Adoptive Therapy With TCR Gene-engineered T Cells to Treat Patients With MAGE-C2-positive Melanoma and Head and Neck Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Objective anti-tumor responses of MC2 TCR T cells
研究概览
简要总结
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).
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent;
- •Age ≥ 18 years;
- •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;
- •Patients must be HLA-A2*0201 positive;
- •Primary tumor and/or metastasis (archival or fresh biopsy) is positive for MC2 (>5% of tumor cells) according to immunohistochemistry;
- •Measurable disease according to RECIST v1.1;
- •At least one lesion, suitable for sequential mandatory tumor biopsies;
- •ECOG performance status of 0 or
- •Life expectancy ≥ 12 weeks;
- •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;
- •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;
- •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;
- •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;
- •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;
- •seronegative for HIV antibody;
- •seronegative for hepatitis B antigen, and hepatitis C antibody;
- •seronegative for lues.
排除标准
- •Subjects who meet any of the following criteria will be excluded from participation of this study:
- •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;
- •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;
- •Presence of leptomeningeal metastasis;
- •Presence of malignant pleural effusion or ascites;
- •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;
- •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;
- •Any active systemic infections, coagulation disorders or other active major medical illnesses, such as active autoimmune diseases requiring anti-TNF treatment;
- •History of myocardial infarction, cardial angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment;
- •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;
- •Women who are pregnant or breastfeeding. A negative pregnancy test before inclusion in the trial is required for all women of child bearing age;
- •Use of any live vaccines against infectious diseases within the last 3 months;
- •Active infection requiring systemic antibiotic therapy at start of study treatment;
- •Prior allogenic bone marrow or solid organ transplant;
- •History of known hypersensitivity to any of the investigational drugs used in this study;
- •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.
结局指标
主要结局
Objective anti-tumor responses of MC2 TCR T cells
时间窗: 2 years
Anti-tumor responses are recorded according to RECIST v1.1 using the MTD from outcome 1
Maximum Tolerated Dose (MTD) of MC2 TCR T cells
时间窗: 1 year
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
次要结局
未报告次要终点
研究者
A.A.M. van der Veldt
Principal Investigator
Erasmus Medical Center