Abstract CT204: High cytotoxic T-cell or polymorphonuclear cell infiltrates in the tumor microenvironment correlate with responses to BL8040 plus pembrolizumab combination therapy in metastatic pancreatic tumors: Scientific correlates of a phase II clinical trial
Authors: Barreto Carmelia M. Noia , Ledesma Debora A. , Gite Swati , Solis Luisa M. , Jiang Mei , Pandurengan Renganayaki K. , Wolff Robert , Javle Milind , Pant Shubham , Varadhachary Gauri , Shroff Rachna , Vainstein-Haras Abi , Sorani Ella , Lustig Tzipora M. , Kashtan Osnat , Gozlan Yosi , Townson Steven M. , Fahey Jeanne M. , Yao James , Wistuba Ignacio I. , Overman Michael , Fogelman David , Parra Edwin R. 
Published: September 2020

Background: We recently conducted a clinical trial assessing Pembrolizumab (P) and BL-8040 (BL) in patients with pancreatic cancer. We prospectively collected serial biopsies to help understand the impact of this treatment on the tumor microenvironment (TME). Methods: Twenty patients were enrolled and were treated with BL8040 (1.25mg/kg) monotherapy for 2 weeks followed by dual therapy with BL8040 (d1, 4, 8, 11) plus Pembrolizumab (200 mg IV, d1) every 3 weeks. Biopsies were collected at baseline (T0) and during therapy. Some patients had biopsies after BL monotherapy (Tm) and some after combined therapy (Tc) due to a protocol change mid-study. Malignant cells expressing PD-L1 were assessed using immunohistochemistry (IHC) and TME was studied using 3 multiplex immunofluorescence panels including one each for T-cells subpopulations, macrophages and myeloid-derived suppressor cells (MDSCs). Median densities of the different phenotypes were analyzed in tumor and stromal compartments and correlated with serial biopsies. Results: Of 20 patients enrolled and 15 were evaluable for response of whom 2 had stability and 1 had a partial response. 17 patients had at least one viable biopsy; 4 had biopsies at T0 and Tm, 3 had biopsies at T0, Tm, and Tc, and 2 had biopsies at T0 and Tc. In general, we noted that cytotoxic T cells increased from baseline when measured at Tm or Tc. In contrast, MDSC counts and overall T cells decreased at Tm or Tc from baseline. Additionally, we saw an increase in CD 68+ and PD-L1 expressing macrophages (P=0.059 and P=0.046, respectively). Patients who had clinical benefit (PR/SD) had greater numbers of cytotoxic T-cells (CD3+CD8+, median, 226.08 cells/mm2) and regulatory T cells (CD3+FOXP3+, median, 48.20 cells/mm2) at baseline than PD patients (median, 26.15 cells/mm2, P=0.03; 13.31 cells/mm2, P=0.016, respectively). Conversely, at T0, the lowest numbers of tumor cytotoxic T-cells activated CD3+CD8+GB+ (median, 0.34 cells/mm2) and highest numbers of PMN-cells (CD66b+CD11b+, median, 16.66 cells/mm2) were observed in patients with PD when compared with PR or SD (median, 4.54 cells/mm2, P=0.097; 3.38 cells/mm2, P=0.023, respectively), suggesting that highest densities of PMN-cells may contribute to downregulation of T-cells in those cases. Conclusions: Higher cytotoxic T-cells or PMN-cell counts at T0 may predict changes in the TME and radiologic response to treatment with BL8040+Pembrolizumab therapy in metastatic pancreatic cancer. PMN-cells may play a role promoting immune suppression of T-cells, increase the risk of metastasis and interfering with the treatment. Trial Registration: NCT02907099, Ethics Approval: This study was approved by the M.D. Anderson Institutional Review Board, approval number 2016-0410.

Citation Format: Carmelia M. Noia Barreto, Debora A. Ledesma, Swati Gite, Luisa M. Solis, Mei Jiang, Renganayaki K. Pandurengan, Robert Wolff, Milind Javle, Shubham Pant, Gauri Varadhachary, Rachna Shroff, Abi Vainstein-Haras, Ella Sorani, Tzipora M. Lustig, Osnat Kashtan, Yosi Gozlan, Steven M. Townson, Jeanne M. Fahey, James Yao, Ignacio I. Wistuba, Michael Overman, David Fogelman, Edwin R. Parra. High cytotoxic T-cell or polymorphonuclear cell infiltrates in the tumor microenvironment correlate with responses to BL8040 plus pembrolizumab combination therapy in metastatic pancreatic tumors: Scientific correlates of a phase II clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT204.