# A novel and effective immunotherapeutic approach for tumors with a low mutational load and few tumor-infiltrating lymphocytes, such as ovarian cancer > **NIH NIH R44** · CYNVEC, LLC · 2020 · $400,000 ## Abstract ABSTRACT/SUMMARY Significance of the problem: Immunotherapeutic approaches are unsuccessful for most tumors with low mutational loads (i.e., few neoantigens eliciting robust T-cell activation) and few tumor-infiltrating lymphocytes (“cold” tumors). Our preclinical studies involving multiple mouse models indicate that combining a Sindbis virus (SV)–based immunotherapeutic approach with immunomodulatory antibodies (Abs) (e.g., to OX40), leads to regression-free survival by driving activated T cells into cold tumors. The treatment changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated, terminally differentiated, effector T cells with enhanced tumor infiltration capacity despite a repressive tumor microenvironment (TME). Description of the product: We propose to develop innovative third-generation SV vectors to drive activated T cells into “cold” tumors or tumors such as epithelial ovarian cancer (EOC), where a number of factors in the TME impair the presence or activity of TILs. One of these, CYN103, will encode a single-chain antibody (scFV) to OX40 and the full-length tumor-associated antigen (TAA) NY-ESO-1,"expressed in about 40% of EOC cells. Therapeutic development: Early in 2020 Cynvec will begin a Phase 1 clinical trial of a SV vector, CYN102, which encodes NY-ESO-1 in women with chemotherapy-resistant EOC to establish its clinical safety. Given that CYN102 in combination with immunomodulatory Abs has curative effects in preclinical models, we will follow this trial with a Phase 1b trial to evaluate the safety and optimal dosing of CYN103 in women with EOC. Technical innovation of the product: “Armed” SV vectors like CYN103, which encode their own agonistic/antagonistic scFVs or small ligands, can potentially overcome the inherent limitations that curtail efficacy of Abs, such as poor tissue or tumor penetrance and the potential of detrimental Fc-effector functions to deplete immune cells. Also, approved Abs are expensive, and their side effects limit their clinical use. Phase I (Year 1): 1. Engineer third-generation SV vectors for cancer immunotherapy, one of which, CYN103, will carry a dual payload designed to target EOC for use in planned Phase 1b trial. 2. Test and compare the efficacy of (i) CYN103, (ii) a vector encoding NY-ESO-1 only (CYN102), and (iii) a vector encoding scFV to OX40 only in a preclinical syngeneic model of EOC. Milestones: Generation of the CYN103 vector. Show equivalent anti-tumor efficacy in an EOC preclinical model to the combination of CYN102 and anti-OX40. Phase II (Years 2 & 3): 1. Produce CYN103 under Good Manufacturing Practice conditions. 2. Submit an Investigational New Drug (IND) application for CYN103. Milestones: GMP production of clinical grade CYN103. Obtain the preclinical and regulatory data needed to support an IND for a Phase 1b trial of CYN103. Commercial opportunity: EOC treatment in the US costs ~$5–6 billion annually. The size of the mar... ## Key facts - **NIH application ID:** 10004922 - **Project number:** 1R44CA250627-01 - **Recipient organization:** CYNVEC, LLC - **Principal Investigator:** DANIEL MERUELO - **Activity code:** R44 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $400,000 - **Award type:** 1 - **Project period:** 2020-07-09 → 2021-01-01 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10004922 ## Citation > US National Institutes of Health, RePORTER application 10004922, A novel and effective immunotherapeutic approach for tumors with a low mutational load and few tumor-infiltrating lymphocytes, such as ovarian cancer (1R44CA250627-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10004922. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*