6908 w spaces Our major activities in FY2019 were to work with clinical investigators to develop new pharmacodynamic (PD) assays tailored to their clinical trials and to implement these PD assays in the clinical trials we have open in FY2019. Our specific objectives are (1) to determine if a therapy hit its target in the patient; (2) interrogate the impact of the therapy on the host, both at the systemic level, and in the tumor and tumor microenvironment; (3) work with clinical investigators to introduce new technology into their programs, including transfer of our technology intramurally, extramurally and internationally; and (4) work in collaboration with clinical and basic translational investigators to identify new drug targets and new drug mechanisms. We worked on more than 60 clinical trials in FY2019. We have focused on three main areas of biomarker analysis; (1) immune PD, (2) rare cell non-immune PD (i.e. circulating tumor cells), and (3) digital analyses of gene expression that can be performed on fresh, frozen, or formalin-fixed, paraffin-embedded tissue, to greatly facilitate the assessment of gene expression in tumor samples. In addition, we examine systemic effects of immune- and non-immune targeted therapy on immune gene expression in peripheral blood. For the majority of the clinical trials on which we collaborate we are including immune PD as assessed by multiparameter flow cytometry. We have found correlations with response, progression-free survival and overall survival in multiple clinical trials in FY2019. These exploratory data have provided insight into the impact of therapy on peripheral immunity, which, as published in Nature (Wherry et al.) and PNAS (Ramalingam et al.) in 2017, can provide valuable information reflective of the interaction of effector T cells and tumor and serve as a potential blood-based early predictor of response to PD-1 blockade. In a collaboration this year with a clinical team including Drs. Karzai, Madan, Gulley, Lee and Dahut on immune profiling of castration-resistant prostate cancer patients treated with the anti-PD-L1 antibody durvalumab plus the PARP inhibitor olaparib we demonstrated evidence of CD8+ T cell reinvigoration. This collaboration was published in 2019. We have also focused on multiple populations and subpopulations of monocytes, tumor-associated macrophages and myeloid-derived suppressor cells, including, as with T-cells, expression of functional markers. Together these data have afforded us a view of the functional interplay of innate and adaptive immunity in patients at baseline and in response to treatment, which in turn, suggests combination therapies for future clinical studies to enhance antitumor activity. This is particularly important as it is increasingly recognized that immunotherapy may be used in combination with other immune-directed therapies, with or without other classes of drug, i.e. cytotoxic, epigenetic, kinase inhibitors, etc. or as a component of multimodality therapy protocols. Among drug classes we have focused on HDAC inhibitors and chaperone inhibitors. Previously we developed a PD assay for assessment of HDAC inhibitor activity in vivo. The NCI applied for a patent on our work, which issued in 2016. We have implemented this technology in multiple clinical trials in FY2019. In 2017 we published the first immune profiling of the systemic immune response to an HDAC inhibitor in clinical trial and in FY2019, we are performing immune subset analysis on multiple HDAC inhibitor clinical trials, including combination therapy trials with checkpoint inhibitors. We are the National Laboratory Center of a Phase 3 FDA CTEP supported registration trial for the HDAC inhibitor entinostat, for which our PD is an integrated biomarker. We are helping to bring entinostat to Japan for the treatment of women with breast cancer. Working closely with Kyowa Kirin, we completed the Phase I clinical trial of entinostat as monotherapy or in combination with exemestane and this study has been submitted for publication. We are currently working with Kyowa Kirin on a Phase 2 study of entinostat in Japan. Overall, we are working on clinical trials with 15 Branches of the NIH, three biotech companies and on two pharma trials with AstraZeneca, as well as four trials with academia (Johns Hopkins, Cleveland Clinic, Dana Farber, Broad Institute), together encompassing Phase 1, Phase 2, and Phase 3 trials, both nationally and internationally. Working with Dr. Pommier, we contributed to the discovery that class I-selective HDAC inhibitors induce expression of SLFN11, overcoming resistance to DNA-targeted agents and with Bill Reinhold of the Developmental Therapeutics Branch contributed to discussion of the RNA sequencing of the NCI-60. Working on chaperone inhibitors we previously identified Hsp40 as a new anticancer target. NIH filed for patent on this invention and the patent issued in FY2018. With Len Neckers of NCI and Jason Gestwicki of UCSF we are working on two DOD awards that include further development of drugs designed to hit the target we identified in my lab. We have been collaborating with Dr. Widemann and her team, on analysis of the immune infiltrate in NF1-associated tumors, including in 2019, immune analysis of peripheral blood and tumor of NF1-associated plexiform neurofibromas, atypical neurofibromas, atypical neurofibromatous neoplasms of uncertain biologic potential, and malignant peripheral nerve sheath tumors. In FY2019 we have continued our collaborations with Dr. Anish Thomas on immune profiling and circulating tumor cell analyses of his small cell lung cancer clinical trials, one of which was published in 2019. We have continued our collaborations with Dr. Jay Berzofsky and his team on circulating tumor cells and immune subsets in breast cancer and prostate cancer patients treated with vaccine therapy. We have been collaborating with Drs. Christian Hinrichs and Clint Allen on analysis of viral gene expression and analysis of immune gene expression in biopsy samples from their recurrent respiratory papillomatosis patients, and this study was published in 2019. We performed PD analyses for Dr. Jung-min Lee's clinical trials of the PD-L1 inhibitor durvalumab and the PARP inhibitor olaparib and the VEGFR1-3 inhibitor cediranib in women's cancers, which was published in 2019 and additional studies are ongoing and in preparation for publication. We are working with Dr. Andrea Apolo's on biomarker analysis of her Phase 2 trial of cabozantinib trial, which is in preparation for publication as well as her trial of cabozantinib, nivolumab and ipilimumab and her COXEN trial. In FY2019 we are also collaborating with Dr. Christine Alewine on pharmacodynamics analysis of her LMB-100 plus Nab-Paclitaxel trial. In 2019 we also published a collaboration with Dr. Jennifer Jones on exosomes and we are working on studies incorporating exosome and circulating tumor cell analyses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICSC006743-26
Application #
10015101
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Christenson, Jessica L; Trepel, Jane B; Ali, Haythem Y et al. (2018) Harnessing a Different Dependency: How to Identify and Target Androgen Receptor-Positive Versus Quadruple-Negative Breast Cancer. Horm Cancer 9:82-94
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Neckers, Len; Blagg, Brian; Haystead, Timothy et al. (2018) Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development. Cell Stress Chaperones 23:467-482
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