11.5. Dose Adjustment Criteria Any Grade 3 or higher AE determined to be treatment -related (HS-110 and/or nivolumab and/or pembrolizumab ± pemetrexed ) will be discussed with the Medical Monitor before continuing with dosing, with the following exceptions: • Local injection site reactions lasting <72 hours, including pain, redness, swelling, induration, or pruritus • Systemic injection reactions lasting < 72 hours of fever, myalgia, headache, or fatigue • For patients in Treatment Arm 5: known and manageable reactions considered “expected” with nivolumab per the package insert • For patients in Treatment Arm 6: known and manageable reactions considered “expected” with pembrolizumab and/or pemetrexed per the package inserts. Where judged appropriate by the Investigator (after discussion with the Medical Monitor) a dose delay may be necessary for ≥ Grade 3 AEs until resolution of the toxicity ( to Grade 1 or less). HS-110: No dose m odifications of HS-110 will be permitted. Nivolumab , pembrolizumab and pemetrexed : Dose modifications are permitted according to their package insert s. If nivolumab , pemb rolizumab and/or pemetrexed is discontinued due to toxicity, patients may continue to receive HS-110. This approach is consistent with results showing clinical benefit in patients even after toxicity -related treatment discontinuation. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 57 of 95 12. STUDY D RUG MATERIALS AND MAN AGEMENT All production, formulation, and packaging of the investigational agent will be in accordance with applicable current Good Manufacturing Practice (cGMP) and meet applicable criteria for use in humans. 12.1. HS-110 HS-110 is provided as single -dose vials containing fully-diluted frozen liquid not requiring additional dilution. The final drug consist s of 10 million cells resuspended in buffered saline containing human serum albumin ( HSA ), dimethyl sulfoxide (DMSO), and pentastarch. Overfill of 0.1 mL is factored into e ach vial to allow extraction of the full 0.5 mL dose for patient administration. Additional detail can be found in the Pharmacy Manual. Each HS-110 dose totaling 1 × 107 cells per dose will be administered as 5 spatially divided intradermal injections (≤ 0.1 mL per injection) in the same extremity to increase volume distribution and enhance antigen presentation to lymph node regions. Vaccine dosing will rotate injection site extremities at every time point : ante ro-lateral left thigh, antero -lateral right thigh, left shoulder, and right shoulder. Missed doses may be made up if the missed dose is given at least 4 days before the subsequent dose. All doses will be administered at the Investigator site. In Arm 5, HS-110 will be administered weekly for 18 weeks. In Arm 6, HS-110 will be administered weekly for 1 3 weeks. Following the 13-week prim ing 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) . 12.2. Study Drug Storage The activity of HS-110 is critically dependent on the viability of the cells in th e preparation and vials must be stored at cryogenic temperature (≤ - 120⁰ C) in liquid nitrogen vapor phase. The product is supplied to the clinical site from the clinical supply depot via shipments in liquid nitrogen dry -shipper units which are validated to maintain temperature for 10 days. Upon arrival, the product must be transferred to controlled liquid nitrogen storage at the clinical site for continued storage. If liquid nitrogen storage is not available at the investigative site, a unit will be suppl ied by the Sponsor. The Sponsor will also arrange for replacement of the liquid nitrogen at regular intervals to ensure that the proper storage temperature is maintained throughout the study. Study staff must take care to minimize temperature excursions du ring transfer of the product from shipping containers to controlled ultralow temperature storage on site. The product should not be retrieved from cryogenic storage until the study subject is present and available for dosing. When removing a product carton from storage to retrieve a vial for dosing, any doses remaining in the carton must be returned to ≤ - 120ºC immediately. Additional study drugs (nivolumab, pembrolizumab, pemetrexed) will be commercially supplied and stored according to instructions in their current approved package insert s. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 58 of 95 12.3. Study Drug Preparation HS-110 must be thawed and the syringes labeled prior to injection. Preparation of the product and syringe labeling procedures is described in the Pharmacy Manual. Note that HS-110 must be administered within 2 hours of removing from liquid nitrogen dewar. 12.4. Labeling HS-110 is labeled with the product name, the dose identification number, storage requirements, and the statement "Caution: New Drug — Limited by Federal (or United States ) law to investigational use." Additional country -level requirements may be included on the carton label. Additional study drugs (n ivolumab , pembrolizumab, and pemetrexed) are used as commercially supplied; labelling is not applicable. 