CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.

主要终点：Maximum Tolerated Dose (MTD) of MC2 TCR T cells · MTD is determined using an accelerated titration phase with T cell doses as described in treatment arm; AEs are recorded according to CTCAE 5.0 · 1 year；Objective anti-tumor responses of MC2 TCR T cells · Anti-tumor responses are recorded according to RECIST v1.1 using the MTD from outcome 1 · 2 years

• Adoptive therapy with autologous MC2 TCR T cells · EXPERIMENTAL · * Accelerated titration phase I design and a subsequent single arm phase II study * Prior to T cell transfer (day 0), patients will be treated with valproic acid (dose 50 mg/kg/d, 7d; days -9 to day -3) and 5' azacytidine (dose 75mg/m2/d, 7d; days -9 to day -3) * Phase I: patients will be treated with one single intravenous administration of MC2 TCR T cells at 5 different escalated doses of 5x10E7, 5x10E8, 5x10E9,1.0x10E10, and the total number of cultured TCR T cells (i.e., usually 1.0-5.0 x10E10 TCR T cells). MC2 TCR T cell infusions will be supported by low dose of IL-2 administrations (s.c. 5x10E5 IU/m2 2qd for 5 days) * T cells will be processed using IL-15 and IL-21 to generate young T cells

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).