Research Project 1 (RP1) builds on the progress and success of Projects 1 and 2 in ICMIC-2. Our hypothesis is that both constitutive and PSMA-activated reporter gene imaging of PSMA directed T cell targeting, distribution and persistence can be performed concurrently in patients with castrate-resistant prostate cancer. The central theme of this proposal is consistent with our ICMIC: "cancer biology integrated with real-time, noninvasive imaging for application in individual patient care and management'. A phase 1 clinical study will determine whether genetically altered, PSMA-directed, adoptive T cell therapy in human subjects results in adequate T cell activation as well as targeting and persistence in prostate cancer (Aim 1). These are novel imaging experiments involving dual human reporter genes, not previously performed in human subjects with cancer. The imaging results will be compared to standard clinical treatment-response measures. In parallel, we will also explore in animal models whether an acidic tumor microenvironment and high lactate levels adversely effect T cell targeting, activation and persistence using a unique combination of imaging strategies (Aim 2). We will also determine in animal models of prostate cancer whether modulation of PSMA expression can enhance PSMA-directed T cell therapy using our novel reporter systems (Aim 3). If positive results in Aims 2 and 3 are obtained, similar studies could be readily performed in patients. Our long-term goals are to further develop unique clinical trials of adoptive therapy that includes reporter imaging to track and monitor T cell activation and persistence in patients. We expect to be able to address novel questions in clinical immunology and immunotherapy, including the effects of the tumor microenvironment and modulation of CAR-directed tumor antigens on treatment response. The relevance and impact of these studies are that: 1) imaging the trafficking and activation status of PSMA directed T cells will provide substantial added value to the management of prostate cancer patients undergoing adoptive T cell therapy;2) the imaging strategies developed and validated in this project could be readily applied to other cancers, as well as applied in other adoptive therapy (e.g., stem cell) protocols and nonmalignant disease;3) the effect of an acidic-high lactate-hypoxic microenvironment could have a significant negative impact on T cell targeting and activation. These hypotheses will initially be explored in animal models. Importantly, the assay systems, imaging strategies and therapeutic counter-measures could be applied and tested in future patient studies, and could serve as a model for similar studies in other cancers as well as for adoptive stem cell therapy in other diseases.

Public Health Relevance

Project 1 involves a phase 1 clinical study to test whether genetically altered, PSMA directed, T cells can be monitored by non-invasive Positron Emission Tomography (PET) imaging, and whether the imaging results can provide an early indication of treatment response (or failure) in patients with castrate-resistant prostate cancer. In parallel, preclinical imaging studies will evaluate the effect of an abnormal tumor microenvironment and the effect of tumor PSMA expression levels on: 1) PSMA-directed T cell targeting, activation and persistence, and on 2) the efficacy of tumor-modulated, PSMA-directed T cell therapy. Importantly, these imaging studies could be readily translated to clinic and serve as a model to study other cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-9)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Cheal, Sarah M; Xu, Hong; Guo, Hong-fen et al. (2014) Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using an IgG-scFv bispecific antibody with high affinity for GD2 and DOTA metal complex. Mol Cancer Ther 13:1803-12
de Biasi, Andreas R; Villena-Vargas, Jonathan; Adusumilli, Prasad S (2014) Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence. Clin Cancer Res 20:5384-91
Vargas, Hebert Alberto; Wassberg, Cecilia; Fox, Josef J et al. (2014) Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival. Radiology 271:220-9
Adusumilli, Prasad S (2014) Translational immunotherapeutics: chemoimmunotherapy for malignant pleural mesothelioma. Cancer 120:3268-71
Eguchi, Takashi; Kadota, Kyuichi; Park, Bernard J et al. (2014) The new IASLC-ATS-ERS lung adenocarcinoma classification: what the surgeon should know. Semin Thorac Cardiovasc Surg 26:210-22
Zhang, Hanwen; Huang, Ruimin; Pillarsetty, NagaVaraKishore et al. (2014) Synthesis and evaluation of 18F-labeled benzylguanidine analogs for targeting the human norepinephrine transporter. Eur J Nucl Med Mol Imaging 41:322-32
Cheal, Sarah M; Punzalan, Blesida; Doran, Michael G et al. (2014) Pairwise comparison of 89Zr- and 124I-labeled cG250 based on positron emission tomography imaging and nonlinear immunokinetic modeling: in vivo carbonic anhydrase IX receptor binding and internalization in mouse xenografts of clear-cell renal cell carcino Eur J Nucl Med Mol Imaging 41:985-94
Zhang, Hanwen; Huang, Ruimin; Cheung, Nai-Kong V et al. (2014) Imaging the norepinephrine transporter in neuroblastoma: a comparison of [18F]-MFBG and 123I-MIBG. Clin Cancer Res 20:2182-91
Beattie, Bradley J; Pentlow, Keith S; O'Donoghue, Joseph et al. (2014) A recommendation for revised dose calibrator measurement procedures for 89Zr and 124I. PLoS One 9:e106868
Lee, Ming-Ching; Buitrago, Daniel H; Kadota, Kyuichi et al. (2014) Recent advances and clinical implications of the micropapillary histological subtype in lung adenocarcinomas. Lung Cancer Manag 3:245-253

Showing the most recent 10 out of 119 publications