19 Heat Biologics Protocol No. HS130 -001 A Phase I Study of HS -130 in combination with HS-110 in patients with solid tumors HS130- 001 6 of 60 Version 2.0 - 11 Feb 2020 Confidential - Entire Page CLINICAL STUDY SYNOPSIS Name of Sponsor: Heat Biologics 627 Davis Drive, Suite 400 Morrisville , NC 27560 (919) 240- 7133 Name of finished product: HS-130/ HS-110 Name of active ingredient: HS-130/ HS-110 Title of the study: A Phase I, first -in-human, dose -escalation study to evaluate the safety and immunologic response after administration of HS -130 in combination with HS- 110 (viagenpumatucel -L) in patients with solid tumors refractory t o standard care Protocol number: HS130- 001 Investigator and study center: Rachel E. Sanborn, MD Providence Cancer Institute , Portland, OR, USA Clinical phase: Phase I Objectives: Primary : • To evaluate safety and tolerability of HS -130 in combination with HS -110 in patients with solid tumors refractory to Standard of Care (SOC) • To determine the recommended phase 2 dose (RP2D) of the combination HS -130 and HS-110 in patients with solid tumors refractory to SOC Secondary: • To determine clinical response to combination treatment with HS -130 and HS- 110 Exploratory : • To study the immunological effect generated by HS- 130 and HS-110 by evaluating proportions of natural killer (NK) and T cell subsets for levels of activation, memory and exhaustion using flow cytometry • To evaluate patient archival tumor tissue for overexpressed Cancer Testis Antigens (CTAs) and shared antigen expression with HS -110 • To evaluate immune reactivation response to CTA expressed in HS -110 (e.g. by ELISPOT) • To determine the presence of a specific cytokine /chemokine signature in response to combination treatment with HS -130 and HS- 110, or any other unspecific inflammatory response • Genomic , immunohistochemical and p roteomic analyses of tumor tissue (pre -dose and on -treatment biopsy ) to identify biomarkers predictive of response or resistance to HS -110/HS -130, for example by multiplex immunohistochemistry ( mIHC) • Assess immunologically active dose based on flow cytometry analysis of blood, using immune marker panels of activation and suppression as defined in Section 8.6.1 Heat Biologics Protocol No. HS130 -001 A Phase I Study of HS -130 in combination with HS-110 in patients with solid tumors HS130- 001 7 of 60 Version 2.0 - 11 Feb 2020 Confidential - Entire Page Study Overview : This is a n open -label, non- controlled, first-in-human, Phase I study of the combined intradermal administration of HS-130 and HS-110 to patients with advanced solid tumors refractory to SOC. Escalating doses of the viable , replication -incompetent , human whole cell vaccines, HS-130 and HS-110, will be administered to patients via intradermal injection s/re-injections (up to 10 total) on Day 1 of a two- week cycl e. The length of each cycle is two weeks, and the DLT window of observation includes the safety data obtained from the first two treatment cycles, Cycle 1 and Cycle 2 ( 4 weeks ). Seven dose levels will be explored , and patients will receive separate escalating doses of HS-130 and HS-110 in alternating fixed 1 :1 or 2 :1 ratio based on the amount of secreted OX40L -Ig (HS-130) and gp96- Ig fusion protein (HS-110) per cell of the drug product . The starting dose of HS -130/HS-110 combination is based on the dose - ranging studies conducted in animal model s of T cell expansion and tumor challenge , as well as established clinical experience from HS -110. The first cohort will employ an accelerated design to evaluate the first 4 dose levels in single patients . There will be a staggered enrollment with a minimum 1-week delay between each patient in cohort 1. If any drug- related ≥ Grade 2 (other than Grade 2 injection site reaction with pain) event occurs during the first cycle of treatment, the study will revert to 3+3 design starting at that dose level. Subsequent cohorts in the dose escalation phase will enroll patients following the standard 3+3 design. Three patients will be enro lled in each subsequent dose cohort, and enrolled with a (minimum) 1-week staggered delay (i.e. Patient 2 to be d osed ≥1-week after Patient 1 received the first dose , and Patient 3 to be dosed ≥1- week after Patient 2 received the first dose) . In the 3- patient cohorts (i.e. 3 patients treated at the same dose) , if 1 out of 3 patients experience a DLT during the first two treatment cycle s, the dose cohort will be expanded up to 6 patients. If ≥ 2 out of 6 patients experience DLTs, the MTD has been exceeded, and dose escalation will cease. Up to 3 additional patients will be enrolled at a lower dose if only 3 patients were treated at that dose level, to confirm safety of that dose. MTD will be defi ned as a dose where ≤ 1 out of 6 patients have DLTs. Once all patients in a cohort have completed the first two cycles of dosing and received at least 2 doses of HS - 130/HS- 110, the safety and tolerability of the combination treatment administered will be reviewed by the safety review committee (SRC). If 0 out of 3 patients or 1 out of 6 patients experience a DLT, then the SRC may recommend enrollment at the next higher dose level. Any patient who does not receive two doses of the study treatment during the DLT window of observation (first 2 cycles) , for reasons other than study drug -related toxicity and did not experience a DLT will not be taken into account in the assessment of the overall DLT rate for the particular dose level cohort and will be replac ed. In the absence of progressive disease and intolerable toxicity after Cycle 2, the patient can continue the combination treatment of HS -130/HS -110 administered every 2-weeks until disease progression, death, patient’s withdrawal of consent, I nvestigator decision to discontinue treatment , or intolerable toxicity, whichever occurs first. Immune response may be a delayed effect, and in immuno- oncology , treatment beyond first progression is commonly used in situations where clinical progression is asymptomatic and/or is not likely to result in life - threatening complications with further progression. There fore, at the discretion of the I nvestigator the treatment with the therapeutic vaccines HS -130/HS -110 may continue despite evidence of disease progression if the investigator considers this of a potential clinical benefit for the patient, and the following criteria are met: • No other approved palliative or curative salvage therapy exists for the indication (e.g. resection of pulmonary metastases in os teosarcoma patients). Heat Biologics Protocol No. HS130 -001 A Phase I Study of HS -130 in combination with HS-110 in patients with solid tumors HS130- 001 8 of 60 Version 2.0 - 11 Feb 2020 Confidential - Entire Page • The patient continues to meet all other study protocol eligibility criteria. • No DLT has been observed, and all toxicities resolved to the baseline level, consistent with the study eligibility criteria.