A FIRST-IN-HUMAN STUDY OF INTRATUMORAL SAR441000, AN MRNA MIXTURE ENCODING IL-12SC, INTERFERON ALPHA2B, GM-CSF AND IL-15SUSHI AS MONOTHERAPY AND IN COMBINATION WITH CEMIPLIMAB IN ADVANCED SOLID TUMORS

Abstract

Background mRNA-based-drugs can be applied for cancer immunotherapy.¹ SAR441000 is a novel saline-formulated mixture of four mRNAs encoding interleukin-12 single chain, interferon alpha-2b, granulocyte-macrophage colony-stimulating factor, and interleukin-15 sushi that we have identified as mediators of tumor regression across different murine tumor models. Local intratumoral administration of SAR441000 in immunocompetent mice, mediates successful antitumor immunity leading to tumor eradication. Effective antitumor activity of these cytokines involved multiple immune cell populations and was accompanied by intratumoral interferon gamma induction, systemic antigen-specific T-cell expansion, increased granzyme B+ T-cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of non-injected distant tumors. Combining the mRNAs with checkpoint inhibitors enhanced antitumor responses in both injected and non-injected tumors, improving survival and tumor regression in mice. Based on these preclinical observations a clinical study was initiated. Methods In a phase 1 dose escalation study, patients with advanced solid tumors were treated with weekly intratumoral administration of SAR441000 monotherapy and in combination with fixed dose of cemiplimab 350 mg. Plasma samples for cytokine analysis and tumor biopsies were collected at baseline and throughout the study to characterize the PK/PD profile of SAR441000, immune cell tumor infiltration by immunohistochemistry and the presence of corresponding tumor proinflammatory signatures by RNA sequencing. Results As of July 2020, 17 patients received SAR441000 monotherapy (melanoma 7, breast 4, sarcoma 2, Cutaneous Squamous Cell 2, Basal Cell 1, and Merkel Cell 1) at dose levels 1 through 7. Six patients received SAR441000 in combination therapy (melanoma 3, breast 3) at dose levels 4 and 5. No patient experienced a Dose Limiting Toxicity. No grade 3, 4 or 5 adverse events related to study treatment were reported. Adverse events related to study treatment in two or more subjects in both treatment groups combined were nonserious grade 1 or 2 fatigue (43%;10/23), vomiting (17%; 4/23), nausea (13%;3/23); local injection site reaction (11.7%, 2/23); and chills, diarrhea, and rash were reported as 9% (2/23), respectively (table 1 and 2). In some patients, increases in plasma IP10 and IFN gamma and CD8+ T cell infiltration in tumor biopsies were observed. Frequency of patients with a TEAE related to SAR44100* by dose group and grade Frequency of patients with a TEAE related to study treatment (SAR441000+cemiplimab) * by dose group and grade Conclusions SAR441000 administered as monotherapy and in combination with cemiplimab was generally well tolerated. An immunomodulatory effect is suggested by downstream effector cytokines and T cell infiltration. These data support further clinical evaluation of SAR441000. Ethics Approval The study was approved by each participating Institution’s Ethics or Institutional Review Board(s). Reference Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics-developing a new class of drugs. Nat. Rev. Drug Discov 2014;13:759–780.