RT Journal Article
SR Electronic
T1 767 Safety and preliminary efficacy of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L/IL-23/IL-36γ for intratumoral (ITu) injection, and durvalumab (IV) in TNBC, HNSCC, and melanoma
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP A798
OP A798
DO 10.1136/jitc-2022-SITC2022.0767
VO 10
IS Suppl 2
A1 Olson, Daniel
A1 Daud, Adil
A1 Shapira-Frommer, Ronnie
A1 Jimeno, Antonio
A1 Reagan, Patrick
A1 Kummar, Shivaani
A1 Abdul-Karim, Raghad
A1 Stemmer, Salomon
A1 McKean, Meredith
A1 Geva, Ravit
A1 Perets, Ruth
A1 Patel, Manish
A1 Marron, Thomas
A1 Gupta, Shilpa
A1 Desai, Anupam
A1 Weber, Jeffrey
A1 Margolin, Kim
A1 Park, Jong Chul
A1 Zacharek, Sima
A1 Laino, Andressa Sodre
A1 Frederick, Joshua
A1 Milberg, Oleg
A1 Zhu, Lili
A1 Mody, Kinjal
A1 Lopez, Natalia
A1 Aanur, Praveen
A1 Meehan, Robert
A1 Johansen, Lisa
A1 Lavoie, Sara
A1 Do, Khanh
A1 Sullivan, Ryan
A1 Sweis, Randy
YR 2022
UL http://jitc.bmj.com/content/10/Suppl_2/A798.abstract
AB Background mRNA-2752 is a first-in-class mRNA-based therapeutic agent encoding T cell co-stimulator OX40L, and pro-inflammatory cytokines IL-23 and IL-36γ. Preclinical data demonstrated activity in a range of tumor microenvironments (TMEs), including immune checkpoint inhibitor (CPI)- refractory cancer models, and synergy when combined with α-PD-L1 antibodies. Data from the dose escalation phase of the study was previously reported and the recommended mRNA-2752 dose for expansion (RDE) was up to 8mg ITu.Methods We evaluated the safety and efficacy of ITu mRNA-2752 administered as monotherapy (Arm A; previously reported ASCO 2020) and in combination with the PD-L1 inhibitor durvalumab (Arm B) in patients (pts) with tumors that were palpable or accessible with image guidance. Here we report preliminary data for the expansion cohorts in TNBC, CPI-refractory melanoma, and HNSCC. Biomarker analyses included IHC/F-IHC of immune status markers and whole transcriptome assessments of paired tumor biopsies. Protein quantification of IL-23, IL-36γ and other pro-inflammatory cytokines were performed in plasma and tumors.Results As of 01JUL 2022, 88 pts were treated, 69 in Arm B with mRNA-2752 dosed by tumor size ranging from 0.25-8 mg. The most common treatment related adverse events occurring in ≥ 10% of pts in Arm B included grade 1/2 injection site erythema/pain/swelling, fever, chills, fatigue, nausea, and flushing. Grade 3 events included injection site pain/erythema, and fever. There were no grade 4/5 related events. Objective responses were observed in immune refractory tumors by RECIST and iRECIST, including a confirmed PR in a PD-L1 low TNBC and confirmed iCR in an immune checkpoint-refractory melanoma pt, respectively. Biomarker analyses of plasma and tumor show mRNA-2752 treatment was associated with elevated pro-inflammatory cytokines, including IL-23, IL-36γ, IFNγ, and TNFα. F-IHC of paired tumor biopsies showed increase in proliferating CD8+ T cells. Transcriptional profiling of the TME demonstrates a pronounced immune response including dendritic cell recruitment and T cell activation, which remained elevated in longitudinal samples. The greatest increases in immune response and markers of cytolytic activity were observed in pts deriving clinical benefit.Conclusions ITu mRNA-2752 + IV durvalumab is safe, tolerable, and shows preliminary efficacy in immune refractory tumors, including TNBC and melanoma. Biomarker analyses indicate mRNA-2752 drives cytokine responses. Consistent with the expected mechanism of action, a productive and sustained inflammatory response is observed in the TME in response to treatment, including signatures of increased innate and adaptive immune cell abundance and effector response.Acknowledgements We thank AstraZeneca for provision of durvalumab for this study.Trial Registration NCT03739931Ethics Approval This study was approved by participating Institutions’ Ethics Board and conducted according to the principles of ICH GCP . Participants gave informed consent before taking part.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review upon request.