Recent observations by the applicants suggest that adoptive transfer of T cells genetically modified toexpress a B cell-specific antibody, incorporated into an artificial chimeric T-cell receptor (CAR), mighteradicate lymphoma cells in a clinical setting. The intent of this proposal is to test whether transgenic Tcells that express CAR targeted to the kappa-light chain of immunoglobulin can be safely administered topatients with follicular lymphoma and whether such immunotherapy induces antitumor effects withoutimpairing humoral immunity. This objective will be vigorously pursued in three specific research aims. First,it will be important to validate and maximize the function of CAR-bearing T cells both in vitro and. in a SCIDmouse model and to devise optimal assaysfor evaluating the persistence and functionality of the transgenicT cells after their infusion into lymphoma patients. Second, the clinical significance of the laboratory findingsunderlying this project will be tested in a Phase I trial designed to evaluatethe safety, properties andantitumor activity of the modified T cells in patients with refractory/relapsed lymphoma, using the biologicalassays developedin Aim 1to assessT-cell function and persistence. Third, studies are planned to extendthe value of the CAR-expressing T cells by engineering them to produce a CD22-targeted immunotoxin afterthe anti-CD19 CAR is engaged by antigen. If safe and effective in a murine xenograft model, this combinedstrategy of adoptive T cell immunotherapy, which exploits two distinct classes of effector mechanisms, willundergo testing in future clinical trials not funded by this award. Upon completion of these aims, it should beclear whether the infusion of anti-kappa CAR-expressingT cells is a legitimate approach to the treatment ofhuman follicular lymphoma, and whether the inducible release of immunotoxin by these cells at the tumorsite will enhance antitumor activity.Lay Abstract: Follicular lymphoma cannot be cured by chemotherapy.Since these tumor cells canoccasionally be recognized and eliminated by other cells of the immune system (T lymphocytes) we willgenetically alter these T lymphocytesinserting an artificial receptor that recognizes a structure on the surfaceof the cancerous B cells. When the T lymphocytes contact the tumor cells, they become activated and kill thecancer. This effect should not significantly damage the remaining normal B-cells preserving the immunity.
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