239 An inducible signal 1 mimic overcomes limited access to antigen for solid tumor cell therapy

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Background Antigen (signal 1) is the ignition and fuel for T cell responses. Chimeric antigen receptors co-opt TCR signaling domains (e.g., ITAM elements) to redirect T cell response to specific antigens. Beyond efforts to improve sensitivity of the CAR ligand-binding domains and enhance the TCR ITAMs through added intracellular domains from other signaling proteins (e.g., CD28 and 4-1BB), little effort has been expended to further manipulate signal 1, other than vaccination (e.g., CLDN6). 1 Most cell therapy engineering is designed to preserve antigen dependence, while boosting sensitivity, persistence, etc. However, solid tumors pose unique challenges compared to blood cancers; for example: (i) access to tumor tissues that express target antigen is highly restricted by the blood vessel walls; and (ii) with limiting antigen, it is unclear how antigen-dependent boosters can be brought into action.Methods Here we describe a simple circuit that addresses this problem by mimicking an antigen stimulus with a small molecule to trigger signaling ( figure 1). Acute and long-term behavior was examined, with an emphasis on inducer-dependent activation of immune function.Results We identified constructs that were shown to affect signaling in a fashion that could be controlled by small-molecule inducers. Acute effects measured in Jurkat cells were also observed in primary T cells. Furthermore, these acute effects translated to long-term effects on T cell survival and proliferation, according to the degree of activation ( figure 2). This tunable-booster approach was extended to TmodTM, a dual-receptor NOT gate based on the LIR-1 inhibitory receptor.2 Conclusions We have developed a modular T cell booster that reversibly activates the cells with a small molecule stimulus. This signal 1 mimetic is designed to allow tuned stimulation to improve the quality and performance of the T cell product in patients. Critically, it bypasses the need for antigen exposure in the patient’s blood, a key difference between blood and solid tumor therapy.References Mackensen A, Haanen JBAG, Koenecke C, Alsdorf W, Wagner-Drouet E, Borchmann P, Heudobler D, Ferstl B, Klobuch S, Bokemeyer C, Desuki A, Lüke F, Kutsch N, Müller F, Smit E, Hillemanns P, Karagiannis P, Wiegert E, He Y, Ho T, Kang-Fortner Q, Schlitter AM, Schulz-Eying C, Finlayson A, Flemmig C, Kühlcke K, Preußner L, Rengstl B, Türeci Ö, şahin U. CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial. Nat Med. 2023;29:2844–2853.Hamburger AE, DiAndreth B, Cui J, Daris ME, Munguia ML, Deshmukh K, Mock JY, Asuelime GE, Lim ED, Kreke MR, Tokatlian T, Kamb A. Engineered T cells directed at tumors with defined allelic loss. Mol Immunol. 2020;128:298-310Abstract 239 Figure 1Platform to induce activation of T cell signal 1, independent of antigen engagement. The booster is induced to dimerize via fused FKBP domains that bind a small molecule (rimiducid), triggering T cell signalingAbstract 239 Figure 2Addition of rimiducid to T cells harboring FKBP fusions trigger signaling. (A) Activation of T cells expressing the signal 1 booster construct after 7 days of treatment -/+100 nM rimiducid in the presence of IL-2. (B) Expansion of T cells expressing the signal 1 booster construct after 7 days of treatment -/+ 100 nM rimiducid

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