To assess the maximum tolerable dose and safety of intrathecal (IT) PD1 antibody administration

Overall survival

leptomeningeal disease

1. Must be ≥ 18 years at the time of signing the informed consent. 2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. 3. Patients with a "good risk" status as defined by the NCCN guidelines (version 1.2021) 4. Tumor board protocol confirming: - a clinical recommendation for intrathecal therapy and evaluation of trial enrollment - a statement on the potential necessity of additional systemic treatment of metastatic tumor outside the CNS 5. Able to adhere to the study visit schedule and other protocol requirements. 6. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment. 7. Patients with Karnofsky performance score > 50% 8. Diagnosis of LMD by CSF and/or MRI a. A thorough CSF evaluation must be performed in every patient prior to the inclusion in this trial. The reason is that a positive CSF cytology is consideredthe gold standard for LMD diagnosis. Furthermore, a thorough CSF evaluation will allow the thorough assessment of potential differential diagnosis (for example, viral meningitis, bacterial meningitis, aseptic meningitis, sarcoidosis etc.) b. Presence of malignant cells on CSF cytology. The frequency of CSF evaluation is based on guideline of the German Society of Neurology: Please note that the first lumbar puncture is only 50-60% sensitive. Repeat collection increases sensitivity up to approximately 80%. Thus, a negative first CSF evaluation should at least be repeated once. According to guidelines from the German Society for Neurology each CSF collection should draw enough, i.e. at least 5- 10 ml CSF and should be processed within one hour of collection. c. MRI diagnosis of LMD: pial enhancement, pial nodular manifestations (as defined per LANO criteria, see appendix). d. A positive CSF cytology and an MRI evidence is enough to determine the LMD diagnosis. e. Please note that approximately 20% of patients with symptomatic LMD might lack positive CSF cytology even upon repeated puncture. In these cases, the LMD diagnosis can also be performed based on cerebral/spinal MRI manifestations and by exclusion of differential diagnosis f. In the absence of diagnostic findings for LMD in the CSF: patients must present with typical clinical and MRI signs of LMD (Le Rhun et al., 2017). If the CSF has signs of pleocytosis (BUT NOT any malignant, atypical or suspicious cells) the differential diagnoses for CSF pleocytosis (aseptic meningitis, viral meningitis, bacterial meningitis) must be excluded. g. Some centers perform biopsies of leptomeninges for obtaining a LMD diagnosis. The LMD diagnosis will be based on histology and should be documented accordingly. Yet, a histological diagnosis of LMD is NOT required for the inclusion in this trial. 9. If radiation therapy had occurred: Please make sure that a documentation of the past radiation therapy is available (including applied dosage and radiation therapy fields): a. Participants eligible for IT-PD1 should have completed their radiation therapy due to clinical indication > 2 weeks prior to enrollment into the trial b. All LMD patients without an indication for radiation therapy (per investigator`s choice) can be enrolled immediately 10. Neurological examination (NANO scale) (Nayak et al., 2017)11. MRI: the assessment at baseline and for subsequent time points should be based on the LANO scorecard (see appendix) according to (Le Rhun et al., 2019) 12. Ability to undergo intrathecal therapy via an intraventricular catheter (e.g. Ommaya reservoir) 13. Primary tumor tissue for the assessment of PD1 and PD-L1 should be available but does not need to be shipped before enrollment of patient into the trial. 14. Female Patient of childbearing potential1 and male patients with female partner of childbearing potential1 is willing to use highly effective contraceptive methods during treatment and for 150 days (male or female, see SmPC) after the last dose. Recommendations highly effective contraceptive methods are: a. combined hormonal contraception associated with inhibition of ovulation (oral-, intravaginal, -transdermal) b. progestogen-only hormonal contraception associated with inhibition of ovulation (pral injectable, implantable), c. intrauterine device (IUD), d. intrauterine hormone - releasing system (IUS), e. bilateral tubal occlusion, f. vasectomized partner2, g. sexual abstinence3

1. Women during pregnancy and lactation. 2. Previous intrathecal nivolumab application. 3. Patient at "poor risk" (NCCN guidelines version 1.2021) 4. The following differential diagnoses to LMD are exclusion criteria a. Aseptic meningitis b. Viral meningitis c. Bacterial meningitis 5. History of hypersensitivity to monoclonal antibodies 6. Participation in other clinical trials or observation period of competing trials. 7. A clinical condition that in the opinion of the investigator would interfere with the evaluation or interpretation of patient safety or trial results or that would prohibit the understanding of informed consent and compliance with the requirements of the protocol 8. Any treatment-related toxicities from prior systemic anti-tumor or immune therapy not having resolved to CTCAE version 5.0 grade 1, with the exception of alopecia 9. Patient with confirmed history of current autoimmune disease 10. Patients with any disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy 11. Clinically significant active infection, for example: a. Presence of human immunodeficiency virus b. Active hepatitis B virus/hepatitis C virus. HIV infection or active Hepatitis B or C infection, PCR-based detection of SARS-Cov2 or active infections requiring oral or intravenous antibiotics or that can cause a severe disease and pose a severe danger to lab personnel working on patients' blood or tissue (e.g. rabies) *. 12. Inability to undergo MRI with contrast agent 13. The underlying primary tumor has not a registered and authorized indication in the European Union for intravenous treatment with nivolumab, pembrolizumab or atezolizumab. The solide tumor registered are, i.e. melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck region,urrothelial carcinoma, squamous cell carcinoma of the oesophagus tumours, triplenegative breast carcinoma 14. Abnormal laboratory values for the following values in haematology, coagulation parameters, liver and renal function: a. Haemoglobin < 8 g/dl b. White blood cell count < 2.0 x 109/L) c. Platelet count decrease < 50 x 109/L d. Bilirubin > 2.5 x upper limit of normal (ULN) according to the performing laboratory`s reference range. Note that benign hereditary hyperbilirubinemia e.g. Gilbert`s syndrome is permitted. e. Alanine aminotransferase > 3 x ULN f. Aspartate aminotransferase > 3 x ULN g. Serum creatinine increase > 1.5 x ULN 15. Patients who have received live or attenuated vaccine therapy used for prevention of infectious disease within 4 weeks of the first IT application of nivolumab 16. Patients requiring chronic systemic corticosteroid therapy (> 10 mg prednisone or equivalent per day) or any other immunosuppressive therapies (including anti-TNF-a therapies).