12.5. Study Drug Accountab ility The Investigator or designee (where applicable) will be responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the Investigator or designated site sta ff (e.g., pharmacist) must maintain current investigational product accountability records throughout the course of the study. These records will contain the following information: • Date, quantity, and vial/bottle number(s) received from and returned to the sponsor (if applicable) . • Patient ID number, date, quantity, and vial/bottle number(s) of agent dispensed . • Date, quantity, and vial/bottle number(s) of accidental loss of study agent (if applicable) . • Date, quantity, and vial/bottle number(s) of study drug destroyed per institutional guidelines (if applicable and approved by Sponsor ). • Documentation of storage conditions . These inventories must be made available for inspection by the study monitor , auditors and/or regulatory inspectors . The Investigator is responsible for ensuring that all used and unused clinical supplies are accounted for. At the end of the trial the study monitor will also collect the original investigational agent dispensing record. A copy of the dispensing record should b e kept at the site and maintained with the study records. 12.6. Occupational Safety Precautions should be taken to avoid direct contact with the study drug. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling precautions will be provided to the Investigator . Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 59 of 95 13. ASSESSMENT OF SAFETY Safety data will be collected throughout the study by a qualified physician, physician assistant, or nursing staff. Measurements used to evaluate safety will include medical history, physical examination, vital signs, clinical laboratory tests, ECGs, and evaluation of AEs. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE v4.03) .22 Clinically significant abnorma l laboratory parameters (as determined by the Investigator) may be repeated. If warranted, additional or more frequent testing than is specified in the protocol if warranted by the physician to monitor and treat AEs and should be document ed in the study record until resolution. 13.1. Physical Examination PEs must be performed by a qualified physician, nurse practitioner, or physician assistant and should include a thoro ugh review of all body systems at Screening (Day -28 to Day -1) and at the EOT Visit . Body systems to be evaluated include Head, Eyes, Ears, Nose and Throat (HEENT), Pulmonary, Cardiovascular, Musculoskeletal, Abdominal/Gastrointestinal, Lymphatic, Neurolo gical, Dermatologic, and Genito -urinary systems . In addition, the full PE will include obtaining the patient’s height and weight . Abbreviated PEs will be conducted at Weeks 2, 3, 4, 5, 7, 11, 15 for arm 5 , and at Weeks 2, 3, 4, 7, and 10 for arm 6. Abbrevi ated PEs are limited to vital signs and physical symptoms unless otherwise clinically indicated. Vital signs include b lood pressure, heart rate, respiratory rate, and temperature , and will be measured after resting in a semi -supine or supine position. 13.2. Clinical Laboratory Evaluations Blood samples will be collected for routine clinical laboratory testing and cardiovascular monitoring . The clinical laboratory parameters will be analyzed at the site’s local laboratory. Laboratory assessments to be completed will include serum chemistry, hematology, Troponin I or T, and urine or serum pregnancy test (females of childbearing potential), and are defined as follows: • Serum Chemistry (5 mL) : To include sodium, calcium, total p rotein, albumin, creatinine, blood urea nitrogen (BUN) , total bilirubin, alkaline phosphatase, AST, ALT, potassium, chloride, sodium bicarbonate, lactate dehydrogenase, and glucose. • Hematology (5 mL) : To include white blood cell (WBC) with differential, pl atelet count, hemoglobin, red blood cell (RBC) count and absolute neutrophils . • Troponin I or T (5 mL) : See Section 13.4 for further details. • Urine or serum (1 mL) pregnancy test : See Section 13.5 for further details. • Additional laboratory assessments may be conducted throughout the study as medically necessary. Heat Biologics, Inc. Viagenpumatucel -L Protocol HS110 -102 CONFIDENTIAL Amendment 6, 24 May 2019 Page 60 of 95 13.3. Injection Site Reactions The grading scale for injection site reactions ( ISRs ) used in this trial can be found in Appendix 2 . Grade 1 ISRs consisting of mild redness, erythema, and swelling around the injection site are anticipated. Grade 1 reactio ns should dissipate over several days to a week with no special treatment. All ISRs , regardless of grade, should be recorded on the Injection Site Reaction CRF page , including a photograph of each reaction where feasible . If an unusual , Grade 3 , or Grade 4 ISR occurs, attempts to obtain photographs at initial report and at follow -up visits, which show resolution over time, are encouraged. A ruler should be in the field of view to allow measurement of the size of the reaction. De-identified photograph( s) should be appended to the CRF.