Looking Forward to A Potential First Cell Therapy Approval for Sarcomas

Afamitresgene autoleucel (afami-cel, formerly ADP-A2M4) is up for priority review by the FDA for treating advanced synovial sarcoma. The investigational T-cell receptor (TCR) T-cell therapy, developed by Adaptimmune Therapeutics, has a Prescription Drug User Fee Act (PDUFA) target action date of August 4, 2024. The therapy’s biologics license application (BLA) is supported by data from the pivotal SPEARHEAD-1 trial (NCT04044768). SPEARHEAD-1 previously met its primary efficacy endpoint of overall objective response (ORR) compared to natural history, with the trial showing a 39% ORR and a median duration of response of around 12 months in patients with advanced synovial sarcoma treated with afami-cel.

CGTLive® spoke with John A. Charlson, MD, associate professor of medicine, Medical College of Wisconsin, and primary investigator of the pivotal SPEARHEAD-1 trial (NCT04044768) assessing afami-cel, to learn more about the advantages of afami-cel for sarcoma and the advantages of TCR therapy for solid tumors in general.

CGTLive: How does TCR therapy differ from other kinds of cell therapies?

Charlson: The modified TCR therapy is using a patient's own innate full receptor, just genetically modifying it and this recognizes tumor antigens in the context of HLA B as opposed to just independent antigen recognition of T-cell. For some of the implications. I suppose an advantage would be to introduce the antigens that are more commonly intracellular or are amenable to the big T cell receptor therapies. One downside is that the TCR is restricted to certain HLA types for which the codification is constructed. So, we're looking at a rare subtype of sarcomas, synovial sarcoma, but also, only a portion of those patients will have the right HLA type to do the therapy. Hopefully, if we demonstrate real utility here, we can expand that to other types of antigens, I know the company is working on that. Maybe it can also be expanded to different HLA types at some type some point in the future. So, I think this is just the first step and a good first step, but there are there are some, some limitations.

What are challenges for treating sarcoma?

Charlson: For sarcoma, and probably other solid tumors as well, the stroma or microenvironment negatively impacts how the immune system attacks the cancer. I would expect there are going to be ways that we can improve, probably how T-cells work against tumors by addressing some of those issues in the future. Sarcomas have a lot of these tumor microenvironments that hopefully we can overcome with this therapy.

How is the upcoming PDUFA date exciting for you?

Charlson: This could be the first, to my knowledge, the first FDA approved TCR therapy for solid tumors - there's really very little affinity for CAR T-cells in solid tumors at this point, either. And so that's really exciting, soft tissue sarcoma is heterogeneous, with at least 50 subtypes of soft tissue sarcoma. So, treatment development for sarcoma is hard, and it's been relatively slow. So, this is super exciting to see this underserved population really take the first step and hopefully broaden out to other tumor types.

This content has been edited for clarity.

REFERENCE

Adaptimmune announces U.S. FDA acceptance of biologics license application for afami-cel for the treatment of advanced synovial sarcoma with priority review. News release. Adaptimmune Therapeutics plc. January 31, 2024. Accessed February 2, 2024. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/260/adaptimmune-announces-u-s-fda-acceptance-of-biologics