MAGE-C2 TCR T Cell Trial to Treat Melanoma and Head and Neck Cancer

Inclusion Criteria:

1. Written informed consent;
2. Age ≥ 18 years;
3. One of the following three malignancies:

• Previously treated for unresectable or metastatic cutaneous or mucosal melanomafor whom no standard treatment is available (anymore);
• Metastatic uveal melanoma, progressing after standard of care therapy, ifavailable;
• R/M HSNCC for whom no standard treatment is available anymore;

4. Patients must be HLA-A2*0201 positive;
5. Primary tumor and/or metastasis (archival or fresh biopsy) is positive for MC2 (>5% oftumor cells) according to immunohistochemistry;
6. Measurable disease according to RECIST v1.1;
7. At least one lesion, suitable for sequential mandatory tumor biopsies;
8. ECOG performance status of 0 or 1. Life expectancy ≥ 12 weeks;
9. Patients with melanoma must have had objective evidence of disease progression whileon or after standard systemic therapy. The last dose of prior therapy (e.g. anti-PD-1, chemotherapy) must have been received more than 4 weeks prior to the start ofstudy treatment. For melanoma patients who are treated with BRAF- and MEK inhibitors,an interval of 2 weeks between discontinuation of BRAF- and MEK inhibition and startof study treatment is sufficient;
10. Patients with R/M HNSCC must have had objective evidence of disease progression andare ineligible for or unwilling to get platinum-based chemotherapy or for whom nostandard treatment is available;
11. Patients of both genders must be willing to practice a highly effective method ofbirth control during treatment and for four months after receiving the preparativeregimen;
12. Patients must meet the following laboratory values at the screening visit in theabsence of growth factors and/or transfusion support: Hematology:

• absolute neutrophil count greater than 1.5x10^9/L;
• platelet count greater than 75x10^9/L;
• hemoglobin greater than 5 mmol/L or 8.0 in g/dl; Chemistry:
• serum ALAT/ASAT less than 3 times the upper limit of normal (ULN), unless patientshave liver metastasis (<5 times ULN);
• serum creatinine < 1.5 ULN;
• total bilirubin ≤ 20 micromol/L, except in patients with Gilbert's Syndrome who musthave a total bilirubin ≤ 50 micromol/L; Serology:
• seronegative for HIV antibody;
• seronegative for hepatitis B antigen, and hepatitis C antibody;
• seronegative for lues.

Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from participation of thisstudy:

1. presence of symptomatic brain metastasis. Note: subjects with symptomatic brainlesions who have been definitively treated with stereotactic radiation therapy,surgery, or gamma knife therapy are eligible;
2. Presence of active brain metastasis defined as new or progressive brain metastasis atthe time of study entry. Note: subjects with treated or stable brain metastasis areeligible;
3. Presence of leptomeningeal metastasis;
4. Presence of malignant pleural effusion or ascites;
5. Systemic chronic steroid therapy (>10 mg/day prednisone or equivalent) or any otherimmunosuppressive therapy within 7 days prior to leukapheresis or 72 hours prior toinfusion of the MC2 TCR T cells. Note: local steroids such as topical, inhaled, nasaland ophthalmic steroids are allowed;
6. Active, known or suspected autoimmune disease or a documented history of autoimmunedisease. Note: subjects with vitiligo, controlled type 1 diabetes mellitus on stableinsulin dose, residual autoimmune-related hypothyroidism only requiring hormonereplacement or psoriasis not requiring systemic treatment are permitted;
7. Any active systemic infections, coagulation disorders or other active major medicalillnesses, such as active autoimmune diseases requiring anti-TNF treatment;
8. History of myocardial infarction, cardial angioplasty or stenting, unstable angina, orother clinically significant cardiac disease within 6 months of enrollment;
9. AEs of previous treatment. Toxicities associated with prior systemic and non- systemictreatment must have recovered to a grade 1 or less. Patients may have undergone minorsurgical procedures or palliative radiotherapy (for non-target lesions) within thepast 4 weeks, as long as all toxicities have recovered to grade 1 or less;
10. Women who are pregnant or breastfeeding. A negative pregnancy test before inclusion inthe trial is required for all women of child bearing age;
11. Use of any live vaccines against infectious diseases within the last 3 months;
12. Active infection requiring systemic antibiotic therapy at start of study treatment;
13. Prior allogenic bone marrow or solid organ transplant;
14. History of known hypersensitivity to any of the investigational drugs used in thisstudy;
15. Malignant disease, other than being treated in this study. Exceptions to thisexclusion include the following: malignancies that were treated curatively and havenot recurred within 2 years prior to start of study treatment, completely resectedbasal cell and squamous cell skin cancers and any completely resected carcinoma insitu.