L19IL2/L19TNF in Skin Cancer Patients

Inclusion Criteria: 1. Patient participation to the present study is subjected to the positive evaluation of a local interdisciplinary tumor board, in the context of available treatment alternatives. Whatever the tumor (list of eligible tumors below) the local interdisciplinary tumor board has to consider that a local response to injection of L19IL2/L19TNF may be of benefit for the patient, in the context of this tumor and available therapeutic opportunities, benefit defined by any of the following objectives: (1) to avoid surgery considered difficult or mutilating or (2) as a neoadjuvant treatment with the objective to permit surgery considered initially impossible, or to facilitate surgery considered difficult or mutilating, or to secure surgery considered of uncertain effect or (3) as a salvage treatment to control a tumor proved resistant to treatment alternatives or (4) as a palliative treatment improving patient comfort. 2. Patient must have at least one skin tumor that is amenable to intratumoral injection. 3. All tumors must be histologically confirmed before treatment. 4. Patients with skin tumors eligible to the present study include: * BCC patients with difficult-to-treat lesions: as defined by EADO operational staging system (stages IIa to IIIb) \[1\]. Patients must either (i) have already received, or (ii) have progressed after, or (iii) be resistant to, or (iv) not be candidate to all possible alternative treatments, including notably use or re-use of surgery, radiotherapy, hedgehog inhibitors. * Non-metastatic cSCC patients: * either advanced SCC for which a simple surgical excision is difficult or impossible, or * common SCC at high risk of recurrence, for which surgery alone is deemed uncertain by the tumor board, according to EADO /EORTC interdisciplinary guidelines \[2\]. Patients must either (i) have already received, or (ii) have progressed after, or (iii) be resistant to, or (iv) not be candidate to all possible alternative treatments, including notably use or re-use of surgery, radiotherapy, cetuximab and/or other anti-PD1 checkpoint inhibitors. * KA: particularly when surgical excision is considered as too much mutilating for this type of tumor * MCC: particularly when either primary tumor is considered unresectable, or skin metastases or local relapse are primarily or secondarily resistant to anti-PD1 (progress under anti-PD1). Patients must either (i) have already received, or (ii) have progressed after, or (iii) be resistant to, or (iv) not be candidate to all possible alternative treatments, including notably use or re-use of surgery, radiotherapy, and/or any anti-PD1 checkpoint inhibitors. * CTCL: Tumoral stage of Mycosis fungoides subtypes which are resistant to usual systemic treatments. In order to validate the first inclusion criterion of this trial, the tumor board will take into account that the treatment under investigation is intended to be only a palliative local therapy and cannot compete with a general efficacious strategy, if any. * KS: Classic or endemic, histologically confirmed KS, particularly when local response can be considered of either functional or cosmetic benefit. In order to validate the first inclusion criterion of this trial, the tumor board will take into account that the treatment under investigation is intended to be only a palliative local therapy and cannot compete with a general efficacious strategy, if any. * MATS: Advanced or refractory MATS. 5. Subjects must have radiographically or clinically measurable disease, defined as at least one injectable lesion that is ≥ 10 mm in diameter in at least 1 dimension, or an aggregate of injectable lesions that measures ≥ 10 mm in diameter in at least 1 dimension. 6. Subjects must be able and willing to undergo serial biopsies of injected lesion(s) and, when applicable and clinically feasible, non-injected lesions. 7. Male or female patients from the age of 18 years. 8. ECOG Performance Status/WHO Performance Status ≤ 1. 9. Hemoglobin \> 10.0 g/dL. 10. Platelets \> 100 x 109/L. 11. ALT and AST, GGT and Lipase ≤ 1.5 x the upper limit of normal (ULN). 12. Serum creatinine \< 1.5 x ULN and GFR \> 60 mL/min. 13. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v. 5.0) Grade ≤ 1 unless otherwise specified. 14. Women of childbearing potential (WOCBP) must have negative pregnancy test results at screening. WOCBP must be using, from screening to three months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomised partner. 15. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration. 16. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures. Exclusion Criteria: 1. Previous or concurrent cancer type that is distinct from the cancers being evaluated in this study, exception made for any other cancer curatively treated ≥ 2 years prior to study entry. Patients suffering from cSCC post-organ transplantation, or cSCC patients with concomitant chronic lymphocytic leukemia are excluded from the study. 2. Previous topical or systemic chemotherapy, immunotherapy, or radiation therapy at the tumor sites within 4 weeks prior to study drug administration. 3. Presence of active severe bacterial or viral infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study. In particular, a documented test for HIV, HBV, HCV and Covid-19 excluding active infection is needed. 4. Impaired cardiocirculatory functions due to any of the following conditions: 1. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris. 2. Inadequately controlled cardiac arrhythmias including atrial fibrillation. 3. Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria). 4. Any abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator. 5. Uncontrolled hypertension. 6. Ischemic peripheral vascular disease (Grade IIb-IV). 5. Known arterial aneurysms. 6. INR \> 3. 7. Known uncontrolled coagulopathy or bleeding disorder. 8. Known hepatic cirrhosis or severe pre-existing hepatic impairment. 9. Moderate to severe respiratory failure. 10. Active autoimmune disease. 11. Patient requires or is taking systemic corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions and asthma/COPD is not considered an exclusion criterion. 12. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies. 13. Pregnancy or breast-feeding. 14. Severe diabetic retinopathy. 15. Recovery from major trauma including surgery within 4 weeks prior to enrollment. 16. Patient with iatrogenic or pathologic severe immune suppression. 17. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.