mage-c2 tcr t cell trial to treat melanoma and head and neck cancer

Conditions: Melanoma; Melanoma, Uveal; Head and Neck Cancer

Summary: 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

Eligibility criteria:
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.