Targeted immunotherapies for hematologic malignancies

Our overall goal is to develop novel targeted immunotherapies for patients with hematologic malignancies. The group develops adoptive T cell therapies with native or engineered receptors and evaluates combinatorial strategies. The objective is to efficiently target tumor cells, mitigate immunosuppressive tumor microenvironment factors, favor tumor-targeted migration and longevity of transferred T cells, control potential toxicities, identify novel personalized targets, and move developments to the clinic.

• To engineer human T cells for targeting hematologic malignancies (chimeric antigen receptors, transgenic T cell receptors, engager molecules etc)

• To determine if function and persistence of transgenic T cells can be enhanced through (a) reactivating viruses, (b) immune checkpoint blockade or (c) vaccination

• To develop combinatorial approaches to T cell therapy targeting both the tumor cells and their microenvironment (e.g. engineer tumor-directed migration, resistance to immune inhibitory signals)

• To engineer signaling switches in T cells that revert tumor-associated immune inhibitory signals.

• To evaluate 3D culture systems to better model the tumor microenvironment in vitro and apply them to evaluate transgenic T cell function

• To identify immunogenic mutational tumor neo-antigens in patients with hematologic malignancies and to isolate their neo-antigen specific TCRs for personalized medicine applications.

We apply principles from immunology, hematology, cancer and systems biology, use gene transfer and editing technologies to engineer T cells, and collaborate with experts in protein engineering, gene editing, proteomics/ peptidomics, immunomonitoring, bioinformatics, bioengineering, clinical hematology and immuno-oncology. 

• Bajwa G, Lanz I, Cardenas M, Brenner MK, Arber C. Transgenic CD8ab co-receptor rescues endogenous TCR function in TCR-transgenic virus-specific T cells. Journal for Immunotherapy of Cancer, 2020 Nov;8(2):e001487. doi: 10.1136/jitc-2020-001487. PMID 33148692

• Rath JA*, Bajwa G*, Carreres B, Hoyer E, Gruber I, Martínez-Paniagua MA, Yu Y, Nouraee N, Sadeghi F, Wu M, Wang T, Hebeisen M, Rufer N, Varadarajan N, Ho PC, Brenner MK, Gfeller D, Arber C. Single-cell transcriptomics identifies multiple pathways underlying potent anti-tumor function of TCR and CD8ab engineered human CD4+ T cells. *equal contribution first authorship. Science Advances, 2020, Jul 3;6(27):eaaz7809. doi: 10.1126/sciadv.aaz7809. eCollection 2020 Jul. PMID: 32923584

• Rath JA and Arber C. Engineering strategies to enhance TCR based adoptive T cell therapy. Cells 2020, June 18;9(6):1485. doi: 10.3390/cells9061485. PMID: 32570906

• Young M, Dahoun T, Sokrat B, Arber C, Chen KM, Bouvier M, Barth P. Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways. PNAS 2018, Jul 3;115(27):7051-7056. Epub 2018 Jun 18, doi: 10.1073/pnas.1718489115.  PMID: 29915030

• Nishimura CD, Brenner DA, Mukherjee M, Hirsch RA, Ott L, Wu MF, Liu H, Dakhova O, Orange JS, Brenner MK, Lin CY, Arber C. C-MPL provides tumor-targeted T cell receptor-transgenic T cells with co-stimulation and cytokine signals. Blood. 2017 Dec 21;130(25):2739-2749. Epub 2017 Oct 27. doi: 10.1182/blood-2017-02-769463 PMID:29079582

• Arber C, Feng X, Abhyankar H, Romero E, Wu MF, Heslop HE, Barth P, Dotti G, Savoldo B. Survivin specific T cell receptor targets tumor but not T cells. The Journal of Clinical Investigation. 2015 Jan;125(1):157-68. Epub 2014 Nov 21. doi: 10.1172/JCI75876. PMID: 25415440