Ph I/II Trial of Systemic VSV-IFNβ-NIS in Combination With Checkpoint Inhibitor Therapy in Patients With Select Solid Tumors

Inclusion Criteria: * Histologically confirmed diagnosis of: * Arm 1: dose level 1 and below: Advanced and/or metastatic solid tumors for which no existing options are felt to provide clinical benefit * Arm 2: dose level 2: Advanced and/or metastatic NSCLC OR NEC in which radiological progression has been demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit. * Arm 3: Advanced and/or metastatic NEC in which radiological progression has been demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit. * Arm 4: Advanced and/or metastatic NSCLC in which radiological progression has been demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit. * Arm 5: NEC: poorly differentiated NEC (large or small cell, or not further specified) with progressive disease following at least one prior line of systemic therapy. * Arm 6: RCC: histologically confirmed diagnosis of advanced or metastatic RCC, including all IMDC risk categories (favorable, intermediate, and poor risk). * Measurable disease based on RECIST 1.1. The first 3 patients in the safety run-in phase do not need measurable disease. Part C: advanced NEC (neuroendocrine carcinoma based on histopathology according to WHO criteria. Patients with small cell carcinoma, large cell neuroendocrine carcinoma, and neuroendocrine carcinoma not otherwise specified, of any primary organ are eligible in which radiological progression has been demonstrated during therapy with a PD-(L)1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit. * Performance status of 0 or 1 on the ECOG Performance Scale. * Life expectancy of \>3 months if not on active anti-cancer therapy * Willingness to provide biological samples required for the duration of the study including a fresh tumor biopsy sample. * Adequate organ function using predefined laboratory values obtained ≤14 days prior to registration. * Negative pregnancy test for female patients of childbearing potential * Absence of active CNS involvement. NOTE: Pre-enrollment imaging of asymptomatic patients not mandatory * Ability to provide written informed consent. * Willing and able to comply with scheduled visits, treatment schedule, and laboratory testing. Exclusion Criteria: * Availability of and patient acceptance of curative therapy. a. For NSCLC cohort: i. Known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 \[L858R\] substitution mutations). All patients with non-squamous histology must have been tested for EGFR mutation status; use of an FDA-approved test is strongly encouraged. ii. Non-squamous histology and unknown or indeterminate EGFR status. b. Part D NSCLC cohort: Known ALK translocations which are sensitive to available targeted inhibitor therapy. If tested, use of an FDA-approved test is strongly encouraged. Patients with unknown or indeterminate ALK status may be enrolled. * Recent or ongoing serious infection, including: 1. Any active Grade 3 or higher (per the NCI CTCAE, version 4.03) viral, bacterial, or fungal infection within 2 weeks of registration. 2. Known seropositivity for or active infection by the human immunodeficiency virus (HIV). 3. Acute hepatitis B or acute hepatitis C. Patients with chronic hepatitis B or hepatitis C may be enrolled provided their liver function is adequate as per section 3.17 4. Known history of active TB (Bacillus tuberculosis). * Any serious health condition, which, in the opinion of the investigator, would place the patient at undue risk from the study, including uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months) * Prior therapy within the following timeframe before the planned start of study treatment as follows: * Chemotherapy, small molecule inhibitors, radiation, interventional radiology procedure, and/or other investigational agent: ≤3 weeks or 5 half-lives, whichever is shorter * Other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or experimental therapies: ≤4 weeks (≤3 weeks with documented disease progression) * Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks prior to randomization. Subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of randomization are strongly encouraged to receive palliative radiotherapy prior to randomization. * NSCLC patients only: prior chemotherapy or immunotherapy or a combination of chemotherapy and immunotherapy for stage IV NSCLC. * RCC patients: i. Previously received a CTLA-4 inhibitor in the first-line setting. ii. Relapsed/progressed during adjuvant immunotherapy with a PD-(L)1 inhibitor or relapse within 12 months after completion of adjuvant immunotherapy * New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or SVT) (Appendix II). * Any known or suspected active organ-threatening autoimmune disease, such as inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis, with the exception of hypothyroidism and type 1 diabetes that are controlled with treatment. * Immunodeficiency or immunosuppression, including systemic corticosteroids at \>10mg/day prednisone or equivalent within 1 week prior to planned start of study treatment * History of severe immune-mediated adverse reaction to immune checkpoint inhibitors. * Toxicities from previous therapies that have not resolved to a grade 1 or less. * History of non-infectious pneumonitis that required steroids, or current pneumonitis, or carcinomatous meningitis, or interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. * High volume disease, as assessed clinically via parameters such as radiologic impression and tumor markers or LDH. * Portal vein thrombosis involving more than intrahepatic portal vein branches: thrombosis of the right or left portal vein branch or the bifurcation, partial or complete obstruction of the portal vein trunk. * Known concurrent malignancy that is progressing or requires active treatment. EXCEPTIONS: basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in-situ cervical cancer that has been treated with curative intent, prostate cancer confined to the prostate gland with Gleason score \<6 or PSA \<1, as well as any stage I cancer treated with curative intent or any prior cancer with a disease-free interval of ≥3 years. * Other concurrent anti-cancer therapy (chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (used for a non-FDA approved indication and in the context of a research investigation)). * Neuroendocrine neoplasms described as "well-differentiated" or "moderately differentiated" on pathologic review, or reported as "carcinoid", i.e., not true poorly differentiated neuroendocrine carcinoma \[Nagtegaal 2020\]. * Has received a live vaccine within 30 days of planned start of study treatment. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines and are NOT allowed. * 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 women or women of reproductive ability who are unwilling to use highly effective contraception * Nursing women * Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking the drug and for 4 weeks after stopping treatment. * Prisoners or subjects who are involuntarily incarcerated. * Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness