Patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) respond well to chimeric antigen receptor (CAR)-redirected T cells specific for the CD19 antigen and encoding costimulatory endodomains. Despite encouraging recent reports of therapeutic efficacy, this approach does not distinguish between normal and malignant B cells, setting the stage for profound B cell depletion, hypogammaglobulinemia and perhaps other delayed toxic effects due to the persistence of activated T cells. To circumvent this obstacle without substantial loss of antitumor potency, we are testing in a phase 1 clinical trial (Aim 1) of Project 2, CAR-modified T cells that recognize the Ig kappa light chain of malignant B cells The central hypothesis is that such therapy will eradicate kappa-positive NHL and CLL cells while sparing normal B cells that express the nontargeted light chain, thus preserving B cell function at a critical time in the patient's clinical course. To reduce the likelihood of suboptimal cell killing due to varying levels or a complete loss of tumor antigen expression, we have chosen CD23 - which is independently expressed by CLL cells - as a second target antigen. This modification could boost the tumor cell kill achieved with T cells that recognize kappa light chain, a prediction we intend to test in a preclinical model (Aim 2). In an additional model we plan to add selected immunomodulatory drugs to the T cell regimen to subvert the immune-inhibitory tumor micro-environment, overcoming tumor-associated neoangiogenesis, Treg cell recruitment and inhibitory immune.cytokines (Aim 3), all of which continue to impede the development of effective T cell immunotherapy. Better control of tumor cell evasion tactics is expected to enhance antitumor effects beyond those typically seen with use of CAR-modified T cells alone. The information gained from the clinical evaluation in Aim 1, together with the preclinical studies in Aims 2 and 3, should inform the design of

Public Health Relevance

Engineering the T cell arm of the immune system to eliminate tumor cells has already shown great promise for the development of effective and clinically feasible cancer treatments. The T cell immunotherapy proposed here should more readily destroy lymphoma and chronic leukemia cells without eliminating excessive numbers of normal B cells, thus adding an important new weapon to the growing arsenal of cellular therapies becoming available to combat human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA126752-07
Application #
8547752
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$220,788
Indirect Cost
$66,821
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Kalra, Mamta; Gerdemann, Ulrike; Luu, Jessica D et al. (2018) Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy. Cytotherapy :
Ngai, Ho; Tian, Gengwen; Courtney, Amy N et al. (2018) IL-21 Selectively Protects CD62L+ NKT Cells and Enhances Their Effector Functions for Adoptive Immunotherapy. J Immunol 201:2141-2153
Morita, Daisuke; Nishio, Nobuhiro; Saito, Shoji et al. (2018) Enhanced Expression of Anti-CD19 Chimeric Antigen Receptor in piggyBac Transposon-Engineered T Cells. Mol Ther Methods Clin Dev 8:131-140
Bollard, Catherine M; Tripic, Tamara; Cruz, Conrad Russell et al. (2018) Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma. J Clin Oncol 36:1128-1139

Showing the most recent 10 out of 270 publications