Over the last 15 years on this grant, we have established that biologically active, CDR grafted humanized IgG, novel radioconjugates and toxin conjugates, many based on the anti-CD33 Ig HuM195, can be constructed, characterized, and translated into successful clinical trials in patients with AML. Most recently, we described a novel class of radio-immuno-pharmaceutical, """"""""a targetable atomic nanogenerator,"""""""" with exceptional potency that has entered human clinical phase I use and that already shows anti-leukemia activity at the lowest doses. The long-term goals of the program have been to understand and improve alpha particle immunotherapy. We are now exploring the biology and radiobiology of the tumor and its environment, especially its vasculature, to better understand how to make more effective alpha-emitting agents. In the current proposal, we plan to build on this scientific foundation in targeted radioimmunotherapeutics: (1) to answer several new questions that have emerged out of our previous work targeting vasculature;(2) to explain the mechanisms of action and resistance to antibody targeted alpha-particle irradiation. Throughout this work, as before, we aim to ultimately provide therapeutic agents and concepts for their appropriate use and direct application to human clinical trials. The potency and short range of alphas makes them appealing agents for selective killing of tumor neovasculature. Initial studies showed that we could deplete and normalize residual tumor vessels in animal models with effective anti-cancer activity.
In Aim 1, we plan to explore how to best utilize this finding to optimize combining alpha immunotherapy to neovasculature with agents directed to the tumor cells themselves. We also explore mechanisms by determining how the properties of the subsequent anti-tumor agents affect kinetics and tumor therapy outcomes following vessel targeting.
In Aim 2, we will examine potential mechanisms of cellular resistance to alpha particle damage including: a) DNA damage sensors and transducers or apoptosis mediators or cell cycle checkpoints that distinguish alpha-resistant from sensitive cells or affect alpha sensitivity;b) DNA repair or damage mitigation mechanisms. Understanding this critical biology should allow better strategies to avoid normal cell killing and tissue damage, while enhancing tumor cell kill.

Public Health Relevance

Recently, we described a novel class of radioimmunopharmaceutical, """"""""a targetable atomic nanogenerator,"""""""" with exceptional potency that has entered human use with anti- leukemia activity already evident at the lowest doses in its initial phase 1 trial. The long- term goals of the project are to develop simple targeting vehicles that kill via alpha particle emission and that make use of our understanding of the tumor's response to alpha particle damage.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055349-19
Application #
8210362
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
1991-09-26
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
19
Fiscal Year
2012
Total Cost
$423,006
Indirect Cost
$200,254
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Gejman, Ron S; Chang, Aaron Y; Jones, Heather F et al. (2018) Rejection of immunogenic tumor clones is limited by clonal fraction. Elife 7:
Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141
McDevitt, Michael R; Thorek, Daniel L J; Hashimoto, Takeshi et al. (2018) Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer. Nat Commun 9:1629
Maslak, Peter G; Dao, Tao; Bernal, Yvette et al. (2018) Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia. Blood Adv 2:224-234
Mulvey, J Justin; Littmann, Eric R; Ling, Lilan et al. (2018) The effects of amine-modified single-walled carbon nanotubes on the mouse microbiota. Int J Nanomedicine 13:5275-5286
Casey, E; Bournazos, S; Mo, G et al. (2018) A new mouse expressing human Fc? receptors to better predict therapeutic efficacy of human anti-cancer antibodies. Leukemia 32:547-549
Zauderer, Marjorie G; Tsao, Anne S; Dao, Tao et al. (2017) A Randomized Phase II Trial of Adjuvant Galinpepimut-S, WT-1 Analogue Peptide Vaccine, After Multimodality Therapy for Patients with Malignant Pleural Mesothelioma. Clin Cancer Res 23:7483-7489
Mathias, M D; Sockolosky, J T; Chang, A Y et al. (2017) CD47 blockade enhances therapeutic activity of TCR mimic antibodies to ultra-low density cancer epitopes. Leukemia 31:2254-2257
Chang, Aaron Y; Dao, Tao; Gejman, Ron S et al. (2017) A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. J Clin Invest 127:2705-2718
Mondello, Patrizia; Derenzini, Enrico; Asgari, Zahra et al. (2017) Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma. Oncotarget 8:14017-14028

Showing the most recent 10 out of 116 publications