Article Text
Abstract
Background Adoptive cell therapy with T-cell receptor-modified T-cells (TCR-T) is emerging as an attractive therapeutic approach in patients with solid tumors. Recently, we have shown promising results of IMA203, a TCR-T product targeting the cancer testis antigen PRAME in heavily pretreated melanoma patients. Patients with active brain metastases are usually excluded from such trials due to concerns regarding an increased risk for immune effector cell-associated neurotoxicity (ICANS).
Methods Here we report two cases of patients with BRAF-mutated advanced melanoma, who were screened for the IMA203-101 trial but found to be non-eligible due to active central nervous system (CNS) metastases. Instead, they received IMA203 as compassionate use at the University Hospitals of Bonn and Dresden, Germany.
Results Both patients had progression of CNS metastases during BRAF-/MEK-inhibition (MAPKi) and exhausted all other available standard of care treatment options including interferon-alpha, immune checkpoint inhibition, resection and radiotherapy before treatment with IMA203. Patient 1, a 31-year-old female, received an IMA203 dose of 6.11x108 TCR-T cells on day 0 after omittance of MAPKi during lymphodepletion. Two days later, the patient presented with reduced consciousness and enlargement of known CNS metastases construed as disease progression due to MAPKi pause. Short-course high-dose dexamethasone concurrent with re-initiation of MAPKi led to rapid symptom relief. On day +11, the patient was discharged without signs of cytokine release syndrome (CRS) or ICANS. Significant tumor reduction was seen on day +43 and day +94 and progression only occurred on day +134. Patient 2, a 28-year-old female, received IMA203 (dose: 12.9x108 TCR-T cells) with ongoing MAPKi. On day +2, the patient developed CRS and ICANS grade I, which were treated with tocilizumab/dexamethasone. On day +3, the patient showed increasing cognitive impairments and brain edema interpreted as ICANS grade II. Treatment with high-dose steroids resulted in rapid improvement. On day +15, the patient was discharged without further complications and had regression of the CNS-metastases on day +42 and day +90. The tumor progressed 5 months after treatment with IMA203.
Conclusions Here we show that application of IMA203 TCR-T in two heavily pretreated melanoma patients with active CNS metastases and the combination with MAPKi was safe with clinically manageable CRS and CNS side effects. Even though it is hard to discern the individual contribution of MAPKi and IMA203 to the observed CNS responses, we think that it is reasonable to assume CNS activity of IMA203 given disease progression under previous MAPKi treatment.
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