Drs Richard D. Carvajal and Marlana M. Orloff comment on tebentafusp’s mechanism of action (MOA) and explain what makes the therapy attractive for uveal melanoma.
Richard D. Carvajal, MD: Let’s shift gears to tebentafusp, an immunotherapy where there is clear success. I wonder if you can describe for the audience how this drug works? What's its mechanism?
Marlana M. Orloff, MD: Yes, it goes by a couple of different names now: an ImmTAC or an immune mobilizing monoclonal T-cell receptor against cancer, or simply kind of a TCR [T-cell receptor], but the way that I like to describe it is that it's like a magnet. On one end, it binds a T cell with an anti-CD3 [cluster of differentiation 3] end that would otherwise maybe not necessarily be attracted to the cancer, and then on the other end, it binds the antigen gp100 on the surface of the tumor and basically forces the T cell to engage with the cancer. Again, acknowledging a possible mechanism of innate resistance and just having the immune system kind of not acknowledge uveal melanoma, this is a really high-affinity magnet that just drags the immune system over to the cancer and forces them to engage. That's the mechanism in the simplest terms. As a target, gp100 is pretty uniformly expressed on uveal melanoma. The other place that we see it is melanocytes, most commonly in the skin.
Richard D. Carvajal, MD: Yes, and with that binding this really optimized T-cell receptor, it's important to highlight that it only recognizes that gp100 protein in the context of HLA-A*0201. It's important for the audience to understand that what is the HLA [human leukocyte antigen] status is how the immune system is able to recognize certain fragments and certain antigens. We think about 40%-50% of the Caucasian population is HLA-A*0201-positive, and this drug was designed only to identify the fragment in that context, so the efficacy of this drug is there just for that portion of the patient population.
Marlana M. Orloff, MD: It’s important that both providers and patients understand that HLA is basically your immune type. When I describe that to patients, I say, OK, you have a blood type, and your blood type doesn't change. With other immunotherapies, like PD1 inhibitors, looking at biomarkers like PDL1 as something that may predict response, PDL1 may be dynamic, you could rebiopsy and you may see it and you may not, and it may change over time. HLA is one of those things that does not change. It's a simple blood test, but it's like your blood type. I know that patients may get tested, and they may not be A0201 and you may get this question, can we check it again? It's just not something like that. Like you said, it's important because it's that mechanism antigen presentation that interacts with the immune system, and it needs to be there. And the reason they chose this one, as you said, is that it's just the most common in the patient population for which we see uveal melanoma.
Transcript Edited for Clarity