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Weiner Lab Research Interests
Weiner Lab Research Interests
Dr. Weiner’s research interests include antibody-based cancer immunotherapy and using functional genomics approaches to understand the determinants of tumor cell resistance to antibodies and other drugs. He has been continuously peer-review funded by the NCI for 30 years. His research has long focused on developing novel cancer immunotherapies. His research focus on immunotherapy and functional genomics is specifically relevant to his activities as a member of Lombardi’s MolEcular and TRanslational Oncology (METRO) Program. He has a long history of research in identifying molecular determinants of sensitivity to antibody-dependent cell mediated cytotoxicity (ADCC) and resistance to immune attack, with a growing focus on pancreatic adenocarcinoma (PDAC). He is Principal Investigator of this laboratory.
About Dr. Weiner
About Dr. Weiner
Dr. Louis Weiner is director of Georgetown Lombardi Comprehensive Cancer Center, one of 51 National Cancer Institute (NCI)-designated comprehensive cancer centers in the United States. He holds the Francis L. and Charlotte G. Gragnani Chair and is professor of oncology and chair of the Department of Oncology at Georgetown University Medical Center. He also serves as the Director of the MedStar Georgetown Cancer Institute, a cancer service line serving patients in the Washington DC and Baltimore metropolitan areas. He is responsible for the operation and development of the cancer center, including its research, clinical, and educational missions. The clinical mission includes leading the MedStar-Georgetown Cancer Institute in the metropolitan Washington area. Weiner is known for his laboratory and clinical research focusing on new therapeutic approaches that mobilize the patient’s immune system to fight cancer using monoclonal antibodies and other modalities of therapy. In recent years his research focus has focused on the study of mechanisms cancers employ to defeat immune attack, with an increasing emphasis on pancreatic ductal adenocarcinoma.
Prior to joining Georgetown Lombardi as director in 2008, Weiner served as chairman of the medical oncology department and vice president for translational research at Fox Chase Cancer Center in Philadelphia, PA, and also served as professor in the department of medicine at Temple University School of Medicine. He is an active member of the American Society of Clinical Oncology and the American Association for Cancer Research (AACR), and founded the AACR Cancer Immunology Working Group. He served as chair of the NCI Board of Scientific Counselors for Clinical Sciences and Epidemiology (2012-2018) and was a member of the NCI Clinical Trials Advisory Committee (CTAC; 2014-2018). He also served on the NCI’s blue ribbon panel working group on immunotherapy for the National Cancer Moonshot Initiative and the Advisory Panel of the National Institutes of Health (NIH) Center for Scientific Research (CSR), which administers NIH research grants.
Weiner earned his bachelor degree in biology with honors from the University of Pennsylvania and his M.D. from Mount Sinai School of Medicine. After completing his internship, residency, and service as chief medical resident at the University of Vermont’s Medical Center Hospital, he held clinical and research fellowships in hematology and oncology at Tufts University School of Medicine in Boston.
Contributions to Science:
Contributions to Science:
1. Enhancing Antibody Dependent Cellular Cytotoxicity (ADCC) as an Anti-Tumor Mechanism.
1. Enhancing Antibody Dependent Cellular Cytotoxicity (ADCC) as an Anti-Tumor Mechanism.
ADCC is a potent in vitro mechanism by which Fc receptor bearing leukocytes lyse or phagocytose tumors (1). We were leaders in combining monoclonal antibodies with cytokine therapy (e.g., 2). To further exploit the immunologic killing properties of antibodies we pioneered the clinical development of bispecific antibodies (BsAb) targeting tumor antigens and FcgRIII (CD16) (3). We demonstrated that treatment with this BsAb induces adaptive immune responses directed against the target antigen (HER2). This work led to the concept that ADCC induction can prime adaptive immune responses. Later work identified molecular regulators of ADCC, including KIR molecules expressed on NK cells. This body of work has informed the development of new antibody therapies (4).
1) Smaglo BG, Aldeghaither D, Weiner LM. The development of immunoconjugates for targeted cancer therapy.Nat Rev Clin Oncol. 2014 Nov;11 (11):637-648. doi: 10.1038/nrclinonc.2014.159. Epub 2014 Sep 30.
2) Weiner LM, Moldofsky PJ, Gatenby RA, O'Dwyer J, O'Brien J, Litwin S, Comis RL. Antibody delivery and effector cell activation in a phase II trial of recombinant gamma-interferon and the murine monoclonal antibody CO17-1A in advanced colorectal carcinoma. Cancer Res. 1988 May 1;48(9):2568-73. PMID: 3128400.
