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 """"""""next-generation"""""""" clinical trials of CAR-redirected T cells, opening the way for wider application of this novel and potentially highly effective form of immunotherapy.
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.
|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 Îº 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