Inclusion Criteria:
1. Signed informed consent approved by the IRB
2. Adults ≥ 18 years of age
3. Patients with either:
* A newly suspected diagnosis of GBM based on MRI
* A previous diagnosis of GBM and who have not received prior RT or systemic therapy for their brain tumor
4. Patients who in the opinion of the treating neurosurgeon require resection
5. Patient is willing to undergo planned surgical procedures
6. Patient agrees to make biospecimens that will be prospectively collected (after date of consent) available for research
7. Patients who have undergone a diagnostic biopsy or open surgical procedure prior to enrolling in this study:
* If adequate archival tissue, defined as at least 3 blocks, is readily available, there is clear documentation of its availability, and the patient must consents to provide that tissue, the patient does not need to undergo another biopsy prior to, or on study, in order to be eligible for this trial
* If archival tissue is sufficient as described above, patient must have either residual enhancing disease requiring resection, or molecularly confirmed GBM with a clear clinical indication for additional resection, as determined by the country PI (or delegate) and the designated trial surgeon.
* If archival tissue is insufficient, or if the patient previously underwent a needle biopsy and there is no clear documentation of tissue availability, and the patient wishes to enroll, the patient must agree to undergo a repeat biopsy as part of this study prior to Screening.
8. Hematological function as follows:
* Absolute neutrophil count ≥ 1.5 x 109/L
* Platelet count ≥ 100 x 109/L
* Haemoglobin \> 90 g/L
* Prothrombin time (PT) or partial thromboplastin time (PTT) \< 1.5 x upper limit of normal (ULN)
9. Renal function as follows:
• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min using the Cockcroft-Gault formula (Appendix 1)
10. Hepatic function as follows:
* Total bilirubin ≤ 1.5 x ULN (Exception: Patient has known or suspected Gilbert's Syndrome for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable)
* Alkaline phosphatase (ALP) ≤ 2.5 x ULN
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
* Serum albumin ≥ 25 g/L
11. Eastern Co-operative Oncology Group (ECOG) performance status of 0-1 (Appendix 2)
12. Life expectancy of at least 12 months
13. Negative human immunodeficiency virus (HIV) test at Screening
14. Negative hepatitis B surface antigen (HbsAg) test at Screening or positive test followed by a negative hepatitis B virus (HBV) DNA test at Screening
15. Negative hepatitis C antibody (anti-HCV) test at Screening or positive test followed by a negative HCV RNA test at Screening
16. Able to undergo brain MRI with and without contrast
17. People of childbearing potential must agree to use a highly effective contraceptive method (with a failure rate of \< 1%) during study treatment and for at least 6 months following the last dose of study drug and agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period. Acceptable methods of contraception are:
* Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
* Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
* Intrauterine device: Intrauterine hormone-releasing system
* Bilateral tubal occlusion
* Vasectomised partner
* Sexual abstinence: Considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence needs will be evaluated in relation to the duration of the study and to the usual lifestyle of the patient Note: People are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the person has been confirmed by follow-up hormone level assessment are they considered not of childbearing potential.
18. Sexually active patients that are able to produce a sperm, must use a condom during intercourse and must agree to refrain from sperm donation, from registration on the study until 3 months after the last dose of treatment
19. People of childbearing potential must have a negative highly sensitive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) at the time of screening and within 48 hours of starting the study drug(s)
20. Ability to adhere to the study visit schedule and all protocol requirements
Exclusion Criteria:
1. Tumors where a gross total resection is not considered feasible by the treating neurosurgeon
2. Tumor involves cerebellum, brainstem, or deep basal ganglia
3. Patients who require urgent resection for mass effect, cerebral edema, or hydrocephalus in the opinion of the treating neurosurgeon
4. Patients with contraindications to MRI or unwilling to undergo MRI
5. History of CNS bleeding as defined by stroke within 6 months prior to registration
6. Contraindication to surgery
7. Treatment with immunosuppressive medications Note: Low-dose corticosteroids (≤ 2 mg/day dexamethasone or equivalent) for tumor-associated edema is permitted. Patients who require corticosteroids \> 2mg/day dexamethasone (or equivalent) for acute emergencies during the screening window will be eligible, if the corticosteroid dosing reduces to ≤ 2 mg/day dexamethasone (or equivalent) at least one day prior to the initial trial-mandated biopsy.
8. Active autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis
9. Active tuberculosis
10. Patient has had a previous SARS-CoV-2 infection either suspected or confirmed within 4 weeks prior to screening. Acute symptoms must have resolved and based on treating physician's assessment, there are no sequelae that would place the patient at a higher risk of receiving trial treatment
11. Evidence of acute intracranial/intra-tumoral hemorrhage, which requires urgent intervention
12. Severe infection within 4 weeks prior to registration
13. Treatment with a live, attenuated vaccine within 4 weeks prior to registration, or anticipation of need for such a vaccine during study or within 5 months after final dose of nivolumab and relatlimab
14. Patients with prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin or other malignancies with no evidence of disease for 2 years or more
15. Major surgical procedure, other than for diagnosis, within 4 weeks prior to registration
16. History of idiopathic pulmonary fibrosis, organising pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted
17. Patient is pregnant or breastfeeding/chestfeeding
18. Prior allogeneic stem cell or solid organ transplantation
19. Known allergy or sensitivity nivolumab, relatlimab, temozolomide or their excipients
20. Patient has any kind of disorder that, in the opinion of the site PI, may compromise the ability of the patient to give written informed consent and/or to comply with all required study procedures
21. Patients with a history of myocarditis
22. Patient has troponin T (TnT) or I (TnI) \> 2 × ULN Note: Patients with TnT or TnI levels between \> 1 × to 2 × ULN will be eligible if repeat levels within 24 hours are ≤ 1 × ULN. If TnT or TnI levels are between \> 1 × to 2 × ULN within 24 hours, the patient must be evaluated by a cardiologist. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are \< 2 × ULN, the patient must be evaluated by a cardiologist. After cardiologist evaluation, the patient may be eligible if the site PI assesses a favorable benefit/risk
23. Left ventricular ejection fraction (LVEF) \< 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 6 months prior to registration
24. History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the site PI would pose a risk to patient safety or interfere with the study evaluation, procedures or completion