3) Weiner LM, Clark JI, Davey M, Li WS, Garcia de Palazzo I, Ring DB, Alpaugh RK. Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. Cancer Res. 1995 Oct 15;55(20):4586-93. PMID: 7553634.
4) Weiner LM. Building better magic bullets: improving unconjugated monoclonal antibody therapy for cancer. Nature Reviews Cancer 7:701-706, 2007. PMID: 17721434
2. Manipulating Antibody Structure to Improve Selective Tumor Targeting.
2. Manipulating Antibody Structure to Improve Selective Tumor Targeting.
Effective antibody therapy requires an understanding of structure: function relationships to elucidate the contributions of antibody size, valence target affinities and Fc domain-based interactions. We have made major contributions in these areas, showing that single-chain Fv molecules improve in vivo tumor penetration and tumor targeting selectivity (e.g., 5), that tumor-targeting antibodies could be generated from human phage-display libraries. The affinities of these antibodies for a tumor antigen can be manipulated through chain-shuffling and site-directed mutagenesis, yielding molecules with widely varying in vitro binding and in vivo tumor targeting and tumor penetration properties. We showed that high-affinity antibodies are internalized and degraded by tumor cells, leading to an apparent reduction in delivery and diffusion throughout tumors (e.g., 6). In the course of this work we developed and tested the first tumor-targeting diabodies and other novel molecular formats. After converting these molecules into IgG formats we elucidated the relative importance of affinities to tumor antigens and Fc domains in mediating ADCC (7). This body of work has had a seminal and lasting influence on the design of human antibodies for cancer therapy (8).
5) Adams GP, McCartney JE, Tai MS, Oppermann H, Huston JS, Stafford WF 3rd, Bookman MA, Fand I, Houston LL, Weiner LM. Highly specific in vivo tumor targeting by monovalent and divalent forms of 741F8 anti-c-erbB-2 single-chain Fv. Cancer Res. 1993 Sep 1;53(17):4026-34. PMID: 7689421.
6) Adams GP, Schier R, McCall AM, Simmons HH, Horak EM, Alpaugh RK, Marks JD, Weiner LM. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 2001 Jun 15;61(12):4750-5. PMID: 11406547.
7) Tang Y, Lou J, Alpaugh RK, Robinson MK, Marks JD, Weiner LM. Regulation of antibody-dependent cellular cytotoxicity by IgG intrinsic and apparent affinity for target antigen. J Immunol. 2007 Sep 1;179(5):2815-23. PMID: 17709495.
8) Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat Biotechnol. 2005 Sep;23(9):1147-57. Review. PMID: 16151408.
3. Identifying Tumor Cell-Based Determinants of Antibody-Mediated Cell Killing.
3. Identifying Tumor Cell-Based Determinants of Antibody-Mediated Cell Killing.
Virtually all clinically effective unconjugated monoclonal antibodies manipulate signaling. I was principal investigator of the initial clinical evaluation of one such antibody, panitumumab, which targets the epidermal growth factor receptor (EGFR)(9). However, the tumor cell-based determinants of efficacy have been remarkably understudied. To address this knowledge gap we employed functional genomics approaches to identify the molecular determinants of tumor cell sensitivity to antibody therapy. The first study employed a 638-element EGFR focused siRNA library that was created using systems biology tools. This library was used to iteratively interrogate 16 malignant cell lines overexpressing EGFR for response to the anti-EGFR antibody, cetuximab, and to small-molecule EGFR inhibitors. We identified a core group of 60 genes whose knockdown sensitized tumor cells to anti-EGFR mediated cytotoxicity (10). We then examined these 60 genes to identify 4 genes whose knockdown also sensitized EGFR-overexpressing cell lines to cetuximab promoted ADCC (11). One of these genes, ABL, can be pharmacologically targeted; this formed the basis of an ongoing clinical trial of cetuximab combined with nilotinib in patients with colorectal and head/neck cancers. In a related set of studies we employed a synthetic lethal screening approach to interrogate a customized c-met targeted siRNA library and identified FGFR2 as a gene (and protein) whose knockdown or pharmacological inhibition promotes the therapeutic efficacy of antibodies directed against c-met (12).
9) Weiner LM, Belldegrun AS, Crawford J, Tolcher AW, Lockbaum P, Arends RH, Navale L, Amado RG, Schwab G, Figlin RA. Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies. Clin Cancer Res. 2008 Jan 15;14(2):502-8. doi: 10.1158/1078-0432.CCR-07-1509. PMID: 18223225
10) Astsaturov I, Ratushny V, Sukhanova A, Einarson MB, Bagnyukova T, Zhou Y, Devarajan K, Silverman JS, Tikhmyanova N, Skobeleva N, Pecherskaya A, Nasto RE, Sharma C, Jablonski SA, Serebriiskii IG, Weiner LM*, Golemis EA*. Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Sci Signal. 2010 Sep 21;3(140):ra67. *Co-Corresponding authors. PMID: 2085866. PMCID: PMC2950064.
