Abstract 3607: Case study: Efficacy and persistence of autologous T cell therapy targeting SLC45A2 in uveal melanoma
Authors: Singh Shailbala , Ryu Esther , Campbell Katie M. , Smith Amber , Phillips Suzanne , Soto Luisa , Lai Ivy , Lizee Gregory , Vincent Benjamin , Thompson Marshall , Hoos William , Patel Sapna , Yee Cassian 
Published: March 2024

Background: Metastatic uveal melanoma (UM) is an aggressive cancer, with a 1-year overall survival of &lt; 50%. While the bispecific T-cell engager tabentafusp is approved for HLA-A2+ patients with gp100+ UM, there are limited treatment options for patients who do not express HLA-A2. We present a strategy and proof-of-concept for designing and manufacturing a tumor-selective endogenous T-cell therapy (ETC) for a patient with metastatic UM.

Methods: PBMC were collected by apheresis in 2013 upon first diagnosis with uveal melanoma; 8 years later, following progression, cryopreserved PBMC were used to generate autologous antigen-specific T cells for adoptive therapy. The validated tumor antigen SLC45A2 was found to be overexpressed in the patient’s metastatic tumor based on RNA expression profiling. Peripheral blood derived SLC45A2-specific HLA-A2402-restricted central memory CD8+ T cells were generated via a process of in vitro priming, IL-21 treatment, tetramer-guided sorting and cell expansion. Clinical response was assessed via longitudinal CT imaging and ctDNA-based MRD monitoring. Persistence of transferred T cells was measured via serial flow cytometry and RNA-sequencing of PBMCs, along with TCR and RNA sequencing of tumor tissue collected post infusion.

Results: A 39 year old male received SLC45A2-specific ETC therapy and checkpoint inhibitor treatment for advanced metastatic UM (GNAQ (Q209P), BAP1 (E398*, LOF). Bulk RNAseq data from baseline biopsies were queried for known tumor-associated antigens, and SLC45A2 was expressed at high levels. The patient experienced widespread disease stabilization with minimal toxicity. SLC45A2-specific CD8+ T cells persisted in circulation up to 181 days after the first infusion and 43 days after the second infusion, ranging from 6.7% - 1.5% of total circulating CD3 T cells. T cell clones from the infusion product included the dominating TCR subclone in tumor tissue collected 6 weeks post infusion, comprising 33% of the TCRá and 26% of TCRâ population. SLC45A2-specific T cells were identified in the tumor infiltrating lymphocytes in a separate lesion collected 10 months after the first infusion. A duodenum lesion progressed during treatment, and RNAseq demonstrated reduced expression of genes associated with HLA presentation and SLC45A2 and reduced TIL infiltration, suggesting tissue-specific immune editing of the tumor cell population.

Conclusions: 1. Tumor-reactive antigen-specific T cells can be isolated and expanded for adoptive therapy using PBMCs cryopreserved for &gt; 8 years. 2. Following infusion, peripheral blood and tumor profiling support the persistence of transferred T cells in a patient with metastatic uveal melanoma. 3. Disease stabilization in aggressive metastatic UM was achieved with minimal toxicity. Overall, our study provides evidence and rationale for utilizing autologous antigen-specific T cells for treating rare cancers.

Citation Format: Shailbala Singh, Esther Ryu, Katie M. Campbell, Amber Smith, Suzanne Phillips, Luisa Soto, Ivy Lai, Gregory Lizee, Benjamin Vincent, Marshall Thompson, William Hoos, Sapna Patel, Cassian Yee. Case study: Efficacy and persistence of autologous T cell therapy targeting SLC45A2 in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3607.