Understanding PRAME Expression and the SUPRAME Phase 3 Clinical Trial Design

The discussion centers on PRAME, a tumor-associated antigen gaining prominence as a target in TCR-transduced T-cell therapies and T-cell engagers due to its selective expression in tumor cells. Although PRAME is minimally expressed in normal tissues, it requires MHC presentation—specifically HLA-A*02:01—for therapeutic targeting, limiting applicability based on patient genetics. This constraint has implications for trial design and diversity, particularly in multiethnic populations where HLA-A*02:01 prevalence is lower.

A new clinical trial is underway that’s evaluating a gene-engineered TCR-T product in melanoma and focusing on patients with the HLA-A*02:01 haplotype. The trial involves leukapheresis followed by randomization to receive either the cell therapy or standard-of-care treatment, with cell infusion preceded by lymphodepleting chemotherapy and followed by optional low-dose IL-2—differentiating it from more intensive TIL regimens. The trial is notable for being the first to directly compare adoptive cell therapies—TCR-T vs TILs—in solid tumors, potentially providing valuable insights into clinical and logistical outcomes.

The trial design is seen as more patient-friendly due to outpatient compatibility and shorter manufacturing timelines, with a vein-to-vein process lasting approximately 14 days. Although some clinicians expressed concern about the ethics of randomly assigning patients to less-effective control therapies, the inclusion of TIL as a control adds scientific value. Overall, there is strong interest in the trial, as it may expand effective second-line treatment options for appropriately selected patients with melanoma.