T Cells Targeting MAGE-A4 Shrink Tumors

A novel therapy composed of autologous T cells engineered to target the MAGE-A4 cancer testis antigen can successfully shrink a wide range of solid tumors, according to results of a phase I trial. The agent also appears to have a manageable safety profile.

“It's a proof of concept that this kind of therapy can possibly work in solid tumors,” said trial investigator David Hong, MD, of The University of Texas MD Anderson Cancer Center in Houston. Hong presented the findings on May 30 at the 2020 American Society of Clinical Oncology Annual Meeting.

In the trial, 38 patients were treated with escalating doses of ADP-A2M4 (Adaptimmune Therapeutics), an adoptive T-cell therapy engineered to express a T-cell receptor (TCR) directed against an HLA-A2–restricted MAGE-A4 peptide.

Overall, 9 patients—all of whom were HLA-A*02 positive and had advanced cancers that expressed the MAGE-A4 protein—responded to the therapy. Another 18 experienced stable disease.

The effects were especially pronounced in particular subgroups of patients. Seven of 16 patients with synovial sarcoma—a rare soft tissue cancer that expresses MAGE-A4 in more than 80% of cases—had confirmed responses that lasted a median duration of 28 weeks. An additional patient had an unconfirmed response after the data cutoff date. Seven others exhibited stable disease.

“The tumors are shrinking and staying shrunk—that represents a new potential outcome for sarcoma that hasn't been there before,” noted Pauline Funchain, MD, of the Cleveland Clinic in Ohio, who was not involved in the study.

Partial responses were also seen in patients with lung cancer and head and neck tumors, as well as in one person with rectal mucosal melanoma who received ADP-A2M4 and low-dose radiation.

Nearly all participants experienced low blood-cell counts. Half showed signs of cytokine release syndrome, although most reactions were mild. There were two trial-related deaths—one due to bone marrow failure and another due to stroke—which led to changes in the conditioning regimen and eligibility criteria.

A phase II registration trial is ongoing to test ADP-A2M4 in patients with synovial sarcoma and myxoid liposarcoma. A smaller trial will soon start to evaluate the therapy in combination with the anti–PD-1 drug pembrolizumab (Keytruda; Merck) in patients with advanced head and neck cancer.

Adaptimmune is also evaluating a next-generation engineered T-cell candidate, ADP-A2M4CD8, which includes a CD8α co-receptor with the MAGE-A4–targeted TCR. Three of the first four patients treated with the therapy responded—two with gastroesophageal junction (GEJ) cancer and one with head and neck cancer. Moreover, “the responses seen just were that much more dramatic, and they occurred much quicker” than those observed in patients treated with the first-generation product, Hong said.

ADP-A2M4CD8 “is supposed to draw more CD8 T cells into the tumor microenvironment and induce a larger cytotoxic effect—and that's what seems is happening here,” Hong noted. Adaptimmune plans to initiate a phase II trial in patients with GEJ tumors early next year.

The promising clinical results with ADP-A2M4 dovetail with those previously reported for two other TCR-modified T-cell therapies directed against commonly expressed cancer testis antigens: one, a precursor to KITE-718 (Gilead), targets MAGE-A3 and MAGE-A6; the other, GSK3377794 (GlaxoSmithKline/Adaptimmune), targets NY-ESO-1.

“[ADP-A2M4] is the third cancer germline antigen TCR that is clearly demonstrating very convincing antitumor efficacy in a subset of patients without off-target toxicity,” said Chris Klebanoff, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who is involved in the KITE-718 trials and was involved in the development of GSK3377794. “It's extremely validating, and it shows that you can reproducibly do this at scale.” –Elie Dolgin