NEW YORK (Reuters Health) – T cells genetically engineered to target the cancer germline antigen MAGE-A3 appear safe and effective in some patients with metastatic cancer, according to a study in 17 patients.
Melanoma-associated antigen-A3 (MAGE-A3) is the most frequently expressed cancer germline antigen in a variety of cancer types and has been targeted by adoptive cell transfer (ACT) and other cancer immunotherapies.
Dr. Steven A. Rosenberg from the National Cancer Institute in Bethesda, Maryland and colleagues investigated whether ACT using genetically modified CD4+ T cells targeting MAGE-A3 could induce tumor regression in patients with a variety of metastatic solid cancers. They incorporated high-dose IL-2 administration, which has been shown in animal studies to enhance T-cell-mediated antitumor activity.
All 17 trial participants had measurable distant metastatic disease and had been previously treated with at least one standard first-line therapy, the team notes in the Journal of Clinical Oncology, online August 15.
One of eight patients treated during the cell dose-escalation phase experienced an objective complete response in metastatic supraclavicular lymph nodes (from her cervical cancer) that is ongoing at 29 months.
Among nine patients who received the highest dose of T-cell receptor (TCR)-transduced CD4+ T cells, three experienced objective responses, including one each with esophageal cancer and osteosarcoma (both of which progressed at four months) and one with urothelial cancer (which is stable at 19 months).
All patients experienced transient grade 3 and 4 adverse events resulting from nonmyeloablative chemotherapeutic preoperative regimens and high-dose IL-2, with 10 of 17 treated patients experiencing prolonged high fever after cell infusion.
Cell infusion was followed by elevated levels of IL-6 in all patients, IL-10 in 12 patients, IFN-gamma in nine patients, and TNF in three patients. Serum cytokine levels did not seem to correlate with clinical responses or symptoms.
The percentage and total number of TCR-transduced T cells were significantly higher in peripheral blood of patients who received the high cell dose than in patients who received the low cell dose, but there was no relationship between cell persistence and clinical response.
“Our study provides direct evidence that objective tumor regressions can be mediated by MAGE-A3-specific CD4+ T cells in a variety of cancer types; however, additional studies are needed to understand the detailed mechanisms by which human CD4+ T cells mediate tumor regressions,” the researchers note.
They add, “Additional modifications may help to improve the efficacy of this therapy, such as manufacturing less differentiated or Th17-polarized T cells by modifying the cell production process, and combining T-cell therapy with immune checkpoint blockade to prevent T-cell exhaustion.”
Dr. Yi Zhang from The First Affiliated Hospital of Zhengzhou University, in China, who has studied the expression and prognostic relevance of MAGE in a variety of cancers, told Reuters Health by email, “I think the result is encouraging, and at least it provides physicians with information about the efficacy of this kind of immunotherapy in treatment of solid tumor. In addition, it gives physicians more options when treating cancer patients.”
“These results tell us again that immunotherapy for cancer is very promising and will be a very important treatment strategy for cancer,” concluded Dr. Zhang, who was not part of the study. “In general, all patients with MAGE-A3 and (who are) HLA-DPB1*0401 positive and with early or late stages of cancer could benefit from the treatment.”
Dr. Rosenberg was not available for comment by press time.
SOURCE: http://bit.ly/2wE0rIp
J Clin Oncol 2017.
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