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.

Antitumor activity of dual-specific T cells and influenza virus

“…In attempts to generate tumor reactive T cells, genetic modification techniques have been employed resulting in the generation of T cells reactive with ovarian, colon, kidney, breast and other cancers. [19][20][21][22][23][24][25][26] Despite demonstrations of tumor reactivity of genetically redirected T cells, they do not expand or persist in vivo even in the continued presence of antigen. In this respect, these previously described gene-modified T cells can be considered to be poorly responsive to antigen.…”

Epigen, the Last Ligand of ErbB Receptors, Reveals Intricate Relationships between Affinity and Mitogenicity

“…PCR Analysis of EPG Expression-Prostate cancer xenografts were grown in castrated (androgen-independent) and noncastrated (androgendependent) nude mice, as described (14). Total RNA was isolated from 0.1 mg of each tissue using TRIzol (Sigma).…”

Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase

“…The culture medium consisted of phenol red-free RPMI-1640 with 2 mM L-glutamine adjusted to contain 1.5 g l À1 sodium bicarbonate, 4.5 g l À1 glucose, 10 mM HEPES, 1.0 mM sodium pyruvate (all from Invitrogen, Burlington, ON, Canada) and 10% charcoalstripped fetal calf serum (CSFCS, Hyclone, UT, USA). CWR22, 13 WISH-PC14 and WISH-PC23 14 human prostate adenocarcinomas were grown as subcutaneous xenografts in castrated and testosterone-supplemented male (CB.17-SCID BEIGE) mice within the stem and progenitor cells (SPC) colony of the Weizmann Institute of Science, Israel in compliance with institutional guidelines. Professor Eshhar (Weizmann Institute) provided frozen samples of these xenografts.…”