RT Journal Article
SR Electronic
T1 1390 RNA nanoparticle vaccines overcome the immunosuppressive tumor microenvironment of metastatic osteosarcoma
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP A1444
OP A1444
DO 10.1136/jitc-2022-SITC2022.1390
VO 10
IS Suppl 2
A1 Ligon, John
A1 Stover, Brian
A1 Mendez-Gomez, Hector
A1 Grippin, Adam
A1 Weidert, Frances
A1 Fagman, Lana
A1 Chardon-Robles, Jonathan
A1 Castillo, Paul
A1 Silver, Natalie
A1 Lagmay, Joanne
A1 Milner, Rowan
A1 Mitchell, Duane
A1 Sayour, Elias
YR 2022
UL http://jitc.bmj.com/content/10/Suppl_2/A1444.abstract
AB Background We previously developed a complex of tumor-derived mRNA (whole tumor transcriptome) with a liposomal nanoparticle to allow systemic delivery of tumor-specific antigens to antigen presenting cells for induction of antigen specific T cell immunity.1-3 We tested this approach to circumvent the lack of specific targets, overcome antigenic heterogeneity, and reprogram the immunosuppressive tumor microenvironment (TME)4 present in osteosarcoma, where immunotherapy has not yet been effective.Methods Total-tumor mRNA was amplified from tumor cell lines or tumor biopsy tissue before complexation in lipid nanocarriers/cationic lipids, generating an RNA-nanoparticle (RNA-NP) for systemic administration. We also developed non-specific RNA-NPs to measure the anti-tumor effect of an “off-the-shelf” immunomodulator. Preclinical murine models were generated using K7M2, KHOS or 143B osteosarcoma cells in either C57Bl/6, BALB/c or BALB/c SCID mice inoculated by tail vein injection to mimic minimal residual metastatic disease from pulmonary osteosarcoma. We launched a comparative oncology clinical trial for client-owned canine patients (pet-dogs) with osteosarcoma through collaboration with the UF College of Veterinary Medicine (UF IACUC#202111376, PI: Milner).Results In mice inoculated with pulmonary osteosarcoma, total-tumor RNA-NPs elicit significant anti-tumor efficacy in the K7M2 model with long term survivor benefits (7/8 treated mice). These total-tumor RNA-NPs reprogram the TME with significantly less tumor associated macrophages and myeloid-derived suppressor cells (p<0.01). RNA-NPs localize to the perivascular region of the TME, transfect CD45+ myeloid cells, and induce upregulation of genes such as BATF3 known to be related to myeloid reprogramming into activated dendritic cells. Furthermore, monotherapy with non-specific pp65 RNA-NPs generated significant anti-tumor effect in SCID mice (p<0.05). Long-term survivor outcomes from tumor loaded mRNA-NPs correlates with an increase in intratumoral central memory T cells (not observed in animals vaccinated with GFP RNA-NPs). In our first three canine subjects with osteosarcoma, total-tumor RNA-NPs were safe and immunologically active with changes in peripheral blood markers of dendritic cell and T cell activation within 6 hours of vaccine administration.Conclusions RNA-NPs redirect immunosuppressive myeloid cells which are a hallmark of the osteosarcoma TME[4], resulting in an immune activated state and leading to increased intratumoral central memory T cells. These vaccines bypass MHC restriction and can be made readily available for all patients/canines providing a renewable antigen resource that can be used to continuously vaccinate patients. This agent, which is FDA-IND approved (BB-19304, Sayour) and in human clinical trials for patients with brain tumors (NCT04573140), may be a promising potential novel therapy for patients with recurrent pulmonary metastatic osteosarcoma.Acknowledgements John A. Ligon and Brian Stover contributed equally to this work and are co-first authors.ReferencesSayour EJ, Grippin A, De Leon G, Stover B, Rahman M, Karachi A, Wummer B, Moore G, Castillo-Caro P, Fredenburg K, Sarkisian MR, Huang J, Deleyrolle LP, Sahay B, Carrera-Justiz S, Mendez-Gomez HR, Mitchell DA. Personalized Tumor RNA loaded lipid-nanoparticles prime the systemic and intratumoral milieu for response to cancer immunotherapy. Nano Lett. 2018;18(10):6195–206.Sayour EJ, Mendez-Gomez HR, Mitchell DA. Cancer vaccine immunotherapy with RNA-loaded liposomes. Int J Mol Sci 2018;19(10):2890.Sayour EJ, De Leon G, Pham C, Grippin A, Kemeny H, Chua J, Huang J, Sampson JH, Sanchez-Perez L, Flores C, Mitchell DA. Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. Oncoimmunology. 2017;6(1):e1256527.Ligon JA, Choi W, Cojocaru G, Fu W, Hsiue EH, Oke TF, Siegel N, Fong MH, Ladle B, Pratilas CA, Morris CD, Levin A, Rhee DS, Meyer CF, Tam AJ, Blosser R, Thompson ED, Suru A, McConkey D, Housseau F, Anders R, Pardoll DM, Llosa N. Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes. J Immunother Cancer. 2021;9(5):e001772.Ethics Approval Studies approved by UF IACUC 202111376 and 202009941