Assessment of tumors, blood, and ascites to establish correlations with treatment benefit in platinum resistant or refractory ovarian cancer patients treated with igrelimogene litadenorepvec and pembrolizumab combination therapy.

Abstract

5555 Background: Platinum-resistant/refractory ovarian cancer presents a significant therapeutic challenge and despite several attempts, immunotherapies have not delivered satisfactory results to be approved. Identifying biomarkers of response to novel therapies is crucial for personalizing treatments and improving patient outcomes, especially since certain patients do experience long term benefit after the treatment with pembrolizumab and igrelimogene litadenorepvec (TILT-123; an oncolytic adenovirus coding for TNF and IL-2). Methods: Tumor biopsies (n=62), ascites (n=8) and blood (n=234) were collected from 15 patients treated in the PROTA trial (Phase I, NCT05271318). These patients received pembrolizumab intravenously plus igrelimogene litadenorepvec intravenously, followed by local administration intratumorally or intraperitoneally. Sampling took place prior to therapy, during therapy and after it. Tumor proteome (IHC, mIF) and transcriptome was analyzed to assess immune changes and virus presence. Ascites and blood samples were assayed to measure cell counts, phenotypes, cytokine and protein counts, as well as for the presence of antiviral neutralizing antibodies (NAbs). Biological parameters were correlated with overall survival (OS), RECIST 1.1 evaluations and tumor size changes. For analysis of OS, logrank test was used. For group comparisons two-tailed Mann-Whitney U-test was used. Pearson or Spearman tests were used for correlations. Results: Patients experiencing a drop in circulating lymphocytes 8-24 hours after treatment were more likely to experience longer OS (p=0.044). Additionally, patients with a higher lymphocyte count at baseline experienced similar OS benefit (p=0.018) plus a positive correlation with disease control (p=0.023). Most patients (11/15) showed antiviral immunity at baseline but eventually all patients developed neutralizing activity, and the same was observed in ascites. The presence of NAbs at baseline as well as development of highest titers were positively correlated with longer OS (p=0.004) and disease control (p=0.003). Conclusions: Igrelimogene litadenorepvec and pembrolizumab are therapies designed to attract, activate and/or protect lymphocyte-mediated antitumor activity. These findings suggest that having a fit immune system able to mobilize effector immune cells as well as responding to immunostimulant agents increases therapeutic success. As a disease with few therapeutic options, ovarian cancer patients often receive multiple lines of chemotherapy that might decrease the efficacy of immediate immunotherapies. The potential use of these biomarkers will be studied in larger studies to validate their utility in guiding the use of immunotherapy in this challenging patient population. Clinical trial information: NCT05271318 .