens in Patients with Non -Small Cell Lung Cancer (The “DURGA” Trial) Study center(s): Up to 25 U.S. centers Phase of development: 1b/2 Primary Objectives: Phase 1b: To characterize the safety and tolerability of v accination with HS-110 in combination with multiple immune modulating strategies in patients with non -small cell lung cancer (NSCLC) . Phase 2, Arm 5 : To evaluate Objective Response Rate (ORR) by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) . Phase 2, Arm 6: To evaluate Progression Free Survival (PFS) by RECIST 1.1 Secondary Objectives: • 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 patie nts with NSCLC. • Arm 6: To characterize the safety and tolerability of HS-110 in combination with pembrolizumab ± pemetrexed in patients with NSCLC. Exploratory Objectives: • Efficacy parameters of ORR, PFS, DOR, DCR, and DRR will be analyzed using the princi pals 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 lymphocyte subsets. • To e valuat e archival and fresh biopsy tissue for presence of tumor -infiltrating lymphocytes (TIL), level of programmed cell death ligand ( PD-L1) expression, correlation of pre - and post -treatment TIL and PD -L1 measurements with clinical outcomes, and expression of immune active cell subsets 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 6 of 95 Trial 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 as these combination 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 nivo lumab) is complete . 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 TI L status. Patients 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 was expanded to include front l ine patients who have received immunotherapy (wi th or without 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 a ll eligibility criteria will be enrolled to the below treatment arm s and cohorts , until the total sample size for Phase 2 is met ( n=105) in addition to the Phase 1b sample size (n=15) for a total study sample size of approximately 120 evaluable patients: 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 combin ation of weekly HS-110 administered as 5 intradermal 0.1 mL injections at a dose of 1 × 107 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 the completion of 18 weeks of combination therapy, patients may receive either nivolumab dosing schedule listed in the current approved package insert (every 2 weeks o r 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 d isease progression. Arm 6 patients will receive a combination of weekly HS-110 administered a s 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 priming period , HS-110 injections will be administered for boost ing every 3 weeks in combination with SOC pembrolizumab ± pemetrexed until confirmed disease prog ression or unacceptable toxicity, whichever occurs first. 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 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 progression (iCPD) unless clinical progression necessitates otherwise . For all study patients, screening t umor samples (archival or fresh) and on -treatment biopsy tumor samples may be screened for expression of immune active cell subsets and molecules, expression of PD -L1 on tumor cells, and Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 7 of 95 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 mutation burden and immune cell subsets for correlation with clinical ou tcomes . Safety will be assessed by frequency of adverse event s (AEs), evaluation of cl inical laboratory parameters (hematology, liver function, electrolytes, troponin, and renal function) , vital signs, electrocardiogram ( ECG ), and physical exams (PEs) . Efficacy will be assess ed by measures of OS as well as ORR , DOR , DCR, DRR and PFS by RECIST 1.1 . Number of evaluable patients (planned): Up to 120 Phase 1b: 15 patients (complete d in 2017) Phase 2: Up to 105 patients Inclusion criteria : 1. Age ≥ 18 years .