Modified Immune Cells (Autologous Dendritic Cells) and a Vaccine (Prevnar) After High-Dose External Beam Radiation Therapy in Treating Patients With Unresectable Liver Cancer

Eligibility Criteria

• * Age \>= 18 years
• * Pilot study (group 1): Histologic confirmation of intrahepatic CCA
• * Phase II study (group 2): Histological and/or radiologic confirmation of hepatocellular carcinoma (HCC)
• * The following tumor characteristics must be met
• * Unresectable HCC (group 2) or intrahepatic CCA (group 1)
• * Measurable or evaluable disease
• * All lesions should be treatable by EBRT while meeting normal tissue constraints
• * Tumor lesions should be accessible using an ultrasound (US) guided approach for intratumoral DC injection
• * Patients are required to have no evidence of extrahepatic tumor (excluding tumor thrombus) by computed tomography (CT) or magnetic resonance imaging (MRI) scan
• * NOTE: Patients who are not candidates for surgical treatment or for ablation with curative intent are allowed
• * Good candidate for standard of care high-dose conformal EBRT in the view of the investigator
• * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• * Absolute neutrophil count (ANC) \>= 1000/mm\^3 (obtained =\< 14 days prior to registration)
• * Absolute lymphocyte count (ALC) \>= 500/mm\^3 (obtained =\< 14 days prior to registration)
• * Absolute monocyte count (AMC) \>= 300/mm\^3 (obtained =\< 14 days prior to registration)
• * Platelet count \>= 50,000/mm\^3 (obtained =\< 14 days prior to registration)
• * Hemoglobin \>= 9.0 g/dL (obtained =\< 14 days prior to registration)
• * Total bilirubin \< 1.5 mg/dL (obtained =\< 14 days prior to registration)
• * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 5 x upper limit of normal (ULN) (obtained =\< 14 days prior to registration)
• * Creatinine =\< 2 mg/dL (obtained =\< 14 days prior to registration)
• * Prothrombin time/international normalized ratio (PT/ INR) =\< 1.5 x ULN (obtained =\< 14 days prior to registration)
• * Group 2 ONLY: Absence of proteinuria at screening as demonstrated by one of the following:
• * Urine protein/creatinine (UPC) ratio \< 1.0 at screening OR
• * Urine dipstick for proteinuria \< 2+ (patients discovered to have \>= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate =\<1g of protein in 24 hours to be eligible)
• * Negative pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only
• * Ability to provide written consent
• * Willingness to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• * Willingness to provide blood and tissue samples for correlative research purposes
• * Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
• * Pregnant persons
• * Nursing persons
• * Persons of childbearing potential who are unwilling to employ adequate contraception
• * Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
• * Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy
• * NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
• * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• * Receiving any other investigational agent that would be considered a treatment for the primary neoplasm
• * Other active malignancy =\< 3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
• * NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
• * Major surgery =\< 4 weeks prior to enrollment (other than diagnostic surgery or surgical spacer placement in preparation for radiation treatment)
• * History of hypersensitivity or anaphylactoid reactions to pneumococcal vaccine or any component of the formulation, including diphtheria toxoid
• * Active autoimmune disease such as autoimmune hepatitis, Crohn's disease, rheumatoid arthritis, Sjogren's disease, systemic lupus erythematosus, or similar conditions
• * Requires coagulopathy treatment (INR \> 1.5) or use of anti-platelet agents that cannot be discontinued for the intratumoral injection procedure
• * NOTE: Heparin for line patency without detectable lab abnormalities in coagulation will be allowed
• * Corticosteroids =\< 2 weeks prior to registration, including oral, intravenous (IV), subcutaneous, or inhaled routes of administration
• * NOTE: Patients on chronic corticosteroids for adrenal insufficiency or other reasons may enroll if they receive less than 10 mg/day of prednisone (or equivalent)
• * History of myocardial infarction =\< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• * Child Pugh class B or C cirrhosis of the liver
• * Previously received immune modulating therapies including but not limited to immune checkpoint inhibitors targeting PD-1 PDL-1 CTLA4, etc; or prior dendritic cell therapy
• * Prior liver radiation, including radioembolization
• * Barcelona Clinic Liver Cancer (BCLC) stage D disease
• * History of untreated high-risk gastroesophageal varices.