KRAS-Targeted Vaccine Combined With Balstilimab and Botensilimab for Patients With Stage IV MMR-p Colorectal Cancer and Pancreatic Ductal Cancer

Eligibility Criteria

• * Age ≥18 years.
• * Have histologically or cytologically - proven cancer of the pancreas or colon.
• * Have tumor lesions amenable to repeated biopsy, and patient's acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator).
• * Measurable disease as per RECIST 1.1.
• * Have sufficient and accessible tissue for next generation sequencing (NGS) and immune-phenotyping.
• * Have one of the KRAS mutations included in the vaccine at the time of vaccination expressed in tumor.
• * Cohort A: Have received 4-6 months of FOLFIRINOX or gemcitabine+nab-paclitaxel for the 1st line treatment of metastatic unresectable PDAC.
• * Cohort B: Have received 4-6 months of 1st line SOC chemotherapy per NCCN guidelines (FOLFIRINOX, FOLFOX, FOLFIRI +/- targeted therapy with VEGFi or EGFRi) of metastatic CRC.
• * Cohort C: Have received no more than 3 lines of systemic chemotherapy, including prior KRAS inhibitor.
• * Eastern Cooperative Oncology Group (ECOG) performance status 0.
• * Life expectancy of greater than 3 months.
• * Patients must have adequate organ and marrow function defined by study-specified laboratory tests prior to initial study drug.
• * Woman of childbearing potential must have a negative pregnancy test and follow contraceptive guidelines as defined per protocol.
• * Men must use acceptable form of birth control while on study.
• * Ability to understand and willingness to sign a written informed consent document.
• * Is a candidate for definitive surgical resection.
• * Known history or evidence of brain metastases and/or leptomeningeal spread.
• * Prior treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, etc.).
• * Receiving active immunosuppressive agents or chronic use of systemic corticosteroids within 14 days of vaccine treatment.
• * Has active autoimmune disease that has required systemic treatment in the past 5 years, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
• * Known history or concurrent interstitial lung disease.
• * Has a pulse oximetry \< 95% on room air.
• * Requires the use of home oxygen.
• * Infection with HIV or hepatitis B or C.
• * Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements.
• * Has been diagnosed with another cancer or myeloproliferative disorder in the past 5 years except for superficial bladder cancer, non-melanoma skin cancers, DCIS, a low-grade prostate cancer, or a cancer not expected to impact life expectancy and not requiring therapy.
• * Has had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement.
• * Has received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment.
• * If at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements.
• * Any other sound medical, psychiatric, and/or social reason as determined by the Investigator.
• * Unwilling or unable to follow the study schedule for any reason.
• * Are pregnant or breastfeeding.
• * Any radiological or clinical pleural effusions or ascites.
• * History of malignant small bowel obstruction.
• * On parenteral nutrition.
• * Known or suspected hypersensitivity to Hiltonol.