CD4+ T cells genetically engineered to recognize MAGE-A3, a protein found on many types of tumor cells but not on normal cells, were safely given to patients with metastatic cancers, and some of the patients had clinical responses.
Whereas the majority of current adoptive T-cell therapies have used genetically modified unpurified T cells or CD8+ (cytotoxic) T cells, Yong-Chen William Lu, Ph.D., of the surgery branch of the National Cancer Institute conducted a phase I trial of CD4+ (helper) T cells to evaluate their contribution to tumor killing. Preclinical and clinical studies indicated that CD4+ T cells can induce tumor regression.
Dr. Lu explained the individualized process of making the T cells for infusion, during a news conference at the annual meeting of the American Association for Cancer Research. First, T cells are harvested from the peripheral blood of a patient, from which CD4+ T cells are isolated. Using a retroviral vector, scientists insert the gene for a T-cell receptor that recognizes MAGE-A3 in conjunction with the HLA molecule DPB1*0401. In this way, the cells can recognize the tumor antigen in anyone of that HLA type. Then the cells carrying the engineered T-cell receptor are expanded in vitro and infused into the patient.
DPB1*0401 was chosen as the HLA genotype because “it is present in 60% of the Caucasian population. It is the highest one,” Dr. Lu said. MAGE-A3 is expressed on cells during fetal development and is later lost on normal tissues. But several tumor types, including some melanomas and some urothelial, esophageal, and cervical cancers reexpress this protein, making it a good target for immunotherapy.
The trial included patients of the HLA DPB1*0401 type with metastatic cancer that is MAGE-A3 positive. Patients had received at least one first-line treatment for metastatic disease and had been nonresponders or had had a recurrence of the tumor.
This phase I trial involved 14 patients in nine different dose cohorts, receiving from 10 million engineered T cells at the lowest dose to 78-103 billion cells in the highest cohort. Three patients in the middle and highest dosing cohorts achieved partial responses, one each with cervical, esophageal, and urothelial tumors. The partial response lasted 4 months for the patient with esophageal cancer and is ongoing at 7 months for the urothelial and 15 months for the cervical cancer patients.
In response to a question from the audience about adverse effects, Dr. Lu said patients had short-term elevations of circulating cytokines, “which only lasted for a few days,” and a fever lasting 1-2 weeks.
In summary, he said, “We think this first [CD4+] engineered T-cells therapy targeting MAGE-A3 is safe and has shown early clinical response.” Phase II trials are now beginning.
The approach of this immunotherapy method is different from that involved in using checkpoint inhibitors, “which essentially release the brakes of the immune system so the T cells can do their job of attacking the cancer,” commented Dr. Louis Weiner, director of the Georgetown Lombardi Cancer Center in Washington, D.C. “This is actually not trying to release brakes but essentially press on the accelerator, if you will, by using an expanded tumor-specific population of T cells that will then be able to hone in and attack the cancer.” He envisioned a time in the future when this approach could be combined with checkpoint inhibitors for enhanced antitumor effects.
Dr, Weiner also noted that the T cells with receptors engineered to recognize MAGE-A3 are more specific for tumors, compared with approaches using chimeric antigen receptor T cells to treat certain hematologic malignancies. In that setting the chimeric antigen receptor T cells recognize and eliminate, for example, not only malignant B cells bearing a pan-B cell marker but also all normal B cells.
However, in the question and answer period, Dr. Lu said one problem with his approach is the possibility that not all cells in a tumor may express MAGE-A3.
There was no commercial funding of the study. Dr. Lu had no relevant financial disclosures. Dr. Weiner is an adviser, review panel member, or consultant, or has other relationships, with numerous pharmaceutical companies.