Using Tumor Gene Therapy to Overcome Barriers to Immunotherapies

Episode Summary

Executive Summary: Howard Davis, CEO of Ackermis Bio, explains why solid tumors remain difficult for immunotherapy and how the company’s T-Sign tumor gene therapy platform aims to overcome those barriers by delivering engineered adenoviruses systemically to reprogram the tumor microenvironment. The interview covers lead asset NG350A, early clinical and partnership strategy, and the company’s second preclinical program.

Main Topics: Why solid tumors resist immunotherapy: Davis outlines how immunosuppressive signaling, stroma, hypoxia, and high intratumoral pressure prevent immune recognition and attack in solid tumors, limiting the impact of current immunotherapies. T-Sign platform and systemic delivery: Ackermis’s T-Sign uses engineered chimeric adenoviral vectors that replicate in epithelial-derived tumor cells after IV delivery, enabling local transgene expression in primary or metastatic tumors without intratumoral injection. Payload flexibility and tumor microenvironment engineering: The platform can express cytokines, chemokines, antibodies, bispecifics, receptors, ligands, and antigens to convert cold tumors into hot ones or create targets for other therapies. Lead program NG350A and CD40 agonism: NG350A expresses a local CD40 agonist monoclonal antibody to activate dendritic cells and promote anti-tumor T-cell responses, with the advantage of local exposure and reduced systemic toxicity. Clinical development strategy and partnerships: Early studies focus on monotherapy safety and PK/PD, with later combination work alongside pembrolizumab and a pancreatic cancer expansion study supported by the Parker Institute and Cancer Research Institute. Funding and corporate growth: A $30 million convertible note financing, plus new U.S.-based investors, supports the company’s transatlantic expansion and funds development into 2024 while additional capital is being raised. Second program NG7XX: A preclinical vector expressing IL-12, IL-15, and a chemokine is being advanced to heat up tumors and will likely follow a similar monotherapy-then-combination path.

Key Arguments: Solid tumors are harder to treat than liquid tumors because they create a physically and biologically immunosuppressive microenvironment that blocks immune access and activation. A systemic, tumor-selective viral platform can address that problem more effectively than intratumoral injection because it can reach primary and metastatic disease through the bloodstream. T-Sign’s ability to carry different payloads makes it versatile across multiple epithelial-derived cancers and different immuno-oncology strategies. Local expression of a CD40 agonist may allow stronger pathway activation than systemic dosing while avoiding the dose-limiting toxicities associated with naked CD40 antibodies. The company’s clinical strategy is to establish safety first, then move into indication-specific expansion cohorts and combination studies to seek proof of concept. Partnerships with the Parker Institute and Cancer Research Institute provide funding, clinical expertise, and access to leading pancreatic cancer networks, accelerating development. The company expects its platform to be useful both as monotherapy and as a priming/neoadjuvant tool to enhance other IO modalities, including cell therapy and PD-1s.

Data Points: Company financing: $30 million - Convertible note financing announced in January to support development and expansion Transgene cassette size: Up to about 3.5 kilobases - Approximate payload capacity for T-Sign vectors Number of proteins expressed in one cassette: Up to 5 proteins - Maximum described for a single T-Sign payload Clinical study type: Phase 1a - Initial NG350A studies were safety/dose-escalation studies Clinical study type: Phase 1b - Planned expansion cohort study for NG350A in a single indication Timing of funding runway: Into 2024 - Current financing expected to fund operations through 2024 NG350A combination partner: Pembrolizumab - Fortify study evaluates NG350A with a PD-1 inhibitor Disease areas mentioned: Colorectal, pancreatic, and head and neck cancers - Examples of epithelial-derived tumor types enrolled in early studies Program names: Fortitude, Fortify, Revolution - Clinical studies of NG350A; Revolution is the pancreatic expansion cohort Upcoming readouts: 2024 - Expected timing for data from the pancreatic expansion study and indication prioritization Investor groups: Arch Ventures, Parker Institute for Cancer Immunotherapy, Westlake Village BioPartners - New investors in the January financing

Pivotal Quotes: "turns solid tumors into drug factories" — Narrator: Describes the conceptual goal of Ackermis Bio’s platform "the ability to locally express that CD40 agonist monoclonal antibody directly in the tumor will allow us to hit that pathway much harder" — Howard Davis: Explaining why NG350A could outperform systemic CD40 agonism "very difficult for the immune system actually to even recognize the tumor, much less attack it and try to clear it" — Howard Davis: On the biological barriers that make solid tumors resistant to immunotherapy

Implications: If successful, Ackermis’s systemic tumor-gene therapy could expand immunotherapy into solid tumors by converting them into localized immune-activating sites, potentially improving efficacy while reducing toxicity and enabling combinations with checkpoint and cell therapies.