Abstract CT210: A Phase I, open-label, multicenter, dose escalation study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral injection alone and in combination with immune checkpoint blockade

Autor: Kristen Hopson, Lisa Johansen, Sima Zacharek, Joshua Frederick, Jessica D. McDermott, Todd M. Bauer, Tal Zaks, Ding Wang, Robert S. Meehan, William Randolph, Antonio Jimeno, Manish R. Patel
Rok vydání: 2019
Předmět:
Zdroj: Cancer Research. 79:CT210-CT210
ISSN: 1538-7445
0008-5472
Popis: Recent outcomes of immune therapies have created a paradigm shift in cancer treatment. Significant improvements in cancers with clear unmet need have been demonstrated most impacted by administration of check point inhibitor (CPI) antibodies but not all patients benefit. mRNA-2752 is a novel drug that encodes OX40L, IL-23, and IL-36γ. mRNA-2752 brings 2 approaches in 1 therapy: pro-inflammatory cytokines/chemokines to ignite and/or transform an inflammatory response within the tumor microenvironment (TME), and T-cell co-stimulators that could strengthen specific anti-cancer adaptive immune responses. Binding of OX40 by OX40L in the presence of a recognized antigen enhances the expansion of CD4+ and CD8+ T-cells, increases T-cell effector function, and enhances survival of experienced T-cells for increased memory capacity thus introduction of OX40L can serve to boost T-cell responses, and in the case of local therapies, may restrict responses to epitopes presented in the tumor microenvironment (TME). Additionally, it is hypothesized that the expression of pro-inflammatory cytokines within a tumor may ignite or transform an otherwise non-productive TME into a productive immune response. Interleukin-1 and IL-12 family members have been shown to work in concert with one another in immune responses to pathogens, as well as in mediating anti-cancer responses. IL-1 family member IL-36γ acts more as a classic alarmin and directly on antigen presenting cells. IL-12 family member IL-23 positively modulates various classes of cells that bridge innate and adaptive immunity, such as innate lymphoid cells, γδT-cells, and natural killer T-cells. Intratumoral (ITu) administered therapies for cancer, such as mRNA-2752, may result in systemic immune recognition of tumoral antigens, which as monotherapies can cause regression of multiple metastatic lesions. There can also be synergy with CPIs. Methods: The sponsor is conducting a Phase 1, open-label, multicenter, dose escalation study of ITu injections of mRNA-2752 alone and in combination with intravenously administered CPI using an mTPI design. The study consists of 3 dose escalation and dose confirmation parts on 3 treatment arms: mRNA-2752 monotherapy, mRNA-2752 in combination with Durvalumab, and mRNA-2752 in combination with Tremelimumab. This will be followed by dose expansion. The primary objective is to assess the safety and tolerability of mRNA-2752 administered alone and in combination with immune checkpoint blockade and to define the maximum tolerated dose and/or recommended dose for expansion as monotherapy and in combination with CPI. Key secondary objectives include assessing the anti-tumor activity of mRNA-2752 alone and in combination using RECIST v1.1/iRECIST with CPI, and the pharmacokinetics (PK). Mandatory paired tumor biopsies will be collected to assess modulation of relevant blood-borne and tumor biomarkers and potential correlation to the clinical outcomes. Eligibility criteria include pts > 18 years of age with histologically confirmed advanced or metastatic disease with at least 1 measurable lesion, ECOG ≤ 1, normal organ function and a tumor burden of sufficient size to support injection of mRNA-2752. The study is open and enrolling. NCT03739931. Citation Format: Todd Bauer, Manish Patel, Antonio Jimeno, Ding Wang, Jessica McDermott, Sima Zacharek, William Randolph, Lisa Johansen, Kristen Hopson, Joshua Frederick, Tal Zaks, Robert S. Meehan. A Phase I, open-label, multicenter, dose escalation study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ, for intratumoral injection alone and in combination with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT210.
Databáze: OpenAIRE
Externí odkaz: