Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II-Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3

Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class Irestricted Tcell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8(+) T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4(+) Tcell therapy using an MHC class IIrestricted, HLADPB1* 0401-restricted TCR that recognized the cancer germline antigen, MAGEA3 (melanoma-associated antigen-A3). Patients and Methods Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4(+) T cells, retrovirally transduced with MAGEA3 TCR plus systemic highdose IL-2. A cell dose escalation was conducted, starting at 10(7) total cells and escalating at halflog increments to approximately 10(11) cells. Nine patients were treated at the highest dose level (0.78 to 1.23 x 10(11) cells). Results Seventeen patients were treated. During the cell dose-escalation phase, an objective complete response was observed in a patient with metastatic cervical cancer who received 2.7 x 10(9) cells (ongoing at >= 29 months). Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration, 4 months), a patient with urothelial cancer (ongoing at >= 19 months), and a patient with osteosarcoma (duration, 4 months). Most patients experienced transient fevers and the expected hematologic toxicities from lymphodepletion pretreatment. Two patients experienced transient grade 3 and 4 transaminase elevations. There were no treatment-related deaths. Conclusion These results demonstrate the safety and efficacy of administering autologous CD4(+) T cells that are genetically engineered to express an MHC class IIrestricted antitumor TCR that targets MAGEA3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer.