Abstract 5652: Translational evidence of reactivated innate and adaptive immunity with intratumoral IMO-2125 in combination with systemic checkpoint inhibitors from a Phase I/II study in patients with anti-PD-1 refractory metastatic melanoma
Authors: Haymaker Cara , Uemura Marc , Murthy Ravi , James Marihella , Wang Daqing , Brevard Julie , Swann Suzanne , Geib James , Cornfeld Mark , Chunduru Srinivas , Agrawal Sudhir , Yee Cassian , Wargo Jennifer , Amaria Rodabe , Patel Sapna , Tawbi Hussein , Glitza Isabella , Woodman Scott , Hwu Wen-Jen , Davies Michael A. , Hwu Patrick , Overwjik Willem , Bernatchez Chantale , Diab Adi 
Published: July 2017

Background: While checkpoint inhibitor (CPI) therapy has transformed metastatic melanoma (MM) treatment, many patients remain refractory. We reasoned that combining CPI with an agent that activates antigen presenting cells and improves T-cell priming may result in improved response. Our approach is to modulate the tumor microenvironment through image-guided intratumoral (i.t.) injection of the TLR9 agonist, IMO-2125, in combination with either ipilimumab (ipi) or pembrolizumab (pembro). We hypothesize that this will result in dendritic cell (DC) activation and induction of tumor-specific CD8+T-cells which will synergize with ipilimumab or pembrolizumab to overcome immune-escape. Based on this rationale we initiated a phase I/II clinical trial.

Study Design/Methods: Adults with refractory MM that have had prior PD-1 blockade therapy (with or without a BRAF inhibitor) are eligible. IMO-2125, in doses escalating from 4mg to 32mg, is given i.t. weeks 1, 2, 3, 5, 8, and 11 along with standard doses of ipilimumab or pembrolizumab. Primary endpoints are safety, tumor response, and PK. Multiple biopsies are obtained in both the injected and distant tumor pre- and on-treatment. Immune analyses include DC subsets and their activation status as well as T cell activation, function and proliferation. T-cell repertoire diversity is evaluated by high-throughput CDR3 sequencing and changes in gene expression signatures are assessed by nanoString. Changes in circulating cytokines are also being assessed during therapy.

Results: Enrollment is proceeding on both the IMO-ipilimumab and IMO-pembrolizumab dose-escalation arms of the trial. Safety is acceptable with no DLT recorded to date. Durable clinical responses (including 1 CR) have been observed with IMO-ipilimumab in patients who were refractory to PD-1 inhibitor. Fresh tumor biopsies show maturation (upregulation of HLA-DR) of the myeloid DC1 subset (CD1c+CD303-), upregulation of PD-L1 by malignant cells, as well as an IFNα response gene signature in the IMO-2125 injected tumor lesion 24 hrs post-treatment compared to pre-treatment biopsy. On-treatment biopsy results show a higher expression of CD56+ and Ki67+ effector CD8+ T-cells in responding patients. Initial CDR3 sequencing demonstrates increased diversity in the injected lesions of all patients assessed and expansion of top clones present in the distant lesion in a responding patient. Plasma analysis showed an increase in IFNγ levels in the plasma of responding patients.

Conclusions: These results demonstrate that IMO-2125 with a checkpoint inhibitor is a viable strategy to revive the immune response in tumors that are refractory to PD-1 inhibitors. Further clinical evaluation of both the IMO-ipilimumab and IMO-pembrolizumab combination is planned in a Phase 2 expansion of the current trial.

Citation Format: Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Rodabe Amaria, Sapna Patel, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem Overwjik, Chantale Bernatchez, Adi Diab. Translational evidence of reactivated innate and adaptive immunity with intratumoral IMO-2125 in combination with systemic checkpoint inhibitors from a Phase I/II study in patients with anti-PD-1 refractory metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5652. doi:10.1158/1538-7445.AM2017-5652