ACIS Research Coordinator Kevin attended the 40th Anniversary Meeting of the Society for Immunotherapy of Cancer (SITC)

ACIS Research Coordinator Kevin attended the 40^th Anniversary Meeting of the Society for Immunotherapy of Cancer (SITC), near Washington DC, from Nov 6-9, 2025. He had the opportunity to meet the clinical development team from IMMATICS from both Germany and the US.

Summary of Uveal Melanoma Abstracts from SITC 2025:

Clinical Abstracts:

Abstract #598 Phase 2 trial of TIL therapy for metastatic uveal melanoma: Evaluating cellular potency and tumor transcriptomic predictors of response
Dr. Udai Kammula, from the University of Pittsburgh, presented a thorough summary of their clinical trial experience with TIL therapy (tumor infiltrating lymphocytes) in 33 patients with metastatic uveal melanoma. Patients were entered into the trial regardless of HLA status or number and type of prior metastatic therapies. These patients had a median of 2 prior therapies, 64% were HLA negative, 70% had both liver and extrahepatic mets (27% had liver mets only), 64% had prior immune checkpoint blockade therapy. Genomic mutation findings among these 33 patients: GNAQ 46%, GNA11 49%, SF3B1 42%, and BAP-1 loss 58%. Patients were first pre-treated with non-myeloablative lymphodepletion chemo (NMALD: fludarabine+cyclophosphamide), then IL-2, and them TIL therapy for up to 6 treatments. Patients’ cells were “manufactured” in a specialty immunology lab for an average time of 33 days to compose the TIL therapy, and resulted in an average potency of 52 billion cells for their TIL infusion. The TIL infusion cell product was 69% CD4 positive and 29% CD8 positive (all key factors that may support the following clinical results).

Safety of the TIL regimen was as expected: 100% of patients had experienced neutropenia, lymphopenia and leukopenia, 91% thrombocytopenia, 70% anemia, 52% serious hypophosphatemia and 21% hyponatremia (mostly managed with growth factors and transfusion supportive care, although one patient died from myocarditis).  Among 31 TIL-treated patients evaluable for efficacy, the Objective Response Rate (ORR) was 23%, with 7 patients having Partial Responses, and median duration of response was 10.8 months. Among 19 patients who had “reactive TILs” following infusion, the ORR was 36.8% and with 7 PRs observed, supporting the observation that potency of the TIL infusion product may impact more favorably on efficacy outcomes (another TIL therapy under investigation in metastatic UM produces significantly lower TIL cell potency in the infusion product).

The investigators also included a novel biomarker test before the TIL regimen was administered: UMIS tumor transcriptome, which may be predictive for patients who may produce the greatest TIL potency infusions and
perhaps obtain the best responses.  This early observation will require further evaluation in larger numbers of
TIL-treated patients, and likely a randomized trial.

Abstract #1039  EVALUATING THE PROGNOSTIC IMPACT OF TEBENTAFUSP-ASSOCIATED CUTANEOUS TOXICITIES
ON SURVIVAL IN 83 UVEAL MELANOMA PATIENTS: A MULTI-INSTITUTIONAL COHORT STUDY
Dermatology investigators from Ludwig Maximilian University-Munich, Mass. General Brigham and Dana Farber Cancer Institute-Boston evaluated the existing medical records of patients who were HLA-A*02:01-positive with a diagnosis of metastatic uveal melanoma, and treated with tebentafusp from January 2018 through May 2025.

Results:  Cutaneous/skin adverse events (cAEs) were observed in 78.3% (n=65) of patients, with 50.8% (n=33) having Grade 1 and 49.2% (n=32) having Grade ≥2. Of these 65 patients, 60 (90.7%) experienced a cAE within 1 month of tebentafusp initiation. Progression after tebentafusp initiation was observed in 86.7% (n=72) of treated patients. RECIST best tumor response consisted of 12.0% (n=10) partial response, 43.4% (n=36) stable disease, and 44.6% (n=37) progressive disease. Patients who experienced skin toxicity exhibited a significantly longer OS versus those without cAEs in both univariate (median 23.0 months versus 7.5 months, p=2.65e-05) and multivariate Cox regression analyses (hazard ratio (HR) [95% CI] = 0.27 [0.12, 0.63], p=0.002). Furthermore, OS benefit was accentuated in patients with Grade 2 or above (0.22 [0.09, 0.54] p=0.001) and Grade 1 (0.35 [0.14, 0.85], p=0.02) cAEs, versus patients without cAEs. These retrospective clinical observations suggest that tebentafusp-associated cAEs may serve as an early clinical marker of therapeutic efficacy. Future studies are warranted to elucidate the underlying mechanisms driving this relationship.

Basic Science/Laboratory Abstracts:

Abstract #959  Tebentafusp controls disease and prolongs survival by increasing the T cell : tumor cell ratio, activating T cells and inhibiting tumor proliferation in metastatic uveal melanoma patients. Dr. Adel Benlahrech (immunologist from Immunocore) presented a poster which described further investigation of
a novel “T cell fitness” blood test (TCF) in metastatic uveal melanoma patients before they received tebentafusp therapy. An earlier clinical report by Dr. Joseph Sacco at ESMO 2024 observed this TCF gene signature was associated with clinical benefit and Overall Survival from tebentafusp. Immunocore’s further lab investigation reveals tebentafusp-mediated tumor killing increases with higher T cell to tumor ratio (in cell lines). Among a subset of patients with high TCF, tebentafusp appears to turn immunologic-cold tumors hot by increasing T cell migration into tumors. T cells activated by tebentafusp slow tumor growth (in a cell line model) through down-regulation of key cancer cell growth genes: MKI67, SOX10 and MITF. Finally, in metastatic uveal melanoma patients with a high TCF signature, tebentafusp induces acute inflammation in tumors along with down-regulation of the 3 tumor growth genes, and may offer an explanation for the observed improved disease control and Overall Survival following tebentafuso when this high TCF gene signature is determined prior to therapy.

Abstract #182  DetermaIO Stratifies the Tumor Microenvironment (TME) and Immunotherapy Response in Melanoma: A Pilot Study Including Cutaneous and Uveal Subtypes

Dr. Rino Seedor from Thomas Jefferson Univ.- Philadelphia presented a poster describing a 27-gene expression profile of the TME which may identify immune-HOT tumors vs. immune-COLD tumors in patients. The 27-GEP and resulting “IO Score” has been previously-validated in non-small cell lung cancer, triple negative breast cancer and colorectal cancer. Dr. Sedor and her research team evaluated 31 biopsies from patients with cutaneous, uveal  and other melanomas, prior to receiving ipi+nivio immunotherapy. Across the various melanomas, the Disease Control Rate from ipi+nivo immunotherapy by IO Score status was found to be:  76% in patients with IO+ HOT tumors vs. 43% in IO- COLD tumors. Among 4 uveal melanoma patients, 2 were IO+ (with one patient achieving stable disease), while the other two patients who were IO- had progressive disease on ipi+nivo. Based upon these initial observations, the investigators propose a further and larger validation study in melanoma patients.