MAGE-A3 BASED IMMUNOTHERAPY

In a study reported in the Journal of Clinical Oncology, Lu et al found that autologous CD4-positive T cells engineered to express a major histocompatibility complex (MHC) class II–restricted T-cell receptor (TCR) targeting the cancer germline antigen MAGE-A3 (melanoma-associated antigen-A3) produced responses in several types of metastatic cancer. Most current strategies using adoptive transfer of modified T cells employ genes that encode MHC class I–restricted TCRs or chimeric antigen receptors to modify CD8-positive T cells.

Study Details

In the study, 17 patients with metastatic cancers underwent a lymphodepleting preparative regimen followed by adoptive transfer of purified CD4-positive T cells retrovirally transduced with MAGE-A3 TCR plus systemic high-dose interleukin-2. A cell dose-escalation phase started at 107 total cells and increased by half-log increments to approximately 1011 cells.

Responses

An objective complete response (ongoing at 29+ months) was observed in a patient with metastatic cervical cancer who received 2.7 x 109 cells during the dose-escalation phase. Among 9 patients treated at the highest dose level of 0.78 to 1.23 x 1011 cells, objective partial responses were observed in a patient with esophageal cancer (4 months), a patient with urothelial cancer (ongoing at 19+ months), and a patient with osteosarcoma (4 months).

Toxicity

Most patients experienced transient fever and hematologic toxicities, which were expected from the lymphodepleting regimen. Transient grade 3 and 4 transaminase increases occurred in two patients. No treatment-related deaths were observed.

The investigators concluded: “These results demonstrate the safety and efficacy of administering autologous CD4-[positive] T cells that are genetically engineered to express an MHC class II-restricted antitumor TCR that targets MAGE-A3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer.”

The study was supported by the National Cancer Institute.

Steven A. Rosenberg, MD, of the National Cancer Institute, is the corresponding author of the Journal of Clinical Oncology article.