Study of Personalized Tumor Vaccines (PCVs) and a PD-L1 Blocker in Patients With Pancreatic Cancer That Can be Treated With Surgery

Inclusion Criteria:

• Subjects must be >/= 18 years of age at time of informed consent

• Able to comply with the study protocol, in the investigator's judgment

• Subjective with radiographically resectable primary pancreatic tumors withradiographic features consistent with adenocarcinoma will be evaluated for surgicalresection

• Tumors must be radiographically resectable, defined as:

• A clear fat plane around the celiac and superior mesenteric arteries

• patent superior mesenteric and portal veins without primary tumor involvement

• No encasement of the superior mesenteric vein or portal veins

• No encasement of the superior mesenteric or hepatic arteries

• No metastatic disease

• No extra-regional nodal disease

• Subjects with histologically confirmed resected ductal pancreatic adenocarcinomawith macroscopic complete resection (R0 and R1) will be selected for neoantigenvaccine creation. Subjects with neuroendocrine (and mixed type) tumors are excluded

• Pancreatic cancer surgical staging: T 1-3, N0-2, M0

° Per AJCC 8th edition staging

• Performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) Scale ofPerformance Status (Section 20.0 APPENDICES, Appendix1)

• Subjects must not have had prior chemotherapy, radiation therapy, or immunotherapyfor PDAC

• Subjects must be able to read, understand, and sign informed consent

• Women of childbearing potential must have a negative serum or urine pregnancy testwithin 14 days prior to study initiation

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive measures that result in a failurerate of less than (<) 1% per year during the treatment period and for at least 5months after the last dose of atezolizumab and for at least 90 days after the lastdose of RO7198457. A woman is considered to be of childbearing potential if she ispostmenarcheal, has not reached a postmenopausal state (>/= 12 continuous months ofamenorrhea with no identified cause other than menopause), and has not undergonesurgical sterilization (removal of ovaries and/or uterus)

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse a condom during the entire study period and up to 90 days after lastadministration of RO7198457. Male participants should not donate sperm for 90 daysafter the last dose of RO7198457

• Examples of contraceptive methods with a failure rate of <1% per year includebilateral tubal ligation, male sterilization and established proper use of hormonalcontraceptives that inhibit ovulation, hormone-releasing intrauterine devices andcopper intrauterine devices

• Hormonal contraceptive methods must be supplemented by a barrier method plusspermicide

• The reliability of sexual abstinence should be evaluated in relation to the durationof the clinical trial and the preferred and usual lifestyle of the patient. Periodicabstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) andwithdrawal are not acceptable methods of contraception

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

• Prior neoadjuvant treatment or radiation therapy for PDAC

• Prior therapy with uPD-1 antibody or any other immune therapy

• Borderline resectable, locally unresectable or metastatic PDAC

• Pancreas tumor histology other than PDAC

• Pregnancy, breastfeeding, or intending to become pregnant during the study or within 90 days after the last dose of study treatment

• Life expectancy less than 12 weeks

• Inability to comply with study and/or follow-up procedures

• Any other malignancy for which the patient is undergoing active treatment which willbe concurrent with the investigational agent in this study.

• Patients with unresolved Clavien-Dindo >/= Grade 3 (Section 20.0 APPENDICES ,Appendix 2) postoperative complications

• Actie, uncontrolled bacterial, viral, or fungal infection(s) requiring systemictherapy, defined as ongoing signs/symptoms related to the infection withoutimprovement despite appropriate antibiotics, antiviral therapy, and/or othertreatment

• Active tuberculosis

• Known infection with hepatitis B or C, or history of human immunodeficiency virus (HIV) infection or subjects receiving immunosuppressive or myelosuppressivemedications that would, in the opinion of the investigator, increase the risk ofserious neutropenic complications

• Known hypersensitivity or allergy to the active substance or to any of theexcipients of RO7198457, atezolizumab, oxaliplatin, leucovorin, irinotecan, orfluorouracil

• Serious medical risk factors involving any of the major organ systems, or seriouspsychiatric disorders, which could compromise the subject's safety or the study dataintegrity. These include, but are not limited to:

• History of connective tissue disorders (e.g., lupus, scleroderma, arteritisnodosa)

• History of interstitial lung disease, slowly progressive dyspnea andunproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis,pulmonary hypersensitivity pneumonitis, or multiple allergies

• History of the following within 6 months prior to RO7198457 administration: amyocardial infarction, severe/unstable angina pectoris, coronary/peripheralartery bypass graft, New York Heart Association (NYHA) Class III-IV heartfailure, uncontrolled hypertension, clinically significant cardiac dysthythmia,or electrocardiogram (ECG) abnormality (exceptions: atrial fibrillation,paroxysmal supraventricular tachycardia), cerebrovascular accident, transientischemic attack,, or seizure disorder

• History or autoimmune disease, including but not limited to systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome Wegener's granulomatosis, Sjogren'ssyndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, orglomerulonephritis with the following caveats:

• Patients with a history of autoimmune hypothyroidism on a stable dose ofthyroid replacement hormone may be eligible

• Patient with controlled type 1 diabetes mellitus on a stable insulin regimenmay be eligible

• Patients type 2 diabetes mellitus may be eligible

° Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., no psoriatic arthritis) may be eligibleprovided that they meet the following conditions:

• Rash must cover less than 10% of the body surface area (BSA)

• Disease is well controlled at baseline and only requires low potency topicalsteroids

• No acute exacerbations of underlying condition within the last 12 months (e.g., notrequiring psorlen and ultraviolet A (PUVA) radiation, methotrexate retinoids,biologic agents, oral calcineurin inhibitors, high potency, or oral steroids)

• Treatment with systemic immunosuppressive medication (including but not limited toprednisone >10mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide, andTNF-x antagonists) within 2 weeks prior to RO7198457 administration. Patients whohave received acute, low-dose, systemic immunosuppressant medication (e.g., aone-time dose of dexamethasone for nausea) may be enrolled in the study afterdiscussion with and approval by the PI and Co-PI. The use of inhaled corticosteroids (e.g., fluticasone for chronic obstructive pulmonary disease) is allowed. The use oforal mineralocorticoids (e.g., flurocortisone for patients with orthostatichypotension) is allowed. Physiologic doses of corticosteroids for adrenalinsufficiency are allowed.

• Subjects with allergies to IV contrast agents requiring pretreatment withcorticosteroids will be excluded. Corticosteroids are immunosuppressive and mayinterfere with RO7198457 tolerability and efficacy. Given that there are serialcontrast agent-dependent follow-up imaging studies built into the study which willoverlap with vaccination, subjects who require pretreatment with corticosteroidsprior to IV contrast administration will be excluded

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),organizing pneumonia (i.e., bronchioloitis obliterans, cryptogenic organizingpneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome,T-negative severe combined immunodeficiency [SCID]) or combined T- and B-cellimmunodeficiencies (e.g., T- and B-negative SCID, Wiskott-Aldrich syndrome, ataxiatelangiectasia, common variable immunodeficiency)

• Prior allogeneic bone marrow transplantation or prior solid organ transplantation

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition that wouldcontraindicate the use of an investigational drug

• Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse

• Previous splenectomy

• Administration of a live, attenuated vaccine within 4 weeks before RO7198457administration or anticipation that such a live attenuated vaccine will be requiredduring the study. Influenza vaccination should be given during influenza seasononly. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist)within 4 weeks prior to RO7198457 administration or at any time during the study,and for 90 days following the last study treatment