Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes
Jehonathan H. Pinthus, … , Jacob Ramon, Zelig Eshhar
Jehonathan H. Pinthus, … , Jacob Ramon, Zelig Eshhar
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1774-1781. https://doi.org/10.1172/JCI22284.
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Article Oncology

Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes

Abstract

Prostate cancer is currently the most commonly diagnosed noncutaneous malignancy in American men. When metastatic, usually to the bone, the disease is no longer curable and is usually treated palliatively with androgen ablation. However, after conversion to androgen-independent disease, there is no effective therapy currently available. The “T body” approach, which uses genetically reprogrammed lymphocytes derived from the patient and expressing chimeric receptor genes, combines the effector functions of T lymphocytes and NK cells with the ability of antibodies to recognize predefined surface antigens with high specificity and in a non–MHC-restricted manner. We show here the therapeutic efficacy of human lymphocytes bearing erbB2-specific chimeric receptors on human prostate cancer BM lesions in a SCID mouse model after conditioning of the recipient to allow homing and persistent functioning of the adoptively transferred cells. Induction of stromal cell–derived factor-1 production within the BM using low-dose irradiation or cyclophosphamide combined with IL-2 administration enhanced the homing of systemically delivered T bodies, resulting in decreased tumor growth and prostate-specific antigen secretion, prolongation of survival, and even cure of the treated mice. These preclinical studies strongly support the idea that the T body approach has therapeutic potential in disseminated prostate cancer.

Authors

Jehonathan H. Pinthus, Tova Waks, Victoria Malina, Keren Kaufman-Francis, Alon Harmelin, Itzhak Aizenberg, Hannah Kanety, Jacob Ramon, Zelig Eshhar

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Migration of T bodies to the BM of preconditioned mice is mediated in pa...
Migration of T bodies to the BM of preconditioned mice is mediated in part by CXCR4. SCID mice (n = 3 mice per group) were irradiated with 2 Gy TBI or were injected with 200 mg/kg cyclophosphamide, 24 hours before i.v. administration of erbB2-specific CR–bearing lymphocytes. T bodies were preincubated for 30 minutes on ice with mAb against CXCR4 (αCXCR4), irrelevant control mAb against human TfR (αTfR), or no antibody (none) and then were injected systemically into the mice. After 24 hours, BM was extracted and the number of human lymphocytes was measured by FACS analysis (detecting GFP-positive T bodies in the irradiation experiment and CFSE-labeled cells in the cyclophosphamide experiment). Treatment with anti-CXCR4 was significantly different from control treatment (anti-TfR) for both irradiated mice (*P = 0.003) and cyclophosphamide-treated mice (**P = 0.009) and was significantly different from no antibody treatment (P = 0.01 and P = 0.0002, respectively).