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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
United States
Zip Code
Rouce, Rayne H; Heslop, Helen E (2016) Forecasting Cytokine Storms with New Predictive Biomarkers. Cancer Discov 6:579-80
Yang, Liubin; Rodriguez, Benjamin; Mayle, Allison et al. (2016) DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias. Cancer Cell 29:922-34
Bollard, Catherine M; Heslop, Helen E (2016) T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127:3331-40
Rouce, Rayne H; Sharma, Sandhya; Huynh, Mai et al. (2016) Recent advances in T-cell immunotherapy for haematological malignancies. Br J Haematol :
Ramos, Carlos A; Heslop, Helen E; Brenner, Malcolm K (2016) CAR-T Cell Therapy for Lymphoma. Annu Rev Med 67:165-83
Ramos, Carlos A; Savoldo, Barbara; Torrano, Vicky et al. (2016) Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest 126:2588-96
Rau, Rachel E; Rodriguez, Benjamin A; Luo, Min et al. (2016) DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia. Blood 128:971-81
Zhou, Xiaoou; Naik, Swati; Dakhova, Olga et al. (2016) Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation. Mol Ther 24:823-31
Eckstein, Olive S; Wang, Linghua; Punia, Jyotinder N et al. (2016) Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes. Exp Hematol 44:740-4
Naik, Swati; Nicholas, Sarah K; Martinez, Caridad A et al. (2016) Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol 137:1498-1505.e1

Showing the most recent 10 out of 218 publications