Abstract 1975: Potential novel Immuno-oncology mechanism revealed during translational phase I Immuno-blood profiling of experimental ADC medicine OBT076 in a gastric cancer patient

Abstract

Abstract CD205 is a type I transmembrane glycoprotein, with unique characteristics that make it an ideal target for Antibody Drug Conjugate (ADC) therapy. Here we report on a potential novel immuno-oncology mechanism revealed during the Translational Phase I (NCT04064359) immuno-blood profiling of a chemo-refractory patient treated with OBT076, an experimental CD205-directed ADC. A chemo-refractory advanced gastric cancer patient with 60% CD205 expression in the primary tumor via IHC and having previously undergone 2 lines of chemotherapy treatment (Docetaxel/cisplatin/5FU and Ramucirumab/Paclitaxel), received five 21-day cycles of OBT076 (one at 2.5mg/kg and four cycles at 2.0 mg/kg) followed by 1 cycle of Pembrolizumab (PZ; 200mg) ~4 weeks later. Clinical response was evaluated and immunological markers (CD45, CD205, CD4, CD8, and PD1) in peripheral blood cells were quantified using flow cytometry. After 2 OBT076 cycles at 2.0 mg/kg, there was an ~40% shrinkage in the primary gastric tumor size and resolution of ascites and lymph node metastases were observed. Following 2 further cycles and PZ, complete response was achieved for the primary tumor. Flow cytometry showed (1) an initial decrease in the absolute numbers of dendritic cells by day 8, followed by a 2-fold increase in numbers by day 21 after treatment; (2) a near total decrease in the population of CD8+ CD205+ cells by day 8, no recovery in levels were observed; (3) a 3-fold increase in CD4+ and CD8+ T-cell numbers between days 8 and 21 and (4) an initial decrease in CD4+ PD1+ and CD8+ PD1+ T-cell numbers followed by an ~4-fold increase between days 8 and 21. In summary our results show that increases in PD1+ T-cells, T-cell induction, and decreases in immuno-suppressive CD4+ CD205+ and CD8+ CD205+ cells occur simultaneously; coinciding with rapid resolution of the primary tumor, lymph node metastases and ascites. These findings suggest that OBT076 activates the patient’s immune response against the tumor through a potentially novel mechanism: drug-induced depletion of CD8+ CD205+ immuno-suppressive cells and subsequent T-cell activation. Additionally, our data support the use of immune checkpoint inhibitors in conjunction with OBT076 to achieve favorable clinical outcomes. Citation Format: Christian Rohlff, Solmaz Sahebjam, Alain Mita, Rosen Lee, Chander Sekhar Peddaboina, Arnima Bisht, Lindsey Hudson, Wolf Fridman, Abderrahim Fandi, Olivier Rixe. Potential novel Immuno-oncology mechanism revealed during translational phase I Immuno-blood profiling of experimental ADC medicine OBT076 in a gastric cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1975.