Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44V6-specific SCFV: ζ-chimera

Hekele, Armin; Dall, P.; Moritz, Dirk; Wels, Winfried S.; Groner, Bernd; Herrlich, Peter; Ponta, Helmut

doi:10.1002/(sici)1097-0215(19961009)68:2<232::aid-ijc16>3.0.co;2-c

Cited by 54 publications

(16 citation statements)

References 19 publications

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“…In addition, chimeric receptors were constructed that recognize carbohydrate antigens such as Lewis Y (34) or antigens such as the high-molecularweight melanoma-associated antigen (HMW-MAA) only expressed by a subset of tumors (35,36). Redirection of T cells to metastasizing tumor cells was attempted by employing a chimeric receptor with specificity for a metastasis-associated variant of CD44 (37). Approaches for the treatment of hematopoietic malignancies include the use of chimeric receptors that target CD30 expressed on Hodgkin/Reed-Sternberg cells (38), or the B cell lymphoma-associated antigen CD20 (39).…”

Section: T Lymphocytes With Grafted Recognition Specificity For Tumormentioning

confidence: 99%

Chimeric Antigen Receptors for the Retargeting of Cytotoxic Effector Cells

Uherek

Groner

Wels

2001

Journal of Hematotherapy & Stem Cell Research

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T lymphocytes recognize specific antigens through interaction of the T cell receptor (TCR) with short peptides presented by major histocompatibility complex (MHC) class I or II molecules. For initial activation and clonal expansion, naïve T cells are dependent on professional antigen-presenting cells (APCs) that provide additional co-stimulatory signals. TCR activation in the absence of co-stimulation can result in unresponsiveness and clonal anergy. To bypass immunization, different approaches for the derivation of cytotoxic effector cells with grafted recognition specificity have been developed. Chimeric antigen receptors have been constructed that consist of binding domains derived from natural ligands or antibodies specific for cell-surface antigens, genetically fused to effector molecules such as the TCR alpha and beta chains, or components of the TCR-associated CD3 complex. Upon antigen binding, such chimeric receptors link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex. Since the first reports on chimeric antigen receptors, this concept has steadily been refined and the molecular design of chimeric receptors has been optimized. Aided by advances in recombinant antibody technology, chimeric antigen receptors targeted to a wide variety of antigens on the surface of cancer cells and of cells infected by human immunodeficiency virus (HIV) have been generated. In initial clinical studies, infusion of such cells into patients proved to be safe and transient therapeutic effects have been observed.

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Section: T Lymphocytes With Grafted Recognition Specificity For Tumormentioning

confidence: 99%

Chimeric Antigen Receptors for the Retargeting of Cytotoxic Effector Cells

Uherek

Groner

Wels

2001

Journal of Hematotherapy & Stem Cell Research

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“…Moreover, adoptive transfer of genetically engineered ch-Rec POS CTLs has shown in vivo antitumor activity in mice. [25][26][27] We used a chimeric mAb-based receptor derived from the G250 mAb which specifically recognizes G250 TAA on RCCs. 28 Ch-Rec gene-transduced primary human CD3 POS T lymphocytes specifically: (1) recognize and lyse RCCs in an MHC-unrestricted fashion; and (2) produce lymphokines during interaction with RCCs, in spite of the fact that the ch-Rec density was too low to be detected by flow cytometric analysis.…”

Section: Introductionmentioning

confidence: 99%

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

2000

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Genetically engineered expression of tumor-specific single chain antibody chimeric receptors (ch-Rec) on human T lymphocytes endow these cells with the parental monoclonal antibody (mAb) dictated tumor specificity and may be useful for clinical immuno-genetherapy. Therefore it was of importance to assess how the densities of tumor-specific receptors and tumor associated antigens (TAA), respectively, affect primary human T lymphocyte functions in relation to target cell susceptibilities to lysis. We therefore studied the functional balance between ch-Rec densities on human T lymphocytes and TAA on tumor cells. The gene construct encoding a ch-Rec derived from (1) a renal carcinoma cell (RCC) specific mouse mAb (G250), and (2) the human signal transducing Fc(⑀)RI ␥-chain was used. To obtain chRec HIGH-POS and ch-Rec LOW-POS T lymphocytes, two distinct retroviral vectors were used to introduce the gene constructs into primary human T lymphocytes. Levels of ch-Rec-

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“…These cells, which are specific to the same non-MHC and restricted antigen, are capable of working in concert upon stimulation by their predefined target. A large repertoire of CRs that can selectively recognize different tumor-associated antigens has been constructed (10,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) and in practice one can attack a given tumor with a panel of T bodies including several different specificities and CR designs. This arsenal should offer a workable solution to one of the major drawbacks of cancer immunotherapy: the regrowth of escape variants as a result of selective immunological pressure (7,40,41).…”

Section: Discussionmentioning

confidence: 99%

Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes

Pinthus

Waks²,

Malina³

et al. 2004

J. Clin. Invest.

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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.

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Growth retardation of tumors by adoptive transfer of cytotoxic T lymphocytes reprogrammed by CD44V6-specific SCFV: ζ-chimera

Cited by 54 publications

References 19 publications

Chimeric Antigen Receptors for the Retargeting of Cytotoxic Effector Cells

Chimeric Antigen Receptors for the Retargeting of Cytotoxic Effector Cells

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes

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