Results of the first-in-human trial of an enhanced T cell therapy that targets multiple solid tumors bearing the antigen MAGE-A4, showed noteworthy outcomes in several cancers, particularly synovial sarcoma. The multi-center phase I clinical trial (clinical trial ID: NCT03132922) was led by researchers at the University of Texas MD Anderson Cancer Center and sponsored by Adaptimmune, a clinical-stage biopharmaceutical company focused on developing cancer immunotherapies.

The findings were published in the journal Nature Medicine on January 9, 2023 “Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial.”

The enhanced T cell therapy, afamitresgene autoleucel (afami-cel) achieved an objective response rate (ORR) of 44% in patients with synovial sarcoma while the overall response rate across all types of cancers tested in this trial was 24%. (ORR, defined as the proportion of patients with a complete or partial response to treatment is a common endpoint in cancer drug trials.) These early proof-of-concept findings establish acceptable safety of the treatment regimen and support the use of this novel cell therapy for solid tumors.

David Hong, MD, professor of investigational cancer therapeutics, and principal investigator of the study said, “These high response rates are significant because patients with synovial sarcoma really have very few options after high-dose chemotherapy with ifosfamide.”

MAGE-A4 (Melanoma-associated antigen A4) is a protein expressed in solid tumors such as synovial sarcoma (SS), myxoid/round cell liposarcoma (MRCLS), non-small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and ovarian, urothelial, melanoma and gastroesophageal cancers. Its expression in healthy tissue is limited to immune-privileged locations. MAGE-A4 is processed within the cell and fragments of it are flagged on cell surfaces together with human leukocyte antigens (HLAs). The combination of MAGE-A4 and HLAs forms a recognizable epitope for natural low-affinity T cell receptors (TCRs).

Immune checkpoint blockade has good clinical activity in some patients with some solid tumors that express MAGE-A4 such as melanoma, but the response may not be as good in other types of solid tumors such as synovial sarcoma.

Unlike chimeric antigen receptor (CAR)-based cell therapies that detect cell surface proteins, TCR therapies, including afami-cel, can detect proteins found within cells and more accurately target solid tumor cells without the toxicity to healthy cells often occurs with CAR therapies.

Afami-cel is an autologous and enhanced T cell therapy where a specific, high-affinity TCR against a fragment of MAGE-A4 (residues 2030 to 239) presented by HLA-A*02 is transduced through a lentiviral vector.

Earlier preclinical studies have shown that that this enhanced TCR responds strongly upon encountering MAGE-A4 peptide fragments that are presented on several common HLA-A2 alleles, inducing potent cytotoxic effects and effector cytokine release against multiple types of cancers that express MAGE-A4.

As part of the phase I trial, 38 patients with an average of three prior lines of therapy, were treated with afami-cel. Participants were 92% white and 58% male. Sixteen patients had synovial sarcoma, nine patients had ovarian cancer, three had head and neck cancer, two each had esophageal, non-small cell lung, myxoid/round cell liposarcoma and urothelial cancer, and one each had gastric cancer and melanoma.

All patients experienced some treatment-related adverse events, including low blood cell counts (lymphopenia, leukopenia, neutropenia, anemia and thrombocytopenia) and two patients had trial-related deaths. This led to the researchers lowering the maximum age at screening and discontinuing the high-dose cyclophosphamide lymphodepletion.

“The overall toxicity from afami-cel was manageable, and we saw evidence of early activity in [several] cancer types,” said Hong.  “These results suggest this is an approach with the potential to work in solid tumors where there are currently no approved cellular therapies.”

These optimistic results has spurred a phase II trial of afami-cel (NCT04044768) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma.