Michael Lotze

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NAME: Lotze, Michael T.

eRA COMMONS USER NAME (credential, e.g., agency login): Michael_T_Lotze

POSITION TITLE: Director, DAMP Laboratories; Professor Surgery, Immunology, and Bioengineering

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY

Northwestern Honors Prog. in Med Ed, Evanston, IL B. Med Sci 1973 Premedical Studies

Northwestern Univ. Medical School Chicago, IL MD 1974 Medicine

A. Personal Statement. My career has been predicated on the bench to bedside to bench paradigm in cancer, starting within the Surgery Branch of the NCI. There, I championed the in vivo application of IL-2 and IL-4 as cancer therapies in patients with melanoma and renal cancer, developed adoptive transfer of NK/LAK and TIL therapies, and launched gene therapy efforts that continued when I moved to the University of Pittsburgh. At Pitt, I have developed and overseen four separate successful funded Program Project grants on research topics including cytokine gene therapy, dendritic cell (DC) therapy, the tumor microenvironment, and most recently, natural killer cell (NK) and DC integration in the treatment of patients with cancer. For the last 15 years, our group has led investigative efforts on so-called Damage Associated Molecular Pattern Molecules (DAMPs) and their receptors, specifically focusing on HMGB1 and RAGE, particularly in the area of pancreatic cancer. We pioneered this area, running the 3rd International Symposium on DAMPs and Alarmins in Pittsburgh in 2008 (as well as the 4th in Helsinki, the 5th in New York, the 6th and 7th in Heidelberg/Bonn, the 8th at Cold Spring Harbor, the 9thin Okayama) as well as the Translational Research in Mitochondria, Aging and Disease, recently completing its 10th year. We have met the challenges of managing an integrated research program and have recently completed an R01-funded randomized trial to examine the role of autophagy inhibition in the neoadjuvant setting of pancreatic cancer within the Biologic Therapy/DAMP laboratory. I have highlighted references below with Drs. Ellsworth, Zureikat, and Zhang. I have presented numerous oral and poster presentations based on our singular focus on TIL and gamma delta T cells in pancreatic cancer.

B. Positions, Activities, and Honors

Positions

1975-1982 Intern and Resident, Department of Surgery, University of Rochester; Rochester, NY

1978-1980 Staff Fellow, Surgery Branch, National Cancer Institute, Bethesda, MD

1982-1990 Senior Investigator, Surgery Branch, National Cancer Institute, Bethesda, MD

1990-2000 Founding Director, Division of Surgical Oncology, Department of Surgery; Co-director, Biologic Therapy T32 Training Program, University of Pittsburgh Cancer Institute, Univ. Pittsburgh

1999-2001 VP Discovery Research; Immunology, Tissue Repair & Oncology, SmithKline Beecham; High Throughput Biology, GlaxoSmithKline; Philadelphia, PA

2001-2002 Chief Scientific Officer/President, Metacine/Pittsburgh Biotechnology, Inc.; Pittsburgh, PA

2002-2005 Director of Clinical and Translational Research, Molecular Medicine Inst.; Pittsburgh, PA

2005- 2011 Deputy Director for Strategic Partnerships, University of Pittsburgh Cancer Institute

2006-2016 Asst. Vice Chancellor Interdisciplinary Research and Training, UPSHS, Pittsburgh PA

2006- Vice Chair for Research, Department of Surgery; UPSOM

2006-2010 Director, Catalyst Program, UPSHS, Clinical and Translational Research Institute Pittsburgh.

2008-2016 Founding Director, University of Pittsburgh Cancer Institute Academy, now Hillman Academy

2011- Member, Pharmaceutical Collaborations Committee, Drug Discovery Institute

2013-2017 Director, Penn-Pitt Partnership in Veterinary Medicine and Science (P3VMS)

2016-2017 Chief Scientific Officer, Lion/Iovance Biotherapeutics; NYC, Tampa, San Carlos

2017-current Senior Advisor, UPMC Enterprises Immune Transplant and Therapy Center (ITTC)

2019-current Member, SITC Surgical Advisory Committee

2020-2023 Chief Cellular Therapy Officer, Nurix Therapeutics

2021-2025 Founding Director SITC Clinical Immunology Oncology Network (SCION) Program

2024-current Editor in Chief, Journal for the ImmunoTherapy of Cancer

Activities and Honors

1996-2015 Society for the Immunotherapy of Cancer (SITC/SBT), VP, President, and Executive Council

1998 Co-Organizer, 5th International Dendritic Cell Meeting, Pittsburgh, PA

1998 Co-Organizer, 13th Society for Biologic Therapy of Cancer Meeting, Pittsburgh, PA

1990, 1993, With Dr. Olivera J. Finn and colleagues, developed the seminal and sea-changing meetings as

1997, 2000 Co-organizer, 1st-4th Keystone Symp. Cellular Immun. and Immunother. Cancer

2000 Keynote Speaker, AACR Research Special Meeting on Melanoma; Woodlands, Texas

2000 Co-Organizer, American Assoc. of Cancer Research Special Meeting on Cytokines; Vail, CO

2000-2003 Visiting Professor; Shanghai Medical University/Fudan University at Huashan Hospital

2000-2003 SSO Fellowship and Research Grant Committee

2002 Ciphergen ProteinChip Tech. Protein Profiling Advanced Course. With HJ Zeh; July 26, 2002

2003 Co-organizer, iSBTc 5th Symp. on Cellular Immunology & the Immunotherapy of Cancer; Paris.

2003 Co-organizer, iSBTc 1st Workshop on Cancer Biomarkers and Biometrics; Bethesda, MD

2004 Organizer, Dendritic Cells in Chronic Inflammation; 6th TSIS, Munich; March, 2004

2004-2015 Faculty, AACR/ASCO Workshop on Methods in Clinical Cancer Research; Vail

2006-2010 Faculty, 6th-8th Annual Federation of Clinical Immunology Society [FOCiS] Meeting

San Francisco, San Diego, Boston

2006-2010 Board of Directors, FOCiS and Director, FOCiS Centers of Excellence [50 sites worldwide]

2008 Co-organizer, 3rd iD&AS- DAMPs and Alarmins [Pittsburgh; August 31-September 2, 2008]

2006-2009 Clinical Oncology Study Section, NIH

2010 Interventional Immunology Faculty, FOCiS Boston 2010 – Cancer Therapies

2010 Special Site Visit Member, Inflammation and Cancer Program, NCI-Frederick

2011-2019 Founder, Translational Research Mitochondria, Aging, & Disease TriMAD I-VIII, Pitt/Penn/U.PA

2019 Chair, Immunotherapy Study Section, CDRMP; Department of Defense; Dec 8-10, 2019

2019-2024 SITC Cancer ImmunoRx Winter School, Mesa AZ Feb. 18-22, ‘19; Houston, TX Jan 13-17, ’20; Virtual ’21 and ’22; Austin, TX 2023, 2024, and 2025

2022 SITC Lifetime Achievement Award

2020-Current Chair, Scientific Advisory Committee Alliance for Cancer Cell and Gene Therapy (ACGT)

2025-Current Chair, Learning in Artificial and Biologic Systems; Pittsburgh April 9, 2025

C. Selected peer reviewed publications (in chronological order, 544 publications in PubMed; January, 2025). My initial career was spent developing the basis for immunotherapy of patients with cancer; the subsequent period during the last decade has been spent on the role of unscheduled cell death in cancer and the role of DAMPs and autophagy in pancreatic cancer biology as well as serving in the C-suite in two cell therapy companies. Developing strategies to integrate adaptive and innate immune pathways to elicit response to therapy for the 70-80% of patients with limited mutational load and immunity is our current primary goal in colorectal and pancreatic cancer.

a. Most Relevant: DAMPs and T cells in Pancreatic Cancer. My initial career with S. Rosenberg defined the role of T-cell growth factors in expanding and sustaining the specificity of so-called lymphokine-activated killer cells and T-cell clones and lines and developing the clinical trials to test them. My work intersected endothelial biology with immunotherapy in many instances causing a vascular leak syndrome to effect traffic into tumor sites.

