Immunogenomics Demonstrate Predictive Capability to Immunotherapy Resistance in Uveal Melanoma

Immunotherapy Resistance in Uveal

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Immunogenomic factors were found to be predictive of resistance to immunotherapy and to tumor susceptibility to the therapeutic class in patients with metastatic uveal melanoma, according to findings from a study published in Nature Communications.

Investigators profiled human uveal melanoma metastases (n = 100) using clinicogenomics, transcriptomics, and tumor-infiltrating lymphocyte (TIL) potency assessment, and discovered that 55% of metastases had tumor reactive TILs. To better harness the TILs, study authors developed the biomarker uveal melanoma immunogenomic score (UMIS). They showed that UMIS was strongly correlated with the percentage of tumor-reactive TIL cultures (rho = +0.47; P = 7.06e⁻⁷), with reactive TIL cultures being rarely expanded among patients with a UMIS of less than 0.2.

Nineteen of the uveal melanoma metastases were used to manufacture TIL as part of a phase 2 clinical trial (NCT01814046). In this cohort, which included 6 responders, there was a strong correlation between source tumor UMIS and ex vivo anti-tumor reactivity of the post-rapid expansion of the TIL infusion product (n = 17; rho = +0.61; P = .011). UMIS was also strongly correlated with the magnitude of clinical tumor regression following adoptive transfer, including in patients who were refractory to immune checkpoint inhibitor therapy (n = 19; rho = −0.68; P = .001).

“We find that over half of these metastases harbor TILs with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies,” Shravan Leonard-Murali, MD, of the Solid Tumor Cellular Immunotherapy Program, UPMC Hillman Cancer Center, University of Pittsburgh, in Pennsylvania, and coauthors wrote. “However, we observe strikingly low intratumoral T-cell receptor [TCR] clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent TILs, we develop[ed] a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression.”

To conduct their study, investigators obtained 100 metastases from 84 patients with uveal melanoma during eligibility screening for 2 phase 2 studies (NCT01814046 and NCT03467516) conducted at the National Cancer Institute and UPMC Hillman Cancer Center. Prior systemic therapy was not mandatory, but if patients did receive prior treatment, more than 4 weeks needed to have passed before the start of their current study therapy and adverse effects must have recovered to a level of grade 1 or less. Additionally, all patients were required to have an ECOG performance status of 1 or less, a life expectancy over 3 months, as well as adequate hematological, renal, and hepatic function. Those with active systemic infections, coagulation disorders, or other active immune system disorders were excluded.

The median patient age was 56 years (range, 17-78). Most patients were female (52%), had liver involvement (95%), had elevated lactate dehydrogenase (75%), and had M1B or M1C stage disease per AJCC 8th edition (71%). The study included metastases from treatment naive (26%) and refractory patients (76%). In terms of prior immune checkpoint inhibitor therapy, patients received anti–CTLA-4 monotherapy (n = 3) anti–PD-1 monotherapy (n = 11), sequential therapy (n = 8), combination therapy (n = 24), and tebentafusp (Kimmtrak; n = 9); no patients displayed an objective response following treatment with these agents. Patients had a low tumor mutational burden, with a median of 0.64 mutations per megabase. Sixty-two percent of metastases had secondary alterations of BAP1 and 42% had secondary alterations of SF3B1; metastases also displayed chromosome 3 loss (46%) and 8q gain (85%).

To calculate UMIS, investigators utilized a cohort-independent rank-based gene set scoring method to determine the enrichment scores for individual biopsies based upon transcripts per million using a list of 2394 genes to generate a single continuous variable for each metastasis. Each UMIS figure reflected the concordance and mean percentile rank of the list of genes within the sample transcriptome. The median UMIS was 0.237 (range, 0.114 to 0.347) which was used as the cutoff to differentiate between high and low UMIS groups.

Additional findings from the study revealed that UMIS high metastases had more lymphoid cells (proportion ratio = 10.50, P = .047) and fewer tumor cells (proportion ratio = 0.88, P = .047) compared with UMIS low metastases. Additionally, study authors noted that the TIL in the UMIS high metastases had “undergone activation and effector differentiation consistent with an in vivo adaptive anti-tumor response and indicative of a T cell-inflamed microenvironment.”

“Our study revealed the importance of UMIS as a tumor intrinsic biomarker to predict TIL potency and clinical response after adoptive transfer in [patients with] uveal melanoma,” investigators wrote in conclusion. “Whereas recent reports have proposed phenotypic and transcriptomic markers for the purpose of defining neoantigen specific TCR sequences from TIL, we believe UMIS represents a unique tumor biomarker for the identification of tumor reactive TIL capable of ex vivo expansion for clinical adoptive transfer. Importantly, a UMIS level of less than 0.2 identified metastases that were unlikely to yield potent TIL, suggesting that preoperative UMIS measurement could prevent futile invasive surgical harvests. We found UMIS performed significantly better as a tumor intrinsic biomarker of TIL potency when compared to several focused gene expression signatures of T-cell inflammation.”

Reference

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