Single-centre, first-in-man phase I/II trial to demonstrate safety and efficacy of MAGE-C2/HLA-A2 TCR T cells (MC2 TCR T cells) in advanced melanoma (MEL) and head-and-neck carcinoma (HNSCC).

In this patient study, the investigators target the Cancer Germline Antigen (CGA) MAGE-C2 (MC2), and use T cells with a young phenotype. MC2 is highly expressed in melanoma (MEL) and head-and-neck squamous cell carcinoma (HNSSC), but not in healthy adult tissues. The investigators isolated MC2-specific TCRs from MEL patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. Following extensive evaluation of in vitro anti-tumor and self-reactivities, the investigators have selected a TCR that recognizes the ALK epitope in the context of HLA-A2 for clinical development. Furthermore, preclinical studies showed that epigenetic pretreatment of tumor cells, but not normal cells, up-regulated MC2 gene expression and resulted in enhanced recognition of MC2 by the selected TCR. In parallel to the above studies, the investigators renewed their GMP protocol to process T cells, using stimulating antibodies and cytokines, to generate T cells with a young phenotype.

In the current phase I/II study, the investigators explore the safety and anti-tumor efficacy of T cells engineered with the selected TCR in patients with MC2-positive MEL and HNSSC. The study contains the following unique elements:

• CGA not targeted before by T cell therapy
• New T cell processing method to generate young T cells
• Pretreatment of patients with epigenetic drugs
• No chemotherapy prior to T cell infusion

Leads:

• Clinical PI: Astrid van der Veldt, MD, PhD
• Clinical logistics: Karlijn de Joode, MD
• T cell production: Monique de Beijer, PhD; and Cor Lamers, PhD
• Coordinator/Preclinical PI: prof. Reno Debets, PhD

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 melanoma for whom no standard treatment is available (anymore);
   • Metastatic uveal melanoma, progressing after standard of care therapy, if available;
   • 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% of tumor 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 while on 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 of study 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 start of study treatment is sufficient;

10. Patients with R/M HNSCC must have had objective evidence of disease progression and are ineligible for or unwilling to get platinum-based chemotherapy or for whom no standard treatment is available;

11. Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen;

12. Patients must meet the following laboratory values at the screening visit in the absence 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 patients have liver metastasis (<5 times ULN);
• serum creatinine < 1.5 ULN;
• total bilirubin ≤ 20 micromol/L, except in patients with Gilbert's Syndrome who must have 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 this study:

1. presence of symptomatic brain metastasis. Note: subjects with symptomatic brain lesions 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 at the time of study entry. Note: subjects with treated or stable brain metastasis are eligible;
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 other immunosuppressive therapy within 7 days prior to leukapheresis or 72 hours prior to infusion of the MC2 TCR T cells. Note: local steroids such as topical, inhaled, nasal and ophthalmic steroids are allowed;
6. Active, known or suspected autoimmune disease or a documented history of autoimmune disease. Note: subjects with vitiligo, controlled type 1 diabetes mellitus on stable insulin dose, residual autoimmune-related hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment are permitted;
7. Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune diseases requiring anti-TNF treatment;
8. History of myocardial infarction, cardial angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment;
9. AEs of previous treatment. Toxicities associated with prior systemic and non- systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or palliative radiotherapy (for non-target lesions) within the past 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 in the 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 this study;
15. Malignant disease, other than being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to start of study treatment, completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ.