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PET Imaging of TIGIT Expression on Tumor-Infiltrating Lymphocytes

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PET Imaging of TIGIT Expression on Tumor-Infiltrating Lymphocytes Published OnlineFirst January 6, 2021; DOI: 10.1158/1078-0432.CCR-20-2725 CLINICAL CANCER RESEARCH | PRECISION MEDICINE AND IMAGING PET Imaging of TIGIT Expression on Tumor-Infiltrating Lymphocytes A C Travis Shaffer1,2, Arutselvan Natarajan1,2,3, and Sanjiv S. Gambhir1,2,3,4,5,† ABSTRACT ◥ Purpose: Therapeutic checkpoint inhibitors on tumor- (64Cu) and zirconium-89 (89Zr). In vitro characterization of the infiltrating lymphocytes (TIL) are being increasingly utilized in the imaging probes was followed by in vivo evaluation in both xeno- clinic. The T-cell immunoreceptor with Ig and ITIM domains grafts and syngeneic tumor models in mouse. (TIGIT) is an inhibitory receptor expressed on T and natural killer Results: Two anti-TIGIT probes were developed and exhibited cells. The TIGIT signaling pathway is an alternative target for immunoreactivity of >72%, serum stability of >95%, and specificity checkpoint blockade to current PD-1/CTLA-4 strategies. Elevated for TIGIT with both mouse TIGIT-expressing HeLa cells and TIGIT expression in the tumor microenvironment correlates with ex vivo–activated primary splenocytes. In vivo, the 89Zr-labeled better therapeutic responses to anti-TIGIT therapies in preclinical probe demonstrated superior contrast than the 64Cu probe due to models. Therefore, quantifying TIGIT expression in tumors is 89Zr’s longer half-life matching the TIGIT antibody’s pharmaco- necessary for determining whether a patient may respond to kinetics. The 89Zr probe was used to quantify TIGIT expression on anti-TIGIT therapy. PET imaging of TIGIT expression on TILs TILs in B16 melanoma in immunocompetent mice and confirmed can therefore aid diagnosis and in monitoring therapeutic by ex vivo flow cytometry. responses. Conclusions: This study develops and validates novel TIGIT- Experimental Design: Antibody-based TIGIT imaging radio- specific 64Cu and 89Zr PET probes for quantifying TIGIT expression tracers were developed with the PET radionuclides copper-64 on TILs for diagnosis of patient selection for anti-TIGIT therapies. þ þ Introduction cytotoxic T cells, CD4 Th cells, FOXP3 regulatory T cells, and NK cells (5). Both TIGIT and PD-1 are expressed in >70% of human Immune checkpoint receptors expressed on activated T and natural melanoma tumor microenvironments, with PD-1 mainly expressed on killer (NK) cells play a key role in maintaining physiologic self- þ þ CD8 T cells and TIGIT expressed on CD8 T cells, regulatory T cells, tolerance (1). However, these same regulating pathways are exploited and NK cells (6). The ratio of PD-1 to TIGIT expressed by tumor- by tumor cells to evade immune surveillance (2). This tumor survival infiltrating lymphocytes (TIL) is variable, ranging from 0.75 to 4.0 in strategy has been targeted with checkpoint blockade therapies such as colorectal cancer(5). TIGIT can inhibit immune responses of effector T anti-PD-1 and anti-CTLA-4 agents. While these therapies have shown and NK cells by acting through inhibitory signals (7–9) and affecting remarkable responses in a subset of patients, primary and adaptive effector functions of T cells and antigen-presenting cells (10, 11). resistance often occurs (3). This is attributed to a variety of mechan- TIGIT and PD-1 blockade additively increased proliferation, cytokine isms including downregulating MHC to prevent antigen presentation production, and degranulation on TILs (12), making TIGIT a potential and upregulation of other inhibitory receptors such as TIM-3, LAG-3, key addition to current immunotherapies. For this reason, a number of and VISTA (4). clinical trials in solid tumors are combining TIGIT therapies with To reduce the occurrence of tumor escape, other inhibitory targets current checkpoint blockade therapies (13–15). that act through alternative pathways are being extensively explored. The expression of TIGIT on TILs has been reported via IHC, One such checkpoint inhibitor is the T-cell Ig and ITIM domain þ Western blotting, and PCR on hepatocellular carcinoma (16), follic- receptor (TIGIT). TIGIT is an inhibitory receptor expressed on CD8 ular lymphoma (17), squamous cell cancers (5), Hodgkin lympho- ma (18), renal cell carcinoma (19), small cell lung cancer (20), and melanoma (21). TIGIT has been validated as a therapeutic target and 1Department of Radiology, Stanford University, Stanford, California. 2Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California. anti-TIGIT therapies are currently being evaluated in multiple clinical 3Canary Center for Early Cancer Detection, Stanford University, Stanford, trials (Supplementary Table S1). An antibody specific for the TIGIT California. 4Department of Bioengineering, Stanford University, Stanford, receptor (AB154) is being evaluated in a variety of solid cancers California. 5Stanford Bio-X Program, Stanford University, Stanford, California. (NCT03628677). This phase I trial is evaluating the safety, tolerability, Note: Supplementary data for this article are available at Clinical Cancer pharmacokinetics, pharmacodynamics, and clinical activity of AB154 Research Online (http://clincancerres.aacrjournals.org/). as either a monotherapy or in combination with an anti-PD-1 antibody T. Shaffer and A. Natarajan contributed equally to this article. (AB122). In another phase I trial, the anti-TIGIT agent MK-7684 and pembrolizumab was administered in 34 patients with advanced †Deceased. solid tumors for whom standard treatment options had failed Corresponding Authors: Arutselvan Natarajan, Stanford University, 318 Campus (NCT02720068). The response rate was reported as 19% and the Drive, E150-Clark Center, Stanford, CA 94305. Phone: 650-736-9822; Fax: 650- disease control rate was 47% (22). While these results are promising for 724-4948; E-mail: [email protected]; and Travis Shaffer, fi [email protected] a subset of patients, patient strati cation for these therapies would benefit from a quantitative, whole-body measure of TIGIT expression. Clin Cancer Res 2021;XX:XX–XX Generally high but variable TIGIT expression is seen in solid doi: 10.1158/1078-0432.CCR-20-2725 tumors, making this therapy likely applicable to many cancer types. Ó2021 American Association for Cancer Research. However, to determine TIGIT expression, invasive biopsy sampling AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst January 6, 2021; DOI: 10.1158/1078-0432.CCR-20-2725 Shaffer et al. followed by IHC is currently required. While this procedure is the Translational Relevance current gold standard, it does not allow accurate quantitation in Checkpoint blockade therapies have expanded to new inhibitory heterogeneous samples or on distant metastases. A noninvasive receptors where stratification for patient selection and therapeutic imaging agent could detect and quantify TIGIT within the tumor monitoring strategies are needed. This work develops, validates, microenvironment and aid in determining what patients would and applies PET imaging probes for the T-cell immunoreceptor benefit from TIGIT immunotherapies (23). This approach has with Ig and ITIM domains (TIGIT). TIGIT is an inhibitory beentestedwithPETagentsforPD-1,PD-L1,andOx40,allbeing receptor expressed by tumor-infiltrating lymphocytes (TIL) developed as clinical diagnostics (24–26). These PET tracers including T and natural killer cells, and is a therapeutic target allow noninvasive, whole-body, quantitative assessment of receptor in a range of solid tumors. Current methods to assess TIGIT expression to aid in patient stratification. Here we develop TIGIT- expression such as biopsy are invasive and do not provide specific antibody PET tracers and evaluate their application in whole-body quantification of TIGIT expression. To address this quantifying TIGIT expression in vivo (Fig. 1). need, TIGIT-specific immunoPET imaging probes are developed and validated. These probes are shown to specifically target TIGIT in both xenograft and allograft murine models. TIGIT expression Experimental Procedures on TILs in a melanoma allograft model is quantified using PET, Antibodies, chelators, and radiometals confirmed via flow cytometry and ex vivo biodistribution studies. Purified anti-mouse TIGIT mAb (TIGITmAb, clone 1G9) raised in Our data suggest that this approach can act as a companion mouse was purchased from Bio X cell (catalog no. BE0274) or diagnostic for current anti-TIGIT therapies. BioLegend (catalog no. 142102). NHS ester-DOTA (NHS-DOTA, catalog no. B-280) and p-SCN-Deferoxamine (DFO-NCS, catalog no. 64 t ¼ B705) were purchased from Macrocyclics. Copper-64 ( Cu; 1/2 12.7 hours, 17.76–162.8 GBq/mmol) was obtained from the University Figure 1. Quantifying TIGIT expression on TILs can aid in therapeutic decisions. A TIGIT PET agent can act as a companion diagnostic selection of patients for anti-TIGIT therapies. CD155, ligand for TIGIT receptor; MHCI, major histocompatibility complex I; TCR, T-cell receptor. OF2 Clin Cancer Res; 2021 CLINICAL CANCER RESEARCH Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst January 6, 2021; DOI: 10.1158/1078-0432.CCR-20-2725 ImmunoPET Imaging of TIGIT of Wisconsin (Madison, WI). Zirconium-89 (89Zr) in 1.0 mol/L Vivaspin 30 kDa cut-off centrifugal filter and stored in 100 mL aliquots t ¼ > – À oxalic acid ( 1/2 3.3 days, purity 99%; 2 3GBq/mL)wasobtained in 0.1 mol/L ammonium acetate buffer (pH 7.0) at 20 C. from
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