PyroTIMER Technology: Enabling T-Cell Persistence in Immunosuppressive Tumor Microenvironments

Abstract
The challenge of effectively treating cancer is further complicated by the limitations of current CAR-T cell
therapies, especially when confronted with the immunosuppressive tumor microenvironment (TIME). Central to
this issue is the transforming growth factor-beta (TGF-β), which induces T cell exhaustion and curtails their
antitumor potency. Current methodologies to inhibit the TGF-β pathway have yielded suboptimal results due to
transient effects. This project introduces PyroTIMER CAR-T cells, an innovative approach that promises durable
inhibition of all TGF-β isoforms within the TIME. This robust strategy not only targets TGF-β with unprecedented
potency but also incorporates multiple technical advancements, enhancing T cell cytotoxicity and leveraging
patient-derived xenograft (PDX) models for a more accurate representation of the tumor milieu.
The overarching research plan is to thoroughly assess PyroTIMER CAR-T cells in both immunocompetent
syngeneic models and PDX models. Employing multi-parametric flow cytometry, we aim to delve into the immune
dynamics within tumors, elucidating how PyroTIMER CAR-T cells interact with and potentially remodel the TIME.
Our objectives are four-fold: 1. Deciphering the influence of TGF-β on PyroTIMER CAR-T cells. 2. Profiling
cytokine production to gauge risks, particularly concerning cytokine release syndrome (CRS). 3. Investigating
potential exhaustion scenarios in PyroTIMER CAR-T cells. 4. In-depth in vivo evaluations of the safety and
efficacy of PyroTIMER CAR-T cells.
Our long-term trajectory is underpinned by a commitment to patient safety and therapeutic efficacy. By forging
collaborations with pharmaceutical entities, refining manufacturing strategies for scalability, and seeking FDA
endorsement, we aspire to position PyroTIMER CAR-T cells at the forefront of personalized cancer therapies.
This initiative represents a harmonious blend of advanced scientific inquiry, patient well-being, and strategic
commercial planning. Through this endeavor, we aim to redefine CAR-T cell therapy, presenting a novel, potent,
and safer treatment paradigm for cancer patients.

Grant Number: 5R44CA295355-02
NIH Institute/Center: NIH
Principal Investigator: ARCHIS BAGATI