Uncovering the Hidden Secrets of T Cell Biology to Empower the Immune System to Protect

As early as the nineteenth century Streptococcus pyogenes extracts were shown by William Coley to possess potent immunostimulatory properties to inflame the tumor micro-environment and generate favorable anti-cancer responses when injected into solid tumors. Three major waves of IO therapies emerged from this initial discovery and other major breakthroughs including:

• Non-antigen restricted, systemic immune activation (i.e., BCGs and cytokines)
• Cancer vaccines to boost antigen-restricted immune responses to tumors (i.e., Provenge and Guardasil)
• Novel agents/cells that focused on augmenting non-selective T cell responses to cancer (i.e. Checkpoint inhibitors, CAR-T/TCR-T cell therapies and T cell engagers)

Enabling the next generation of precision cancer immunotherapy requires distillation of these learnings combined with novel insights from studies into the T cell immunology of human tumor responses. At Marengo Therapeutics, we believe next wave IO breakthroughs could come from further advancing the quantity and quality of T cell responses in solid tumors, with an emphasis on a few emerging yet promising approaches for immune activation.

One of the most common and promising approaches is immune cell-based therapies for solid tumors based on an understanding of the stable expression of tumor-restricted targets. Our chief development officer, Ke Liu , MD, PhD , has been instrumental to advancing this field during his tenure as head of CBER Oncology at the FDA. The second most common approach is the use of bispecific antibodies and T cell engagers in a well-defined patient population with dominant expression of well characterized tumor antigens. Our chief scientific officer, Andrew Bayliffe , has been developing multi-specific and T cell engaging antibodies during his tenure at GSK. A third, emerging approach is the activation and redirection of specialized T cell subsets including gamma delta T cells, iNKT cells, and MAIT/MR1-restricted T cells.

Building on this collective knowledge base, Marengo is pioneering a unique way to selectively activate, expand, and enhance subsets of alpha beta T cells with different reactivities using multi-specific antibodies targeting the variable beta chain variants of the T cell receptor (TCR) via signal #1, while providing a fine-tuned co-stimulation signal to the same T cell. In preclinical studies, these molecules demonstrated durable anti-tumor responses with long term protection from tumor re?challenge associated with de novo expansion and tumor infiltration of effector memory variable beta T cells with a novel Th1/effector gene signature and striking increase in TCR CDR3 repertoire diversity, in contrast to CD3 or immune checkpoint inhibition (i.e., PD-1). Our anti-variable beta antibodies elicit a novel T cell phenotype that drives better T cell responses to solid tumors via a distinct mechanism to checkpoint inhibitors, which may offer a safe and effective therapy for patients with solid tumors.

The body of results generated by Marengo and its academic collaborators presented at the recent ENA & SITC annual symposiums highlight Marengo’s discovery of this novel T cell biology, demonstrate the utility of our bifunctional STAR platform and validate the clinical potential of Marengo’s lead asset, STAR0602, as it enters human trials. Findings in preclinical animal models evaluating STAR0602 revealed the following:

• STAR0602 monotherapy eradicated tumors or led to substantial regressions – effects that were durable over the long term, with STAR0602-cured mice also showing long-term protection upon tumor re-challenge.
• In vivo antitumor activity was dependent on the accumulation of a specific subset of variable beta T cells in tumors that adopt a novel effector memory phenotype and a striking increase in TCR repertoire diversity.
• The anti-tumor activity of STAR0602 in ex vivo primary human tumor and tumor infiltrating lymphocyte matched model systems was superior to pembrolizumab when tested in parallel at therapeutic concentrations.

Collective results strongy suggest STAR0602 could be used for pan-tumor applications against a range of solid tumors, representing a novel therapeutic strategy for patients. Marengo plans to initiate the START-001 Phase 1/2 clinical study in 4Q2022, in which we will study the safety and preliminary clinical activity of STAR0602 as monotherapy in patients with antigen-rich tumors and refractory to checkpoint inhibition.

By leveraging a deep understanding of T cell biology, STAR0602 represents a promising first step in showcasing Marengo’s STAR platform. We are coupling novel biology and innovative technology to power a pipeline of selective T cell activators that will translate into innovative precision IO medicines for a broad range of solid tumor cancer patients, and soon.?