Tumor-Reactive TIL and UMIS Biomarker Predict Response in Metastatic Uveal Melanoma

Results from a single-center phase 2 trial (NCT03467516) of autologous tumor-infiltrating lymphocyte (TIL) therapy in metastatic uveal melanoma support a precision, biomarker-guided approach to patient selection, according to Udai S. Kammula, MD, FACS.¹^,²

Data presented at the 2026 ASCO Annual Meeting showed that in 32 evaluable patients, the confirmed objective response rate (ORR) was 37% with a tumor-reactive TIL product (n = 19) vs 0% with a nonreactive product (n = 12; P = .026). The median duration of response was 17.3 months with a median follow-up of 5.7 years.¹ In a pooled analysis combining this cohort with an independent phase 2 National Cancer Institute cohort (NCT01814046; n = 52), the ORR was 43% with reactive TIL (n = 28) vs 0% with nonreactive (n = 20) TIL (P = .0005).

Moreover, a pre-procurement transcriptomic biomarker, the Uveal Melanoma Immunogenomic Score (UMIS), predicted TIL product reactivity with an area under the curve of 0.85, vs 0.51 for tumor mutational burden. Among 52 pooled patients, the ORR was 44% with high UMIS (n = 25) vs 8% with low UMIS (n = 26; P = .004).¹^,²

“For the first time, [this research] has established that this mode can work in an immune-cold or immune-resistant cancer, being uveal melanoma, and the fact that we have patients out 5 years corroborates that this could have a big impact for this disease,” Kammula said in an exclusive interview with OncLive®.

In the interview, Kammula discussed the study's key findings, implications for patient selection, and alternative treatment strategies for uveal melanoma. Kammula is a professor of surgery and director of the Solid Tumor Cell Therapy Program at UPMC Hillman Cancer Center, University of Pittsburgh in Pennsylvania.

OncLive: What was the rationale for developing TIL therapy for metastatic uveal melanoma?

Kammula: Uveal melanoma is a resistant cancer that had long been thought to be resistant to immune-based therapies. We had observed many years ago that these cancers harbor special cells called [TILs,] and the goal of this study was to isolate the most optimal population of these cells, infuse them as a cancer therapy, and we saw that it could induce deep and durable responses.

What were the two key findings from this phase 2 TIL therapy trial in uveal melanoma?

One of the challenges with this type of treatment is when you remove a tumor, it's essentially a blind operation, and you're hoping that they harbor these special T cells. Many patients will undergo an operation and receive a TIL product without any antitumor activity, and what our study confirmed are two critical findings.

One, the efficacy of this treatment is completely based on the potency of the infused T cells. The second thing we discovered is there was a precision biomarker, a core biopsy test, that we could perform before the surgery, before the treatment, that could predict two things: one, whether that tumor would have these special T cells, and second, whether they would cause cancer regression. We think this is a major advance because it allows us to be more streamlined and precise with our operative procedure, and also which patients we're going to put onto this treatment.

What do these findings mean for which patients receive TIL therapy in uveal melanoma?

The ultimate goal of precision medicine of any type is to find the optimal treatment for any given patient; the treatment is not meant for everyone. We think that's going to be good in the long run, because it helps [identify] which patients are going to be more likely to respond, especially since all treatments have adverse effects. The other critical future plan is we don't think this biomarker is a static measure of the tumor, [since] it can evolve and change, so this opens up the possibility of maybe priming the patient and then repeating the biopsy. It could be that we find the optimal time to procure a tumor.

What other treatment options exist for patients with uveal melanoma not suited to TIL therapy?

A number of therapeutics are being developed, and it's too early to know right now which ones are going to be the best option. They include a group of T-cell receptor engineered cell products, which are showing some early signs of efficacy. What we need to know is the durability. There are also what we call bispecifics, meaning these are synthetic molecules that target the tumor and recruit the immune system to attack [it]. All of these are early, and more options for these patients are always better.

What else stands out about this TIL therapy research?

The key aspect that we've always felt is the finding that cancers such as uveal melanoma can harbor T cells—when other immune therapies haven't been able to elicit the activity—opens up the door for future cancers. [At the meeting, I also] present[ed] a new trial in which we took the strategy that we used in uveal melanoma and applied it broadly to a number of immunotherapy-resistant cancers; the principles that we learned in uveal melanoma are going to be translatable to a number of diseases like pancreatic cancer, mesothelioma, and other inherently cold cancers.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

References

1. Leonard-Murali S, Bhaskarla C, Yadav GS, et al. Phase 2 trial of TIL therapy for metastatic uveal melanoma: evaluation of T-cell potency and an in-situ precision biomarker. J Clin Oncol. 2026;44(suppl 16):2512. doi:10.1200/JCO.2026.44.16_suppl.2512
2. Leonard-Murali S, Bhaskarla C, Yadav GS, et al. Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility. Nat Commun. 2024;15(1):2863. doi:10.1038/s41467-024-46906-4