T cells expressing CD19-specific chimeric antigen receptors (CAR.CD19) can produce high rates of complete remission among patients with refractory B-cell malignancies. However, these studies have also revealed (i) difficulties in preparing sufficient numbers of CAR-T cells from the majority of pediatric patients with non-Hodgkin lymphoma (NHL), and (ii) a growing fraction of NHL patients with delayed relapse due to inadequate persistence of CAR-T cells or loss of CD19 from tumor cells. The long-term goal of Project 4 is to develop a safe and effective immunotherapy for NHL using both the natural and engineered properties of CD1d-restricted Va24-invariant natural killer T (NKT) cells. NKTs are attractive candidates for immunotherapy. They have antilymphoma activity via direct cytotoxicity against CD1d+ lymphoblasts or by activation of other immune effectors, such as NK cells; further, allogeneic NKTs do not produce graft- versus-host disease (GvHD) and can be prepared as ?off-the-shelf? products. We hypothesize that allogeneic NKTs engineered to express CAR.CD19 will show curative potential against NHL without the introduction of GvHD, a concept supported by our preliminary findings: NKTs transduced with CAR.CD19 directly kill CD19+ B lymphoblasts, can be expanded to clinical scale, and exert potent antitumor activity in xenogeneic lymphoma models. We have also shown that the CD62L+ subset of NKTs is essential for CAR.CD19-Tcell persistence and antitumor activity in vivo, and have devised means to preserve this subset of cells during CAR.CD19-NKT expansion. The following three specific aims will test our hypothesis: 1) Generate allogeneic CAR.CD19-NKTs with preserved CD62L expression and maximal antilymphoma potential, using the costimulatory aAPCs (artificial antigen-presenting cells, previously generated during the current funding period). 2) Determine the safety and antitumor activity of third-party CAR.CD19-NKTs in adult and pediatric patients with relapsed/refractory B-cell NHL. 3) Correlate the persistence, phenotype and function of CAR.CD19-NKTs with clinical responses. This study will the first in man to test the feasibility and therapeutic potential of immunotherapy with CAR-redirected NKTs. Our emphasis on CAR.CD19, with its favorable track record when expressed by T cells in NHL patients, will allow us to assess NKTs as a novel platform for NHL immunotherapy and perhaps other types of cancer as well.
Even as reports of successful CAR-directed T-cell immunotherapy for B-cell cancers continue to appear, it is clear that many patients will not benefit in the long term from this treatment. Thus, alternative sources of immune cells that may offer unique advantages over traditional T cells are urgently needed. This project will explore the clinical utility in lymphoma patients of ?natural killer? T (NKT) cells expressing CAR molecules directed to the CD19 target antigen on tumor cells. NKT cells are promising candidates for immunotherapy because they do not induce graft-vs.-host disease and have multiple routes by which they can kill lymphoma cells.
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