2. Histologically or cytologically confirmed 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 3 lines of therapy, for incurable (i.e. unresectable) or metastatic NSCLC, including cytotoxic chemotherapy, molecularly -targeted agents , or immunotherapy . One prior line of an FDA -approved checkpoint inhibitor (CPI) therapy is permitted, however a treatme nt period with CPI of at least 4 months is required . OR Arm 6: Received front line immunotherapy (with or without chemotherapy) for incurable (i.e. unresectable) or metastatic NSCLC and did not progress clinically or radiographically per RECIST 1.1 at most recent imaging assessment , and will begin maintenance immunotherapy with 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 m onotherapy.] 5. Life expectancy of at least 18 weeks . 6. Arm 5: Documented disease progression at study entry OR 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 condi tions: Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 8 of 95 a. Patient must be treated and radiographically and neurologically stable . Stable 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 ac tive brain lesions in the repeated scan prior to study entry. b. Brain lesions must have 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 × upper limit of normal (ULN) unless patient has Gilbert’s syndrome . − Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 × U LN or ≤ 5 × U LN 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. − Hemoglo bin ≥ 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 1 3 weeks followed by every 3 week boosting injections until disease progression (Arm 6) . 11. Female patients who are of childbearing potential and fertile male 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 patients of childbearing potential must test negative for pregnancy prior to enrolling in the trial. 12. Willing and able to provide ei ther 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. Note that the f resh biopsy at Week 10 may be waived with written authorization from the Sponsor. 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. Exclusion Criteria : 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, or 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 disorde rs, either primary or acquired . 5. Known leptomeningeal disease . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 9 of 95 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 participation in a cl inical study of HS-110. 9. Active, known , or suspected autoimmune disease at any time prior to study entry . 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 MUGA to be obtained 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 >2 60 ms, any evidence of heart block, or a baseline prolonged QTc interval ( e.g., a repeated demonstration of a QTc interval >480 ms) to be obtained within 30 days prior to first dose of st udy drug 12. Refractory to immuno therapy (clinical or radiographic progression after 12 weeks or less of immunotherapy ). Investigational product, dosage and mode of administration: HS-110 (v iagenpumatucel -L) is provided as fully -diluted, frozen liquid not requiring additional dilution. The final drug product will consist of 10 million cells resuspended in buffered saline containing human serum albumin (HSA), dimethyl sulfoxide (DMSO) and pentastarch. Dosing w ill rotate injection site extremities at every time point: antero -lateral left thigh, antero -lateral right thigh, left shoulder, and right shoulder. Arm 5: HS-110 Patients will receive a dose of 1 × 107 HS-110 cells per 0.5 mL administered as 5 spatially divided intradermal injections ( ≤ 0.1 mL per injection) once weekly for 18 weeks , or until confirmed radiographic or clinical progression or unacceptable toxicity, whichever occurs first . Nivolumab Patients will receive SOC nivolumab every 2 weeks during the 18 -week combination treatment period or until PD or unacceptable toxicity , whichever occurs first . After 18 weeks of combination treatment, SOC nivolumab may be administered per either dosing schedule in the current approved nivolu mab package insert (every 2 weeks or every 4 weeks) per Investigator discretion . Arm 6: HS-110 Patients will receive a dose of 1 × 107 HS-110 cells per 0.5 mL administered as 5 spatially divided intradermal injections ( ≤ 0.1 mL per injection) once weekly for 13 weeks in combination with SOC pembrolizumab +/- Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 10 of 95 pemetrexed every 3 weeks. Following the 1 3-week prim ing period, HS-110 injections will be administered for boosting every 3 weeks in combination with pembrolizumab +/- pemetrexed until confirmed radiographic or clinical progression or unacceptable toxicity, whichever occurs first. Pembrolizumab ± Pemetrexed Patients in this group will receive SOC every 3 weeks per the pembrolizumab and pemetrexed package inserts for the treatment of NSCLC. Safety Parameters: Primary Endpoint : Phase 1b: Safety and Tolerability: Measured by the frequency of treatment emergent adverse events (TEAEs)/serious adverse events (SAE s), including clinically significant (CS) abnormal laboratory parameters, ECGs, PEs, and vital signs in patients receiving at least 1 dose of HS-110. Effica cy Parameters: Primary Endpoint s: Phase 2: Arm 5 - Objective Response Rate: Defined as the number of patients achieving a best overall response of complete response ( CR) or partial response ( PR) by RECIST 1.1 , divided by the total number of enrolled patients. This will be calculated for each cohort. Note that ORR will be a secondary endpoint for Arm 6. Phase 2: Arm 6 - Progression -Free Survival: Calculated as the time