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RESEARCH FOCUS AREA
- Glioblastoma
- Cancer immunology and immunotherapy
- Aging and cancer
- Neuroimmunology
- Mechanisms of resistance to therapy for cancer
RESEARCH SUMMARY
Our laboratory has 3 primary research goals. The FIRST goal is to understand how glioblastoma (GBM) cell indoleamine 2,3 dioxygenase 1 (IDO; IDO1) increases immunosuppressive T-reg infiltration, suppresses the immune response, and decreases overall survival in mouse models and human subjects with glioblastoma. Our previous work discovered that glioblastoma cell IDO1 non-enzymically upregulates immunosuppressive complement factor H (CFH) and factor H-like 1 (FHL-1) in human GBM cells, which in-turn, suppresses the anti-tumor immune response through intratumoral T-reg and MDSC accumulation. The SECOND goal is the active application of immunotherapy for patients with glioblastoma. Our group was the first to show that the simultaneous treatment with radiation, anti-PD-1 mAb, and pharmacological IDO1 enzyme inhibition leads to an unprecedented survival benefit in experimental models with intracranial brain tumors. This preclinical observation motivated the now ongoing phase I clinical trial of newly diagnosed glioblastoma patients treated with simultaneous radiation, nivolumab (anti-PD-1 mAb), and BMS-986205 (IDO1 enzyme inhibition) [NCT04047706]. The Wainwright Laboratory has performed the immunocorrelative profiling of patient-isolated PBMCs, tumor, stool, and serum that’s aimed at generating a predictive algorithm for stratifying responders [overall survival (OS) ≥20 months] versus non-responders (OS < 20 months). The THIRD goal is to better understand why older adults with glioblastoma die significantly faster as compared to younger adults with glioblastoma. We were the first group to show that advanced age increases immunosuppression in both the mouse and human brain. We were also the first to demonstrate that there is a functional consequence of increased immunosuppression in the aged brain that decreases the efficacy of immunotherapy with radiation, anti-PD-1 mAb, and IDO1 enzyme inhibitor treatment in older adults with GBM. Currently, our group is working with medicinal chemist, Dr. Gary Schiltz, PhD, to generate new drugs that aim to reverse immunosuppression in the aged brain (and simultaneously against tumor cells) of adults with glioblastoma.
The Wainwright Laboratory is an active training ground for students in high school, undergraduate school, graduate school, postdoctoral fellowship, medical school, and medical residency.
EDUCATION
- BS in Biology and Music, Bradley University
- MS, PhD in Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago
- Postdoctoral fellowship, University of Chicago
SELECT PUBLICATONS:
- Advanced age in humans and mouse models of glioblastoma show decreased survival from extratumoral influence Johnson, M; Bell, A; Lauing KL; Ladomersky, E; Zhai, L; Penco-Campillo, M; Shah, Y; Mauer, E; Xiu, J; Nicolaides, T; Drumm, M; McCortney, K; Elemento, O; Kim, M; Bommi, P; Low, JT; Memon, R; Wu, J; Zhao, J; Mi, X; Glantz, MJ; Sengupta S; Castro, B; Yamini, B; Horbinski, C; Baker, DJ; Walunas, TL; Schiltz, GE; Lukas, RV; Wainwright, DA Clin Cancer Res. 2023 Sep 19. doi: 10.1158/1078-0432.CCR-23-0834. Online ahead of print. PMID: 37725593
- Identification and characterization of a novel indoleamine 2,3-dioxygenase 1 protein degrader for glioblastoma Bollu, LR; Bommi, PV; Monsen, PJ; Zhai, L; Lauing, KL; Bell, A; Kim, M; Ladomersky, E; Yang, X; Platanias, LC; Matei, DE; Bonini, MG; Munshi, HG; Hashizume, R; Wu, JD; Zhang, B; James, CD; Chen, P; Kocherginsky, M; Horbinski, C; Cameron, MD; Grigorescu, AA; Yamini, B; Lukas, RV; Schiltz, GE; Wainwright, DA Journal of Medicinal Chemistry 2022 Dec 8;65(23):15642-15662. doi: 10.1021/acs.jmedchem.2c00771. Epub 2022 Nov 21. PMID: 36410047; PMCID: PMC9743093
