1. Carlson, Robert H.

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NEW ORLEANS-CD4 T cell-based immunotherapy targeting MAGE-A3 protein was found safe and showed early clinical responses in patients with a variety of metastatic cancers.

MAGE-A3 Protein. MAG... - Click to enlarge in new windowMAGE-A3 Protein. MAGE-A3 Protein

Data from a phase I study with 14 patients treated with this novel immunotherapy were presented at the American Association for Cancer Research annual meeting.


MAGE-A3 is frequently expressed in melanoma and in urothelial, esophageal, and cervical cancers but not in normal tissues, and is therefore a desirable target for anticancer therapy, said first author Yong-Chen William Lu, PhD, a research fellow in the Surgery Branch at the National Cancer Institute (NCI).


Senior author is Steven A. Rosenberg, MD, PhD, Chief of the Surgery Branch at the NCI.


"This is the first clinical trial testing an immunotherapy that uses gene-engineered CD4+ T cells against metastatic cancer," Lu said, in a press conference before his oral presentation.


Louis M Weiner, MD, Director, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, press conference moderator, noted several important points in this study.


"This is the opposite of checkpoint inhibition," he said. "This therapy uses an expanded tumor-specific population of T cells that will home in on tumor cells. You can immediately see how that would be complementary with checkpoint inhibition."


T Cells That Target

Weiner said this is not a typical CAR-T (chimeric antigen receptor) cell approach.


"Here, the T cells are being endowed with the capacity to recognize a target and go after it in a tumor-specific way," Weiner said. "This is a very promising conceptual strategy with early responses, and obviously that is very exciting."


Lu said the study appears to answer the question of whether CD4+ helper T cells could do more than "just help."


"The fundamental question we asked is can CD4+ T cells eradicate tumor cells the same as CD8+ T cells," Lu said. "Evidence from preclinical and clinical studies indicates that CD4 T cells can also induce tumor regression, and this could have very important clinical applications."


To test their hypothesis, the researchers isolated an HLA-DPB1*0401-restricted T-cell recognizing MAGE-A3 from a patient's peripheral blood after MAGE-A3 peptide vaccination.


Because HLA-PB1*0401 is present in approximately 60 percent of the Caucasian population and MAGE-A3 is expressed in up to one-third of tumor specimens from a variety of cancer types, this T-cell receptor immunotherapy could potentially be applicable for a significant portion of cancer patients, the researchers said.


Patients enrolled had metastatic cancer and were HLA-DPB1*0401 positive with tumor specimens that were MAGE-A3 positive. They previously received at least one first-line treatment for metastatic disease but did not respond or their disease recurred.


A cell dose-escalation was conducted, treating one patient at each cohort (0.01, 0.03, 0.1, up to 30 billion cells), followed by six patients at the highest dose level (between 78 and 100 billion cells).


Objective partial responses by RECIST criteria were observed in one patient with metastatic cervical cancer (ongoing at more than 15 months), one with metastatic esophageal cancer (duration three months), and one with metastatic urothelial cancer (ongoing at more than seven months).


Lu said high levels of IL-6 were detected in all patients' serum samples after adoptive cell transfer. One month after the treatment, T-cell receptor-transduced T cells persisted at high levels in the peripheral blood of six patients who received the highest dose level, compared with patients who received lower dose levels.


But no cytokine release syndrome was seen, Lu said, and while all patients experienced fever of 39-40[degrees] C, this was easy to control.


"These effects were manageable," he said. This is much safer than C19 CAR-T immunotherapy."


One patient did have grade 3 toxicity with acute renal and liver injury, but Lu said the cause could not be determined and he believed it was an issue with that patient alone. He noted a phase II trial has been initiated. This study was funded by the NIH.


Robert H. Carlson is a contributing writer.