Abstract 1505: Reprogramming cancer into antigen presenting cells as a novel immunotherapy
Authors: Linde Miles H. , Gurev Sarah F. , Phan Paul , Zhao Feifei , Gars Eric J. , Stafford Melissa , Köhnke Thomas , Marshall Payton L. , Fan Amy C. , Dove Christopher G. , Linde Ian L. , Miller Lindsay P. , Majzner Robbie G. , Zhang Tian Yi , Majeti Ravindra 
Published: July 2021

As a therapeutic modality, cancer vaccination leverages the well-characterized ability of antigen presenting cells (APCs) to take up and present tumor antigens in an effort to stimulate potent anti-cancer T cell responses. However, clinical successes with therapeutic cancer vaccination remains limited. Here, we present a novel cancer vaccination approach utilizing myeloid lineage reprogramming to directly convert cancer cells into tumor reprogramed-APCs (TR-APCs).In order to understand the therapeutic potential of TR-APCs, we generated syngeneic murine B-cell acute lymphoblastic leukemia models amenable to myeloid lineage reprogramming via ectopic expression of the myeloid lineage transcription factors PU.1 (Spi1) and C/EBPα (CEBPA). Upon enforced expression of these factors, the resulting TR-APCs acquire both myeloid phenotype and function, including the capacity for phagocytosis and antigen presentation. Crucially, TR-APCs can present endogenous self-derived tumor antigens directly encoded in their genome, without the need for phagocytosis and processing of adjacent tumor cells. In vitro, leukemia-derived TR-APCs express enhanced levels of antigen presentation machinery and co-stimulatory molecules, and potently stimulate tumor-specific CD4+ and CD8+ T cells. While in vivo TR-APC induction elicits only a modest extension to overall survival in immunodeficient hosts, generation of TR-APCs in immunocompetent syngeneic animals leads to complete leukemia eradication and protection from subsequent re-challenge. Further analysis of the in vivo immunological response to TR-APC induction revealed oligoclonal T cell expansion and establishment of cancer-specific immunological memory. Strikingly, use of a dual flank tumor model revealed that local TR-APC induction is sufficient to elicit systemic immunity capable of eradicating distant metastatic sites.

We extended this treatment modality beyond hematologic malignancies, demonstrating that some solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs, and contribute to increased overall survival. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary human B cell acute lymphoblastic leukemia (B-ALL) specimens. Strikingly, primary B-ALL-derived TR-APCs stimulate autologous patient-derived T cells, demonstrating the clinical potential of TR-APCs to enhance antitumor immunity in patients. Thus, TR-APCs represent a novel cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology.

Citation Format: Miles H. Linde, Sarah F. Gurev, Paul Phan, Feifei Zhao, Eric J. Gars, Melissa Stafford, Thomas Köhnke, Payton L. Marshall, Amy C. Fan, Christopher G. Dove, Ian L. Linde, Lindsay P. Miller, Robbie G. Majzner, Tian Yi Zhang, Ravindra Majeti. Reprogramming cancer into antigen presenting cells as a novel immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1505.