1: Lotze MT, Cottrell T, Bifulco C, Chow L, Cope L, Gnjatic S, Maecker HT, Yeong Poh Shen J. SITC Clinical Immuno-Oncology Network (SCION) commentary on measurement and interpretation of essential biomarkers in early clinical trials. J Immunother Cancer. 2024 Mar 21;12(3):e008655. doi: 10.1136/jitc-2023-008655.

2: Dai E, Chen X, Linkermann A, Jiang X, Kang R, Kagan VE, … Lotze MT, Klionsky DJ, Stockwell BR, Kroemer G, Tang D. A guideline on the molecular ecosystem regulating ferroptosis. Nat Cell Biol. 2024 Feb 29. doi: 10.1038/s41556-024-01360-8.

3: Murthy P, Zenati MS, AlMasri SS, DeSilva A, Singhi AD, Paniccia A, Lee KK, Simmons RL, Bahary N, Lotze MT, Zureikat AH. Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer. J Natl Compr Canc Netw. 2023 Dec 27;22(1D):e237070. doi:

10.6004/jnccn.2023.7070. PMID: 38150819.

4: Perales-Linares R, Leli NM, Mohei H, Beghi S, Rivera OD, Kostopoulos N, Giglio A, George SS, Uribe-Herranz M, Costabile F, Pierini S, Pustylnikov S, Skoufos G, Barash Y, Hatzigeorgiou AG, Koumenis C, Maity A, Lotze MT, Facciabene A. Parkin Deficiency Suppresses Antigen Presentation to Promote Tumor Immune

Evasion and Immunotherapy Resistance. Cancer Res. 2023 Nov 1;83(21):3562-3576. doi: 10.1158/0008-5472.CAN-22-2499. PMID: 37578274; PMCID: PMC10618737.

5: Tang D, Kang R, Zeh HJ, Lotze MT. The multifunctional protein HMGB1: 50 years of discovery. Nat Rev Immunol. 2023 Dec;23(12):824-841. doi: 10.1038/s41577-023-00894-6. Epub 2023 Jun 15. PMID: 37322174.

6: Ellsworth SG, Ross A, Shiue KR, Murthy P, Byrne-Steel ML, Patel R, Zellars RC, Kong FS, Miller A, Russ KA, Lotze MT. Survey of Changes in Absolute Lymphocyte Counts and Peripheral Immune Repertoire Diversity after External Beam Radiotherapy. Radiat Res. 2024 Oct 30. doi: 10.1667/RADE-24-00010.1. Epub ahead

of print. PMID: 39472998.

7: Carleton N, Lee S, Li R, Zou J, Brown DD, Hooda J, Chang A, Kumar R, Klei LR, Rigatti LH, Newsome J, John Mary DJS, Atkinson JM, West RE, Nolin TD, Oberly PJ, Huang Z, Poirier D, Diego EJ, Lucas PC, Tseng G, Lotze MT, McAuliffe PF, Zervantonakis IK, Oesterreich S, Lee AV. Systemic and local chronic inflammation

and hormone disposition promote a tumor-permissive environment for breast cancer in older women. bioRxiv [Preprint]. 2024 Oct 21:2024.10.18.616978. doi:10.1101/2024.10.18.616978. PMID: 39484485; PMCID: PMC11526964.

8: Lotze MT, Maeurer M, Quezada SA, Coukos G. Lung Cancer Adoptive Cell Therapy: Inspiring TIL ACT Comes Center Stage. Cancer Discov. 2024 Aug 2;14(8):1366-1368. doi: 10.1158/2159-8290.CD-24-0645. PMID: 39091204.

9: Lotze MT, Olejniczak SH, Skokos D. CD28 co-stimulation: novel insights and applications in cancer immunotherapy. Nat Rev Immunol. 2024 Jul 25. doi: 10.1038/s41577-024-01061-1. Epub ahead of print. PMID: 39054343.

