MAGE-A3—Targeted Adoptive T-Cell Therapy Shows Promise in Solid Tumors

Yong-Chen William Lu

A form of immunotherapy that harnesses the power of CD4 T-cells was shown to be safe and effective in patients with various types of metastatic cancers. The treatment was developed by genetically engineering CD4 T-cells to target a protein called MAGE-A3, which is expressed in many different tumor types.

The research, conducted in the laboratory of Steven A. Rosenberg, MD, at the National Cancer Institute (NCI), was presented at the 2016 AACR Annual Meeting. According to Rosenberg, the study is the first clinical trial testing an immunotherapy that uses genetically engineered CD4 T-cells, rather than CD8 T-cells.

Promising results from a phase I study of this approach were presented at an AACR press briefing by Yong-Chen William Lu, PhD, a fellow in the Surgery Branch of the NCI. Objective responses were observed in 3 of 14 patients (21.4%) with various metastatic tumor types, and the treatment was well tolerated.

CD4 T-Cells in the Driver’s Seat

“Based on our findings, we think there are significant clinical applications,” Lu commented. “We think the treatment is safe, and could be effective in different types of cancer.”Adoptive transfer of genetically modified T-cells is being investigated as salvage treatment in some types of metastatic cancers. Most approaches employ major histocompatibility complex (MHC) class I—restricted T cell receptor (TCR) or chimeric antigen receptor (CAR) technologies to genetically modify CD8+ T cells or bulk T cells, but CD4+ T cells can also induce tumor regression, Lu explained.

“CD8 T-cells can directly kill tumor cells. CD4 T-cells help CD8 cells do this, but preclinical evidence suggests that CD4 T-cells can also sit in the driver’s seat and do the job of killing tumor cells,” he said.

The researchers tested this hypothesis in a phase I trial of patients with metastatic disease who had progressed after at least 1 standard line of treatment. Patients had melanoma, cervical, esophageal, anal, urothelial, and breast cancers.

Patients were required to have the human leukocyte antigen (HLA) allele DPB1*0401 and tumors that were positive for the MAGE-A3 antigen.

Approximately 60% of Caucasians demonstrate the HLA-DPB1*0401 on cell surfaces; HLA is the means through which T-cells can distinguish between normal cells and tumor cells and can recognize the expression of proteins, such as MAGE-A3. This particular immunotherapy was modified with a viral vector harboring a gene for TCR that recognizes MAGE-A3.

Clinical Responses and a Good Safety Profile

According to Rosenberg, use of this HLA allele means that many cancer patients would be candidates for this therapy.Of the 14 patients, 8 were treated with various doses of the modified CD4 T-cells, ranging from 10 million to 30 billion cells; 6 patients received the highest dose level of 100 billion cells.

Objective responses (all partial) were observed in 3 patients, and all were ongoing at the time of the analysis. This included one patient with cervical cancer still responding 15 months after treatment, one patient with urothelial cancer responding after 7 months, and one patient with esophageal cancer responding after 4 months.

There were no responses among the 6 metastatic melanoma patients, but Lu indicated that most of these patients received the very lowest doses during the dose escalation phase.

Most patients experienced high fever and demonstrated high levels of the cytokine IL-6 in their serum, but this was short-lived and not considered to be cytokine release syndrome, which has been observed in patients treated with CAR-T therapy, according to Lu.

“This is much, much safer than CD19 CAR-T therapy and others,” he said.

“Twelve of 14 patients had a high fever lasting about 1 or 2 weeks, but it was very easy to control,” he said.

“Based on the encouraging results in the phase I clinical trial, we have started the phase II trial to study the clinical responses of this TCR therapy in different types of metastatic cancer,” said Lu. “A Promising Conceptual Strategy”

Press briefing moderator Louis M. Weiner, MD, said the findings offer “important messages.” This is a strategy of “pressing on the accelerator,” not “releasing the brakes” of the immune system, as is done with checkpoint inhibitors. “This uses expanded tumor-specific populations of T-cells that will hone in and attack the cancer,” Weiner continued, adding that the two immune strategies could be complementary.

Weiner, director of the Lombardi Comprehensive Cancer Center and chair of the Department of Oncology at Georgetown University Hospital, also pointed out that while the “typical” CAR-T therapy is not useful in solid tumors, harnessing CD4 T-cells appears to be.

“What’s happening is that these T-cells are being endowed with the capacity to recognize and go after the target,” he said. “These T-cells have been changed so that they now think the tumor is a tasty target. This is a very promising conceptual strategy.”

Lu YC, Parker LL, Lu T, et al. A phase I study of an HLA-DPB1*0401-restricted T-cell receptor targeting MAGE-A3 for patients with metastatic cancer. Presented at the 2016 AACR Annual Meeting; April 16-20, New Orleans, Louisiana. Abstract CT003.

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