- A systematic review of pharmacologic treatment efficacy for depression in older patients with cancer Rabin, EE; Kim, M; Mozny, A; Cardoza, K; Bell, AC; Zhai, L; Bommi, P; Lauing, KL; King, AL; Armstrong, TS; Walunas, TL; Fang, D; Roy, I; Peipert, JD; Sieg, E; Mi, X; Amidei, C; Lukas, RV; Wainwright, DA Brain, Behavior, & Immunity – Health 2022 Mar 23;21:100449. doi: 10.1016/j.bbih.2022.100449. PMID: 35368609; PMCID: PMC8968450
- Tumor cell IDO enhances immune suppression and decreases survival independent of tryptophan metabolism in glioblastoma Zhai, L; Bell, A; Ladomersky, E; Lauing, KL; Bollu, L; Nguyen, B; Genet, M; Kim, M; Chen, P; Mi, X; Wu, JD; Schipma, MJ; Wray, B; Griffiths, J; Unwin, RD; Clark, SJ; Acharya, R; Bao, R; Horbinski, C; Lukas, RV; Schiltz, GE; Wainwright, DA Clinical Cancer Research 2021 Dec 1;27(23):6514-6528. doi: 10.1158/1078-0432.CCR-21-1392. Epub 2021 Sep 3. PMID: 34479957; PMCID: PMC8639612
- Glioblastoma as an age-related neurological disorder in adults Kim, M; Ladomersky, E; Mozny, A; Kocherginsky, M; O'Shea, K; Reinstein, ZZ; Zhai, L; Bell, A; Lauing, KL; Bollu, L; Rabin, E; Dixit, K; Kumthekar, P; Platanias, LC; Hou, L; Zheng, Y; Wu, J; Zhang, B; Hrachova, M; Merrill, SA; Mrugala, MM; Prabhu, VC; Horbinski, C; James, CD; Yamini, B; Ostrom, QT; Johnson, MO; Reardon, DA; Lukas, RV; Wainwright, DA Neurooncology Advances 2021 Sep 4;3(1):vdab125. doi: 10.1093/noajnl/vdab125. PMID: 34647022; PMCID: PMC8500689
- Immunosuppressive IDO in cancer: Mechanisms of action, animal models, and targeting strategies Zhai, L; Bell, A; Ladomersky, E; Lauing, KL; Bollu, L; Sosman, JA; Zhang, B; Wu, JD; Miller, SD; Meeks, JJ; Lukas, RV; Wyatt, E; Doglio, L; Schiltz, GE; McCusker, RH; Wainwright, DA Frontiers in Immunology 2020 Jun 16;11:1185. doi: 10.3389/fimmu.2020.01185. PMID: 32612606; PMCID: PMC7308527
- Advanced age increases immunosuppression in the brain and decreases immunotherapeutic efficacy in subjects with glioblastoma Ladomersky, E; Zhai, L; Lauing, KL; Bell, A; Xu, J; Kocherginsky, M; Zhang, B; Wu, JD; Podojil, JR; Platanias, LC; Mochizuki, AY; Prins, RM; Kumthekar, P; Raizer, JJ; Dixit, K; Lukas, RV; Horbinski, C; Wei, M; Zhou, C; Pawelec, G; Campisi, J; Grohmann, U; Prendergast, GC; Munn, DH; Wainwright, DA Clinical Cancer Research 2020 Oct 1;26(19):5232-5245. doi: 10.1158/1078-0432.CCR-19-3874. Epub 2020 Jun 16. PMID: 32546647; PMCID: PMC7541490
- A retrospective survival analysis of Glioblastoma patients treated with selective serotonin reuptake inhibitors Otto-Meyer, S; DeFaccio, R; Dussold, C; Ladomersky, E; Zhai, L; Lauing, KL; Bollu, LR; Amidei, C; Lukas, RV; Scholtens, DM; Wainwright, DA Brain, Behavior, & Immunity - Health 2020 Feb;2:100025. doi: 10.1016/j.bbih.2019.100025. Epub 2019 Dec 16. PMID: 32190845; PMCID: PMC7079579
- The interplay among psychological distress, the immune system, and brain tumor patient outcomes Otto-Meyer, S; Lumibao, J; Kim, E; Ladomersky, E; Zhai, L; Lauing, KL; Scholtens, DM; Penedo, F; Amidei, C; Lukas, RV; Wainwright, DA Current Opinion in Behavioral Sciences 2019 Aug;28:44-50. doi: 10.1016/j.cobeha.2019.01.009. Epub 2019 Feb 26. PMID: 31049368; PMCID: PMC6487487
- The coincidence between increasing age, immunosuppression, and the incidence of patients with glioblastoma Ladomersky, E; Scholtens, DM; Kocherginsky, M; Hibler, EA; Bartom, ET; Otto-Meyer, S; Zhai, L; Lauing, KL; Choi, J; Sosman, JA; Wu, JD; Zhang, B; Lukas, RV; Wainwright, DA Frontiers in Pharmacology 2019 Mar 27;10:200. doi: 10.3389/fphar.2019.00200. PMID: 30971917; PMCID: PMC6446059
- IDO1 inhibition synergizes with radiation and PD-1 blockade to durably increase survival against advanced glioblastoma Ladomersky, E; Zhai, L; Lenzen, A; Lauing, KL; Qian, J; Scholtens, DM; Gritsina, G; Sun, X; Liu, Y; Yu, F; Gong, W; Liu, Y; Jiang, B; Tang, T; Patel, R; Platanias, LC; James, CD; Stupp, R; Lukas, RV; Binder, DC; Wainwright, DA Clinical Cancer Research 2018 Jun 1;24(11):2559-2573. doi: 10.1158/1078-0432.CCR-17-3573. Epub 2018 Mar 2. PMID: 29500275; PMCID: PMC5984675
FULL LIST OF PUBLICATIONS
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