between the date of first dose of HS -110 and the date of PD as defined by RECIST 1.1 or death, whichever occurs first. For patients with no recorded post-baseline tumor assessments, PFS will be censored at the day of first dose . For those who remain alive and have no PD, PFS will be censored on the date of last evaluable tumor assessment. This will be calculated for each cohort. Note that PFS will be a secondary endpoint for Arm 5. Secondary Endpoint s: Overall Survival (OS): Calculated as the duration from date first dose of HS -110 to date of death from any cause or will be censored on the date the patient was last known to be alive. Duration of Response (DOR) : Calculated from the time of first response (CR or PR) until radiographic PD (per RECIST 1.1) or clinical deterioration requ iring a change of treatment. Disease Control Rate (DCR): Defined as the p roportion of evaluable patients whose best overall response is PR, CR, or SD by RECIST 1.1. Durable Response Rate (DRR /): Defined as the % of responders (CR or PR) with durable responses lasting at least 6 months from time of initial response. DRR will be calculated at 6 and 12 months. OS Rate : Defined as the p roportion of patients who are alive at 6 , 12, and 24 months following first dose of HS - 110.PFS Rate: Define d as the p roportion of patients who have not progressed at 6 and 12 months following first dose of HS -110. Safety and Tolerability: Measured by the f requency of TEAEs/SAEs including CS abnormal laboratory parameters, ECGs, PEs, and vital signs in patients receiving at least 1 dose of HS-110. Exploratory Endpoints: Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 11 of 95 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. Peripheral blood IR will be measured by ELISPOT to detect an increase of 2 -fold over baseline of IFNγ and/or granzyme B (gzB) positive T cells, as well as analysis of surface markers that define NK and T cell subsets of activati on, memory and exhaustion by flow cytometry . Evaluation of tumor tissue obtained for presence of TILs and correlation of pre - and post -treatment TIL levels with clinical outcomes . Evaluation of tumor tissue obtained for expression of PD -L1 on tumor cells and correlation of pre - and post - treatment PD -L1 expression with clinical outcomes. Evaluation of peripheral blood TMB to measure the number of mutations within the tumor genome and correlation of TMB levels with clinical outcomes. Other exploratory analysis of peripheral blood and tumor tissue to determine immune changes and response to treatment may be conducted as new technology emerges . Statistical methods: Study populations are defined as follows: Safety Population : all patients who receive at least 1 dose of HS -110. Per-Protocol (PP) Population: all patients who have received at l east 6 doses of HS-110, and who have a pre- treatment tumor assessment and at least one post-treatment tumor assessment. Adenocarcinoma Population: all patie nts in the PP who have adenocarcinoma histology The Phase 1b portion is an exploratory substudy with safety as a primary endpoint. In Phase 2, t he results from each cohort in Arm 5 and Arm 6 will be tabulated separately . Arm 5 will include 2 cohorts , with a primary endpoint of ORR for each cohort: - Cohort A: CPI naïve patients (n=40) - Cohort B: CPI progressor patients (n=60) . Note that this Cohort will be permitted to over -enroll based on patient availability. Arm 6 is an exploratory arm that will include up to 20 patients in 2 cohorts pending patient availability . The primary endpoint for each cohort will be PFS. The distribution of patients between these cohorts will not be control led: - Cohort C: Maintenance pembrolizumab - Cohort D: Maintenance pembrolizumab + pemetrexed Each cohort (A, B, C and D) will be analyzed including patients of all histology types , and then again including only adenocarcinoma patients. Analyses will be performed within each of the cohorts to identify differences in strata for each of the following factors , provided sufficient data exists : • Histology: a denocarcinoma and squamous cell carcinoma • PD-L1 status : negative ( <1% ) and positive (≥1% ) based on tumor cell expression Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 12 of 95 • TIL status : high (> 10%) and low (≤ 10%) • Tumor Mutation Burden : high (10 or more mutations) and low (less than 10 mutations) Additional factors , such as line of treatment or presence of injection site reactions, may be added to statistical models used for analyse s; the method of pooling and testing for interaction among the different factors for the different cohorts will be described in detail in the SAP. With a total enrollment into this hypothesis -generating clinical trial of up to 120 patients across the two treatment arms, this study should have sufficient patients to identify likely subgroups for whom the addition of HS-110 to SOC appears have a clinically meaningful benefit over SOC alone . No formal hypothesis testing wil l be performed. Baseline demographic and clinical data (safety and efficacy) as well as all exploratory endpoints will be summarized using descriptive statistics (means, median s, proportions, standard deviations, minima, and maxima). Time -to-event endpoint s (PFS /iPFS , OS) will be calculated using Kaplan -Meier methodology. All summaries of binary efficacy endpoints such as immune response, DCR /iDCR and ORR will be presented with exact 95% CI for each cohort. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 13 of 95 4. TABLE OF CONTENTS 1. INVESTIGATOR’S AGREE MENT ................................ ................................