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2537 Background: PU-H71 (PU) is an HSP-90 inhibitor that can be labeled with 124I without altering its biochemical properties. Intratumoral drug concentration can be calculated based on 124I-PU-H71 (*PU) PET imaging, leading to a surrogate marker of intratumoral pharmacokinetics. Methods: Patients (pts) with previously treated solid tumors, lymphoma and myeloproliferative neoplasms (MPN) on ruxolitinib were eligible. PU was given days 1, 4, 8, 11 each 21 days at escalating dose levels using a Continuous Reassessment Method (CRM). The primary objective was determination of the MTD. Secondary objectives included plasma and intratumoral PKs measured by pre- and on-treatment core needle biopsies (CNB) and by *PU PET imaging. Results: To date, 40 pts have received PU at doses from 10-400mg/m2. 37 are currently evaluable for DLT, and the last 3 pts needed (per CRM) are being enrolled. Five pts experienced DLTs: 1 (of 2) at 400 mg/m2 - grade 3 mucositis; 4 (of 7) at 350 mg/m2 – 1 pt grade 3 AST and ALT, 1 pt gra...

11076 Background: PU-H71 is a Heat Shock Protein 90 inhibitor that can be labeled with 124I without altering its biochemical properties. Intratumoral drug concentration can be calculated based on 124I-PU-H71 (*PU-H71) region of interest analysis and dilution principle. A microdose pilot study has shown uptake of *PU-H71 in a variety of tumors. *PU-H71 PET is currently being used to estimate intratumoral concentrations in subjects on our phase I study. Methods: Patients with previously treated solid tumors or lymphoma are eligible for this phase 1 trial. PU-H71 is given twice-weekly for 2 weeks each 21 days at escalating dose levels. A mix of *PU-H71 and unlabeled PU-H71 is given during cycle 2 followed by serial PET imaging. Patients on the pilot study are administered a microdose of *PU-H71 alone, followed by serial PET scans. Intratumoral PUH-71 concentration is measured directly in optional pre- and post- treatment core needle tumor biopsies (CNB). Results: To date, 13 patients have received PU-H71 on the phase I trial. Of these, 10 have undergone *PU-H71 PET imaging. 4 imaged patients also volunteered for CNBs, with results reported in the table. Of the 10 patients who underwent *PU-H71 imaging in the phase 1 study, 5 also underwent prior *PU-H71 imaging in the microdose pilot. Intratumoral concentrations as calculated in the pilot and phase I studies were in close concordance. Conclusions: *PU-H71 can be used to visualize PU-H71 uptake in a variety of solid tumors and lymphoma, and *PU-H71 PET scans can be used to estimate intratumoral concentrations of PU-H71. Direct intratumoral measurements of PU-H71 correlate reasonably closely with concentrations calculated from *PU-H71 PET imaging. Further refinement of this imaging tool will allow quantitative assessment of PU-H71 uptake in tumors during the ongoing phase I trial. Clinical trial information: NCT01393509. [Table: see text]

Ample co-stimulatory interactions between antigen-presenting cells and T cells are essential for an effective immune response. Similarly, co-stimulation related immuno-experiences have also been considered critical for the successful tumor eradication by T cells in adoptive immunotherapy cases of: conventional tumor infiltrating T cells for melanoma, chimeric antigen receptor (CAR)-expressing EBV-CTLs for EBV-associated malignancies and the recent CD19 CAR T cells for B-cell neoplasms. However, the specific co-stimulation signals playing the major role in successful immunotherapies are still not identified. Here, a series of constructs has been made to compare the effects of most known co-stimulation molecules, including 4-1BB, CD2, CD27, CD28, CD30, LFA1, GITR, HVEM, ICOS and OX40, in the 1st generation designer T cells bearing anti-CEA scFv-linked CD3ζ signal, and in the 2nd generation designer T cells with anti-CEA scFv linked with CD3ζ plus CD28 signal. Corresponding designer T cells’ function in vitro in proliferation/survival, cytotoxicity and cytokine secretion, and in vivo in animal models, will be tested and compared with the 1st/2nd generation designer T cells. The ones standing out will be delineated for their mechanisms from co-stimulation ligation to specific intracellular signal pathway that lead to the T cell phenotype responsible for final tumor rejection, and will be applied for 3rd generation designer T cell development.

To maintain homeostasis, cells employ intricate molecular machineries comprised of thousands of proteins programmed to execute well-defined functions. Dysregulation of these pathways, through protein mis-expression or mutation, provides biological advantages that confer the malignant phenotype. At the molecular level, this requires cells to invest energy in maintaining the stability and function of these proteins, and for this reason cancer cells co-opt molecular chaperones, including Hsp90. Hsp90 is recognized to play important roles in maintaining the transformed phenotype - the chaperone and its associated co-chaperones assist in the correct folding of cellular proteins, collectively referred to as “client proteins,” many of which are effectors of signal transduction pathways controlling cell growth, differentiation, the DNA damage response, and cell survival. Tumor cell addiction to these proteins (i.e. through mutations, aberrant expression, improper cellular translocation, etc) thus makes them critically reliant on Hsp90. While Hsp90 is expressed in all cells and tissues, it was shown that tumors preferentially contain Hsp90 that is in a higher order multi-chaperone complex with high affinity for certain Hsp90 inhibitors, while normal tissues harbor a latent, uncomplexed Hsp90 that has low affinity for these inhibitors. We here extend this model and propose that Hsp90 forms biochemically distinct complexes in cancer cells. In this view, a major fraction of cancer cell Hsp90 retains “house keeping” chaperone functions similar to normal cells, whereas a functionally distinct Hsp90 pool enriched or expanded in cancer cells specifically interacts with oncogenic proteins required to maintain tumor cell survival. Perhaps this Hsp90 fraction represents a cell stress specific form of chaperone complex that is expanded and constitutively maintained in the tumor cell context. Our data suggest that it may execute functions necessary to maintain the malignant phenotype. One such role is to regulate the folding of mutated (i.e. mB-Raf) or chimeric proteins (i.e. Bcr-Abl). We here also present experimental evidence for an additional role; that is, to facilitate scaffolding and complex formation of molecules involved in aberrantly activated signaling complexes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3029. doi:1538-7445.AM2012-3029