10: Fei N, Wen S, Ramanathan R, Hogg ME, Zureikat AH, Lotze MT, Bahary N, Singhi AD, Zeh HJ, Boone BA. SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma. Clin Transl Sci. 2021 Sep;14(5):1822-1829. doi: 10.1111/cts.13029.

PMID: 34002944; PMCID: PMC8504806.

11: Chopra A, Zamora R, Vodovotz Y, Hodges JC, Barclay D, Brand R, Simmons RL, Lee KK, Paniccia A, Murthy P, Lotze MT, Boone BA, Zureikat AH. Baseline Plasma Inflammatory Profile Is Associated With Response to Neoadjuvant Chemotherapy in Patients With Pancreatic Adenocarcinoma. J Immunother. 2021 Jun 1;44(5):185-192.doi: 10.1097/CJI.0000000000000370. PMID: 33935273; PMCID: PMC8102434.

12: Mendonça Gorgulho C, Krishnamurthy A, Lanzi A, Galon J, Housseau F, Kaneno R, Lotze MT. Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer. J Immunother. 2021 Feb-Mar 01;44(2):49-62. doi:10.1097/CJI.0000000000000357. PMID: 33416261; PMCID: PMC8092416.

13: Biradar S, Lotze MT, Mailliard RB. The Unknown Unknowns: Recovering Gamma- Delta T Cells for Control of Human Immunodeficiency Virus (HIV). Viruses. 2020 Dec 17;12(12):1455. doi: 10.3390/v12121455. PMID: 33348583; PMCID: PMC7766279.

14: Chopra A, Hodges JC, Olson A, Burton S, Ellsworth SG, Bahary N, Singhi AD, Boone BA, Beane JD, Bartlett D, Lee KK, Hogg ME, Lotze MT, Paniccia A, Zeh H, Zureikat AH. Outcomes of Neoadjuvant Chemotherapy Versus Chemoradiation in Localized Pancreatic Cancer: A Case-Control Matched Analysis. Ann Surg Oncol.

2021 Jul;28(7):3779-3788. doi: 10.1245/s10434-020-09391-9. PMID: 33231769; PMCID: PMC8366580.

15. Zeh HJ, Bahary N, Boone BA, Singhi AD, Miller-Ocuin JL, Normolle DP, Zureikat AH, Hogg ME, Bartlett DL, Lee KK, Tsung A, Marsh JW, Murthy P, Tang D, Seiser N, Amaravadi RK, Espina V, Liotta L, Lotze MT. A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients. Clin Cancer Res. 2020 Jul 1;26(13):3126-3134. doi: 10.1158/1078-0432.CCR-19-4042. Epub 2020 Mar 10. PMID: 32156749; PMCID: PMC8086597.

17: Ellsworth SG; Abdelhakiem M; Elgohari B; Mohammed M; Shogan J; Vera A; Burton SA; Olson AC; Lee KKW; Paniccia A; Zhang JY; Lotze MT; Zureikat AH. Lessons learned about acute and late toxicity after two decades of experience with pancreatic SBRT.J Natl Compr Canc Netw (JNCCN) 2025 (in press)

2. Role of Cytokines and Autophagy in Pancreatic Cancer. The notion that extracellular proteins (cytokines) could promote immune reactivity was first demonstrated clinically with interferon alpha, followed by my first studies of interleukin 2 (IL-2), taking it all the way to the clinic (as well as IL-4, IL-10, IL-12, IL-18). It became increasingly clear that although immunity could be elicited in some cancers, a more direct approach to targeting autophagy would be necessary to promote immunity.

a. Toward a comprehensive view of cancer immune responsiveness: A synopsis from the SITC workshop Davide Bedognetti, … Michael T. Lotze; … Alessandra Cesano; Francesco M. Marincola, MD Journal for ImmunoTherapy of Cancer, JITC-D-19-00027R2, in press, 2019.

b. Russell, KL, Mendonça Gorgulho C, Allen A, Vakaki M, Wang Y, Facciabene A, Lee D, Roy P, Buchser WJ, Appleman LJ, Maranchie J, Storkus WJ, and Lotze MT, “Inhibiting Autophagy in Renal Cell Cancer and the Associated Tumor Endothelium” . The Cancer Journal: The Journal of Principles & Practice of Oncology (NIHMS1526925, Publ.ID: PPO-D-19-00071), in press 2019.

c. Li C, Zhang Y, Cheng X, Yuan H, Zhu S, Liu J, Wen Q, Xie Y, Liu J, Kroemer G, Klionsky DJ, Lotze MT, Zeh HJ, Kang R, Tang D. PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Dev Cell. 2018; 46:441-455.PMID: 30100261.

