Inclusion Criteria:
* SAFETY COHORT
1. Patients with advanced/metastatic/unresectable solid tumors progressed on standard therapies. Patients with melanoma and RCC will make up approximately 30% of total cohort.
2. Patients with 1-4 tumor sites that can be irradiated safely
3. Age \> or equal 18 years
4. ECOG performance status 0 or 1
5. Patients must have normal organ and marrow function as defined below:
* Leukocytes ≥ 3000/mcL;
* absolute neutrophil count ≥ 1500/mcL;
* Platelets ≥ 100,000/mcL;
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN) ;
* Total bilirubin ≤ 1.5 × ULN (except participants with Gilbert's Syndrome who must have normal direct bilirubin)
* Serum creatinine ≤ 1.5 × ULN Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non- nodal lesions and short axis for nodal lesions) as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam
6. Ability to understand and the willingness to sign a written informed consent document.
7. Reproductive status
* Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study treatment.
* Women must not be breastfeeding.
* WOCBP must agree to follow instructions for method(s) of contraception (Appendix 5) for the duration of study treatment plus 5 half-lives of nivolumab plus 30 days (duration of ovulatory cycle), for a total of 155 days post treatment completion. Local laws and regulations may require use of alternative and/or additional contraception methods.
* WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, but should still undergo pregnancy testing as described in this section.
* Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (Appendix4) during combination treatment with study treatment BMS-986253 and nivolumab, plus 5 half-lives of nivolumab (∼125 days), plus 90 days (duration of sperm turnover), for a total of 215 days post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time.
* EFFICACY COHORT
1. Patients with anti-PD1/PDL1 refractory melanoma
2. Patients with 1-4 tumor sites that can be irradiated safely
3. Age ≥ 18 years
4. ECOG performance status 0 or 1
5. Patients must have normal organ and marrow function as defined above for safety cohort
6. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non- nodal lesions and short axis for nodal lesions) as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam
7. Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
1. Known or suspected CNS metastases, with the following exceptions:
a) Subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following 18 radiation and/or surgical treatment at the time of randomization. b) Subjects must be off steroids for at least 2 weeks prior to initiation of investigational therapy c) Subjects with signs or symptoms of brain metastases are not eligible unless brain metastases are ruled out by computed tomography or magnetic resonance imaging.
2. Medical History and Concurrent Diseases
* Patients who are receiving any other investigational agents.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and BMS-986253
* Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
* Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
i. Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent ii. Uncontrolled angina within the 3 months prior to consent iii. Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled atrial fibrillation) within a month prior to consent iv. QTc prolongation \> 480 msec v. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association \[NYHA\] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled deep venous thrombosis, etc) vi. Cardiovascular disease-related requirement for daily supplemental oxygen vii. History of two or more coronary revascularization procedures within the 3 months prior to consent viii. Subjects with history of myocarditis, regardless of etiology
* A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
* Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after endocrinopathy).
* Subject has been administered prior chemotherapy or immunotherapy at any time, and any with radiation therapy within 4 weeks prior to time of consent or who has not recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to previously administered agent.
1. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
2. Subjects with endocrinopathy which is adequately controlled with hormone replacement therapy are an exception to this criterion and may qualify for the study.
* If subject underwent major surgery, subject must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
* Subject has a 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.
* A known or underlying medical condition that, in the opinion of the investigator could make the administration of study drug hazardous to the subject or could adversely affect the ability of the subject to comply with or tolerate study therapy.
* Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with the study drugs.
* Subjects who are unable to undergo venipuncture and/or tolerate venous access
* Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy ≤ 7 days prior to initiation of study drug therapy
* Subjects who are on immunosuppressive therapy (systemic steroids 10mg and more daily use)
* 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
* Inability to comply with restrictions and prohibited activities and treatments
