Project 1 proceeds from its demonstration during the last funding cycle that T cells targeting 5 tumor-expressed antigens (PRAME, SSX2, MAGEA4, NY-ESO-1, and Survivin - multiTAA T cells) can be used to effectively treat relapsed/refractory Hodgkin and non-Hodgkin lymphoma. Indeed, 5 of 9 patients with active disease achieved durable compete remissions when infused with multiTAA T cells, an outcome that correlated with the detection of tumor-reactive T cells in peripheral blood. This renewal proposal is designed to improve on these results by addressing two remaining barriers to successful cancer immunotherapy: (a) immune escape due to low target antigen expression and (b) the hostile tumor microenvironment, which can subvert the effector function and limit the persistence of infused T cells. To enhance target antigen expression on malignant cells, we will precondition patients with a DNA hypomethylating agent, 5-azacytidine, that upregulates tumor-associated antigens (TAAs) and then relate the biological effects of treatment to subsequent clinical responses (Aims 1 and 2). We predict that the increased target antigen expression on malignant cells will enhance their killing by the adoptively transferred T cells and lead to more effective recruitment and activation of endogenous cellular immune responses, resulting in epitope spreading that will potentiate the antitumor effects of the multiTAA T cells and thus the clinical benefit to patients. In addition, to convert the hostile tumor milieu into one that promotes rather than inhibits T-cell function, we will engineer our multiTAA T cells to express customized inverted cytokine receptors (ICRs) designed to interact with immunosuppressive tumor-derived molecules (TGF? and IL4) but deliver costimulatory and cytokine signals (4-1BB and IL7) that promote rather than inhibit T cell proliferation, activation, persistence and cytolytic activity (Aim 3). We predict that further benefit will derive from the sequestration of these suppressive tumor molecules, which would otherwise support tumor growth and survival while also polarizing the local environment towards inhibitory and tolerizing (Th2, Treg). Overall, we believe that these modifications will enable the wide introduction of a genuinely transformative cellular therapy for the treatment of relapsed/refractory lymphoma. This gain would not necessarily be limited to lymphoma; rather, the flexibility of the therapeutic strategy should enable the antigenic specificity of the engineered T cells to be tailored to each type of cancer under study.

Public Health Relevance

We have developed a ?personalized? therapy for lymphoma that combines tumor-targeted immune cells (T cells) with a drug that sensitizes cancer cells to T cell killing. We believe that this novel approach will be safe and effective for high-risk lymphoma and ultimately for other cancers as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA126752-12
Application #
9553623
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Bajgain, Pradip; Tawinwung, Supannikar; D'Elia, Lindsey et al. (2018) CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation. J Immunother Cancer 6:34
McLaughlin, Lauren P; Rouce, Rayne; Gottschalk, Stephen et al. (2018) EBV/LMP-specific T cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation. Blood 132:2351-2361
McClain, Kenneth L; Picarsic, Jennifer; Chakraborty, Rikhia et al. (2018) CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer 124:2607-2620
Gomes-Silva, Diogo; Ramos, Carlos A (2018) Cancer Immunotherapy Using CAR-T Cells: From the Research Bench to the Assembly Line. Biotechnol J 13:
Brunetti, Lorenzo; Gundry, Michael C; Kitano, Ayumi et al. (2018) Highly Efficient Gene Disruption of Murine and Human Hematopoietic Progenitor Cells by CRISPR/Cas9. J Vis Exp :
Xiong, Wei; Chen, Yuhui; Kang, Xi et al. (2018) Immunological Synapse Predicts Effectiveness of Chimeric Antigen Receptor Cells. Mol Ther 26:963-975
Heslop, Helen E; Brenner, Malcolm K (2018) Seek and You Will Not Find: Ending the Hunt for Replication-Competent Retroviruses during Human Gene Therapy. Mol Ther 26:1-2
Hogstad, Brandon; Berres, Marie-Luise; Chakraborty, Rikhia et al. (2018) RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp Med 215:319-336
Mamonkin, Maksim; Mukherjee, Malini; Srinivasan, Madhuwanti et al. (2018) Reversible Transgene Expression Reduces Fratricide and Permits 4-1BB Costimulation of CAR T Cells Directed to T-cell Malignancies. Cancer Immunol Res 6:47-58
Velasquez, Mireya Paulina; Bonifant, Challice L; Gottschalk, Stephen (2018) Redirecting T cells to hematological malignancies with bispecific antibodies. Blood 131:30-38

Showing the most recent 10 out of 270 publications