11) Murray JC, Aldeghaither D, Wang S, Nasto RE, Jablonski SA, Tang Y, Weiner LM. c-Abl Modulates Tumor Cell Sensitivity to Antibody-Dependent Cellular Cytotoxicity. Cancer Immunol Res. 2014 Dec;2(12):1186-98. doi:10.1158/2326-6066.CIR-14-0083. Epub 2014 Oct 9. PMID: 25300860; PMCID: PMC4258447.
12) Kim B, Wang S, Lee JM, Jeong Y, Ahn T, Son DS, Park HW, Yoo HS, Song YJ, Lee E, Oh YM, Lee SB, Choi J, Murray JC, Zhou Y, Song PH, Kim KA, Weiner LM. Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy. Oncogene. 2014 Mar 24. doi: 10.1038/onc.2014.51. [Epub ahead of print] PubMed PMID: 24662823.
4. Immunoconjugates for Cancer Therapy.
4. Immunoconjugates for Cancer Therapy.
In addition to the antibody engineering and functional studies described above we have been involved in the production, characterization and clinical testing of many immunoconjugates, including a ricin A chain-based recombinant immunotoxin (13), radioimmunoconjugates, including a novel approach to pretargeted radioimmunotherapy (14), and Staphylococcus Enterotoxin A antibody Fab fusion proteins employing an innovative Bayesian dose escalation strategy (15). This work has helped to guide the field of immunoconjugate therapy (1, 8, 16).
13) Weiner LM, O'Dwyer J, Kitson J, Comis RL, Frankel AE, Bauer RJ, Konrad MS, Groves ES. Phase I evaluation of an anti-breast carcinoma monoclonal antibody 260F9-recombinant ricin A chain immunoconjugate. Cancer Res. 1989 Jul 15;49(14):4062-7. PubMed PMID: 2786751.
14) Knox SJ, Goris ML, Tempero M, Weiden PL, Gentner L, Breitz H, Adams GP, Axworthy D, Gaffiga S, Bryan K, Fisher DR, Colcher D, Horak ID, Weiner LM. Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer. Clin Cancer Res. 2000 Feb;6(2):406-14. PubMed PMID: 10690517.
15) Giantonio BJ, Alpaugh RK, Schultz J, McAleer C, Newton DW, Shannon B, Guedez Y, Kotb M, Vitek L, Persson R, Gunnarsson PO, Kalland T, Dohlsten M, Persson B, Weiner LM. Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer. J Clin Oncol. 1997 May;15(5):1994-2007. PubMed PMID: 9164211.
16) Weiner LM, Dhodapkar MV, Ferrone S. Monoclonal antibodies for cancer immunotherapy. Lancet. 2009 Mar 21;373(9668):1033-40. PMID: 19304016. PMCID: PMC2677705.
5. Antibody-initiated Cancer Immunotherapy.
5. Antibody-initiated Cancer Immunotherapy.
We hypothesized that ADCC induction could initiate adaptive immunity (8) and provided initial evidence in support of this concept. More recently we have manipulated the cytokine milieu in tumor microenvironments to promote antibody-initiated adaptive immunity (17, 18).
17) Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy [published online ahead of print, 2020 Jun 29]. Cancer Metastasis Rev. 2020;10.1007/s10555-020-09909-3. doi:10.1007/s10555-020-09909-3.
18) Ajina R, Zuo A, Wang S, Moussa M, Cooper CJ, Shen Y, Johnson QR, Parks JM, Smith JC, Catalfamo M, Fertig EF, Jablonski SA, Weiner LM. Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion doi: https://doi.org/10.1101/2020.06.15.151274.
19) Ajina R, Zamalin D, Zuo A, et al. SpCas9-expression by tumor cells can cause T cell-dependent tumor rejection in immunocompetent mice. 2019. Oncoimmunology, 2019 Mar 16;8(5):e1577127. doi: 10.1080/2162402X.2019.1577127. eCollection 2019.PMID: 31069138.
20) Aldeghaither DS, Zahavi DJ, Murray JC, et al. A Mechanism of Resistance to Antibody-Targeted Immune Attack. Cancer Immunol Res. 2018 Dec 18. pii: canimm.0266.2018. doi: 10.1158/2326-6066.CIR-18-0266. [Epub ahead of print] PubMed PMID: 30563830. PMCID: PMC6359950.
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