In September 2017, the Food and Drug Administration (FDA) approved the first CAR-T treatment for B-cell acute lymphoblastic leukemia, specifically for children and young adults who no longer respond to standard treatments or have relapsed. The therapy, marketed as Kymriah by Novartis, is based on the research by Carl June, PhD, as reported in both The New York Times and The Washington Post.
Dr. Carl June is a leader in the field of oncology research, having spent many years studying adoptive immunotherapy. In fact, in an interview with Main Line Today, he recalled that his own children called him the “Mouse Doctor." Given his pioneering research with CAR-T therapy, it is a nickname that comes with respect. In the preclinical study published by Barrett and colleagues, they observed in NSG™ mice that T cells expressing anti-CD19 CARs were not only specific killers of CD19 target cells, but were able to reduce tumor burden following administration, resulting in significant prolonged survival in a leukemia xenograft model (Barrett et al., 2011). It was this observation and subsequent research that led the clinical team to attempt the nascent therapy in their first human patient (Porter et al., 2011).
Chimeric antigen receptor (CAR) T cell therapy represents the culmination of years of research in both immunology and oncology fields. This therapy, quickly becoming one of the most sought after tool for the treatment of hematologic malignancies, is based on exploiting the antibody-dependent, MHC-independent antigen recognition paradigm by genetically engineering T cells (Daniyan and Bretjens, 2016). Through manipulation, the engineered T cells specifically target tumor cells, killing them (Posey, Jr., et al., 2016). The efficacy of these cells has been observed in leukemia where non-solid tumor cells, circulating within the lymphatic system, have a greater likelihood of encountering CART-T cells, inducing their killing ability (Wang et al., 2017).
With improved technologies to deliver CARs to T cells, this therapy is rapidly moving from the bench to bedside, with a number of successes already demonstrated in the clinic. To fully understand this therapy, including limitations and capabilities, preclinical testing is a vital part of any research project and researchers often turn to a mouse model system for their preclinical in vivo testing. The Jackson Laboratory is committed to empowering researchers with a myriad of mouse strains for target validation and drug efficacy studies.
Using mice as a model organism for human disease has several advantages, such as size and both genetic and physiological similarity to humans. Finding the right mouse, however, to support receiving human cells, such as tumors, was previously a challenge. Although nude mice are often used as tumor recipients, more immuno-deficient strains, such as the NSG™ are far more effective for studying tumor pathogenicity and drug efficacy. At JAX, we offer the non-obese diabetic (NOD)-scid gamma mouse (NOD.Cg-prkdcscidIl2rgtm1w1; NSG™), which as noted by Hosur and colleagues, is the most widely used immunodeficient Il2rgnull mouse model to support the development of a human hematopoietic and immune system (Hosur et al., 2017). It is this type of humanized mouse model that has been relied on to study tumor progression, metastasis, and other immunological functions (Shultz et al., 2014).
NSG™ mice are widely used to study the interactions between the human immune system and cancer, a practical platform for evaluating immunotherapeutics in the context of human immune cells and human tumors. These mice are the gold standard host for engraftment of human tumors or the establishment of human immune components following hematopoietic stem cell transplant. Furthermore, humanized tumor-bearing NSG™ and NSG™-SGM3 mice (our Onco-Hu® mouse models) allow more precise preclinical evaluation of antibody-based therapeutics, cancer vaccines, checkpoint inhibitor therapies, and adoptive cancer immunotherapies.
Decades of research from Dr. Carl June and others resulted in this breakthrough therapeutic for acute lymphoblastic leukemia. The modification of cytotoxic T lymphocytes (CTLs) with CAR has resulted in an effective immunotherapeutic now approved by the FDA. This approval is only the beginning for this type of therapeutic. However, despite their genetic modifications, some unknowns and disadvantages of using CAR-T cells as an immunotherapeutic exist, such as cellular exhaustion and effector dysfunction (Daniyan and Brentjens, 2016). Another unknown facing CAR-based therapies is whether they are effective against solid tumors. Certainly, there will be treatments in the not-so-distance future that will build upon its success and have enhanced capabilities that can only come from increased biological understanding.
Not all research projects will end with an FDA approval, however, and it is relentless research effort that gets us closer to a therapy or disease understanding. Including the right mouse model, such as NSG™ and other humanized next-generation mice, is crucial to studying the interplay among the human immune system, cancerous cells, and potential therapeutics. Researchers worldwide have been partnering with JAX for over 80 years to incorporate pioneering mouse models and services into their studies. Visit the JAX NSG portfolio page to learn more about NSG™ mice, breakthrough research, and models to use in both oncology and immuno-oncology research.
Barrett DM., Zhao Y., Liu X., Jiang S., Carpenito C., Kalos M, Carroll RG., June CH., Grupp SA., 2011. Treatment of Advanced Leukemia in Mice with mRNA Engineered T cells. Hum Gene Ther. 22(12):1575-86. doi: 10.1089/hum.2011.070 [PMID: 21838572]
Daniyan AF, Brentjens RJ., 2016. At the Bench: Chimeric antigen receptor (CAR) T cell therapy for the treatment of B cell malignancies. J Leukoc Biol. 100(6):1255-1264 [PMID: 27789538]
Grady, D. 2017. “F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000” https://www.nytimes.com/2017/08/30/health/gene-therapy-cancer.html?_r=0
Hosur V, Low BE, Avery C, Shultz LD, Wiles MV.,2017. Development of Humanized Mice in the Age of Genome Editing. J Cell Biochem. 118(10):3043-3048. doi: 10.1002/jcb.26002 [PMID: 28332231]
Hu B, Ren J, Luo Y, Keith B2, Young RM, Scholler J, Zhao Y, June CH., 2017. Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18. Cell Rep. 26;20(13):3025-3033. doi: 10.1016/j.celrep.2017.09.002 [PMID: 28954221]
Jacobs, Melissa. 2014. “CART-19: A Leukemia Breakthrough— A Main Line Doctor leads the Penn Medicine research team” http://www.mainlinetoday.com/Main-Line-Today/Healthcare-Guide/Spring-Summer-2014/Breakthrough-in-Leukemia-from-Penn-Medicine-and-CHOP/
Kannan, V. 2017. “A 'historic' cancer treatment designed by Penn researchers just got approved by the FDA” http://www.thedp.com/article/2017/08/a-historic-cancer-treatment-designed-by-penn-researchers-just-got-approved-by-the-fda
Porter DL, Levine BL, Kalos M, Bagg A, June CH., 2011. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 25; 365(8):725-33. doi: 10.1056/NEJMoa1103849 [PMID: 21830940]
Posey AD Jr, Schwab RD, Boesteanu AC, Steentoft C, Mandel U, Engels B, Stone JD, Madsen TD, Schreiber K, Haines KM, Cogdill AP, Chen TJ, Song D, Scholler J, Kranz DM, Feldman MD, Young R, Keith B, Schreiber H, Clausen H, Johnson LA, June CH., 2016. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity. 21; 44(6):1444-54. doi: 10.1016/j.immuni.2016.05.014 [PMID: 27332733]
Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL. 2014. Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb Protoc. 1(7):694-708. doi: 10.1101/pdb.top073585 [PMID: 24987146]
Wang Y, Luo F, Yang J, Zhao C, Chu Y. 2017. New chimeric antigen receptor design for solid tumors. Front. Immunol. 8: 1934. doi: 10.3389/fimmu.2017.01934 [PMID: 29312360]