A New Immune Cell Treatment for Advanced Eye Cancer and Head/Neck Cancer

Adoptive Therapy With TCR Gene-engineered T Cells to Treat Patients With MAGE-C2-positive Melanoma and Head and Neck Cancer

Erasmus Medical CenterPHASE1 / PHASE2Recruiting
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In Plain English

This trial tests a brand-new way to fight your cancer using your own immune cells. Here's what happens: doctors take T cells (your body's natural cancer-fighting cells) from your blood and reprogram them in the lab to recognize and attack cancer cells that have a specific marker called MAGE-C2. This marker is found on many melanomas and head/neck cancers, but not on healthy cells—so the treatment is designed to target cancer while sparing your normal tissue. Before you receive the engineered cells back, you'll get a special drug (called an epigenetic drug) that makes cancer cells easier for your new T cells to spot and destroy. This is a first-of-its-kind trial, which means doctors are carefully watching to make sure the treatment is safe and actually works. You'll need to have a specific genetic marker called HLA-A*02:01 for this trial—think of it like a cellular barcode that determines whether your cells can work with this particular treatment. Unlike some other cancer treatments, you won't receive chemotherapy before getting your new T cells, which may mean fewer side effects. The whole process takes time: your cells are grown in the lab, and then you receive them back as an infusion.

What This Trial Does

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).

How It Works

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

Who Can Join

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.
Age: 18 Years+

Treatments

Adoptive therapy with autologous MC2 TCR T cells (BIOLOGICAL)

Adoptive therapy with autologous MC2 TCR T cells combined with AZA/VP

Trial Sites (1)

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Erasmus Medical Center

Rotterdam, Netherlands

A.A.M. van der Veldt, MD, PhD · a.vanderveldt@erasmusmc.nl

Recruiting