Abstract
Adoptive transfer of MAGE-A3–targeted CD4+ T cells is safe and achieves responses in several tumor types.
Major finding: Adoptive transfer of MAGE-A3–targeted CD4+ T cells is safe and achieves responses in several tumor types.
Approach: T cells were transduced with an MHC class II–restricted HLA-DPB1*0401–restricted TCR targeting MAGE-A3.
Impact: Autologous CD4+ T-cell therapies targeting MAGE-A3 may benefit patients with metastatic disease.
Adoptive T-cell transfer is being investigated as a treatment for multiple tumor types. One such strategy involves autologous transfer of T cells with a T-cell receptor (TCR) genetically modified to attack the tumor, most commonly altering the class I major histocompatibility complex (MHC) to modify bulk T cells or CD8+ T cells. Autologous transfer of CD4+ T cells has also been shown to induce tumor regression in patients with metastatic melanoma. Lu and colleagues evaluated the safety and efficacy of an adoptive CD4+ T-cell therapy using an MHC class II–restricted HLA-DPB1*0401–restricted TCR to recognize the cancer germline antigen MAGE-A3. A total of 17 patients with advanced refractory or recurrent solid tumors were treated with adoptive transfer of MAGE-A3 TCR CD4+ T cells with high-dose IL2, following lymphodepletion. All patients had measurable distant metastasis. Eight patients were treated during the dose-escalation phase, including a patient with metastatic cervical cancer who achieved a complete response. No unexpected toxicities were observed, so the final 9 patients were treated at the highest dose level, with partial responses observed in 3 patients: 1 patient with esophageal cancer, 1 patient with urothelial cancer, and 1 patient with osteosarcoma. Patients experienced the expected adverse events from lymphodepletion, and two patients experienced transient grade 3–4 transaminase elevation. Serum cytokine levels were elevated after cell infusion, but levels did not correlate with clinical responses or symptoms. Taken together, these findings indicate that adoptive T-cell therapies administering autologous CD4+ T cells targeting MAGE-A3 are safe, produce antitumor activity, and may be effective in treating patients with metastatic cancer.
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