Full List of My Published Work: http://www.ncbi.nlm.nih.gov/sites/myncbi/collections/bibliography/47940360/

D. Research Support

Teaming Award-Momentum Funds 2/01/24-2/01/26

“Pittsburgh Deep Learning Triangulum” Discourse and dialogue between the disparate fields of immunology, neuroscience, and artificial intelligence has the potential to generate breakthroughs in our understanding and development of new deep learning methods and their biological as well as clinical applications. Reductionistic biology enabled great in these two major biologic systems and their interaction with the environment. By coalescing relevant Pitt and CMU colleagues and stimulating vigorous dialogue, the group will identify the most challenging problems in learning whose solutions would be transformative. The PDLT will develop stakeholder relationships with sponsors such as the Chan-Zuckerberg Foundation, ARPA-H, Wellcome Leap, or the Allen Institute to enable new frameworks for deep learning and their applications.

Completed Research Support

Hirschberg Foundation 11/01/19-10/31/20

“Neoadjuvant Autophagy Inhibition in Pancreatic Adenocarcinoma Promotes an Effector T Cell Response and Tertiary Lymphoid Structures” Autophagy is a mechanism of programmed cell survival that is utilized by PDAC cells to survive the stressful conditions of the tumor microenvironment (TME). We launched an NCI-supported randomized phase II trial of neoadjuvant gemcitabine/nab-paclitaxel, with and without autophagy inhibition (NCT01978184). In this study, autophagy inhibition improved Evans grade pathological response and CA 19-9 responses to preoperative Gemcitabine and Nab-Paclitaxel, which correlated with improvements in overall and recurrence free survival. Autophagy inhibition significantly increased CD4+ and CD8+ T cell immune cell infiltration and were correlated with improved survival. Role: Co-I

1R01 CA181450-01 (Lotze/Zeh) 01/01/2014-12/31/2018 National Institutes of Health “Pancreatic Ductal Adenocarcinoma is a Disease of Constitutive Autophagy” The goal of this project is to determine whether pancreatic ductal adenocarcinoma is a disease of constitutive autophagy. Role: Co-PI

R01CA206012 (Facciabene/Lotze) 05/05/2016-4/30/2021

National Institutes of Health “Mitochondria Are Endocellular Symbionts That Serve As Targets For Immune Recognition” This work will investigate the relevance of mitochondrial mutations heterogeneity as targets for the development of immune therapies for renal cancer patients. Role: Co-PI

2R01CA160417 (Tang) 04/01/2018- 03/31/2023

2.5% effort Role: Co-I National Institutes of Health “Mitophagy in the Tumor Microenvironment” We postulate that mitophagy suppresses pancreatic tumorigenesis through the control of the mitochondrial iron-dependent tumor microenvironment. Our proposal will uncover a previously underappreciated role for mitophagy in the tumor microenvironment and suggest targeting these events for tumor therapy.

1 R01 CA236965-01A1 (Jing Hu) 3.0% Effort Role: Co-Investigator 12/01/19-11/30/2024

“Targeting PYK2 for the treatment of PDAC” National Institutes of Health. Our central hypothesis is that PYK2 is a novel downstream effector of mutant KRAS signaling essential

for PDAC carcinogenesis and maintenance and a new actionable target for treating PDAC. We will validate the role of PYK2 in mutant KRAS-driven PDAC carcinogenesis, unravel how PYK2 is hard-wired among mutant KRAS-activated signaling networks and validate PYK2 inhibition as an actionable and effective approach to treating PDAC in preclinical models of PDAC.