SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic TNBC and NSCLC

Inclusion Criteria: 1. Willing and able to provide written informed consent/assent for the trial. 2. Male or female aged ≥18 years on the day of informed consent signing. 3. Histologically confirmed locally advanced or metastatic TNBC that has relapsed on or is refractory to standard of care therapy OR histologically or cytologically confirmed metastatic NSCLC that is immunotherapy and chemotherapy naïve or previously treated with 1 cycle of platinum-containing chemotherapy. Epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC patients and NSCLC patients with EGFR or ALK genomic tumor aberrations that have failed FDA-approved targeted therapy for these aberrations will be eligible for enrollment in the study. 4. Measurable disease based on RECIST 1.1, a target lesion of suitable diameter (at least 1 cm) for SBRT, and a non-target lesion (visceral metastatic lesion) at least 1 cm in diameter for abscopal effect evaluation. 5. Willing to provide biopsy tissues as required by the study. 6. Eastern Cooperative Oncology Group performance status of 0 or 1. 7. Adequate organ function as defined by the following laboratory values: * Absolute neutrophil count ≥1,500/µL (without granulocyte colony stimulating factor support within 14 days of assessment) * Platelets ≥100,000/µL * Hemoglobin ≥8 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin dependency (within 7 days of assessment) * White blood cell count \>2,500/µL and \<15,000/µL * Lymphocyte count ≥500/µL * Serum creatinine \<2 X upper limit of normal (ULN) * Serum total bilirubin ≤1.0 X ULN (Subjects with known Gilbert's disease who have serum bilirubin level ≤3 X ULN may be enrolled) * Asparate transaminase and alanine transaminase ≤2.5 X ULN with normal alkaline phosphatase (≤5 X ULN for subjects with liver metastases) OR ≤1.5 X ULN in conjunction with alkaline phosphatase \>2.5 X ULN * Albumin \>2.5 mg/dL * International normalized ratio or prothrombin time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants * aPTT ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants 8. Life expectancy ≥ 6 months. 9. ≥ 4 weeks since any major surgery, completion of radiation therapy, or completion of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any prior therapy). 10. Female subjects of childbearing potential should have a negative serum pregnancy (beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of the trial treatment and should not be lactating. 11. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study therapy. 12. Male subjects of childbearing potential must agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of study therapy. Exclusion Criteria: 1. Unwilling or unable to comply with the study protocol. 2. Subjects for who bone metastases are the only available non-target lesions for abscopal effect evaluation. 3. Subjects with tumors for which SBRT is not considered appropriate standard therapy. This includes subjects with target lesions less than 1 cm in diameter and those with large central lung lesions. 4. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of trial treatment. 5. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 6. Known history of active tuberculosis (Bacillus Tuberculosis). 7. Known or suspected hypersensitivity to pembrolizumab or any of its excipients or any component of the proposed regimen (gene vector/valacyclovir). 8. Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or chronic pancreatitis. 9. Eastern Cooperative Oncology Group performance status of ≥2 or oxygen dependence (e.g., advanced chronic obstructive pulmonary disease). 10. Inability to swallow food or any condition of the upper gastrointestinal tract that precludes administration of oral medications (valacyclovir). 11. Congestive heart failure: New York Association class III or IV heart failure or unstable angina. 12. Sustained or clinically significant cardiac arrhythmias including sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block (Mobitz II or higher atrioventricular nodal block), prolonged corrected QT interval (longer than 470 milliseconds), or history of acute myocardial infarction. 13. Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes or Parkinson's disease), human immunodeficiency virus (HIV), cirrhosis, uncontrolled hypothyroidism, or cardiac failure. 14. History of syncope or family history of idiopathic sudden death. 15. Targeted small molecule therapy or monoclonal antibody or radiation therapy within 3 weeks prior to study Day 0 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. \- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. 16. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 17. Known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. 18. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 19. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. 20. Active infection requiring systemic therapy. 21. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 22. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 23. Pregnant or breastfeeding, expecting to conceive or father children within the projected duration of the trial, starting with the prescreening or screening visit through 120 days after the last dose of trial treatment, or is unwilling to practice an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to administration of trial treatment. 24. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (TNBC cohort only). 25. Prior treatment with immunomodulatory therapy or immunotherapy (TNBC cohort only). 26. Prior treatment with gene vector therapy. 27. Received prior systemic cytotoxic chemotherapy for metastatic disease (NSCLC cohort). 28. Known history of HIV (HIV 1/2 antibodies). 29. History of liver disease such as cirrhosis or known active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus RNA \[qualitative\] is detected). 30. History of or current alcohol misuse/abuse within the past 12 months. 31. Major surgery within 4 weeks prior to study enrollment. 32. Received a live vaccine within 30 days of planned start of trial therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.