A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer

Kershaw, Michael H.; Westwood, Jennifer A.; Parker, Linda L.; Wang, Gang; Eshhar, Zelig; Mavroukakis, Sharon; White, Donald E.; Wunderlich, John R.; Canevari, Silvana; Rogers-Freezer, Linda; Chen, Clara C.; Yang, James Chih‐Hsin; Rosenberg, Steven A.; Hwu, Patrick

doi:10.1158/1078-0432.ccr-06-1183

Cited by 1,057 publications

(868 citation statements)

References 31 publications

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“…Therefore, each 20 g mouse received approximately 2 Â 10 6 transduced T cells (1 Â 10 8 cells kg À1 ), which is comparable to the dose per kg of gene-modified T cells given to patients. 10,40,41 However, the absolute number of genemodified T cells was considerably less than that used in the clinic. Thus, although there is evidence that there can be close agreement between the transforming potential of retroviral vectors in mouse and human stem cells despite the delivery of much reduced absolute numbers of transduced stem cells in mice, 22,28 it should be noted that this may not be the case when considering T cells.…”

Section: Discussionmentioning

confidence: 99%

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Westwood

Murray²,

Trivett³

et al. 2008

Gene Ther

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There is considerable concern regarding the transforming potential of retroviral vectors currently used for gene therapy, with evidence that retroviral integration can lead to leukemia in recipients of gene-modified stem cells. However, it is not clear whether retroviral-mediated transduction of T cells can lead to malignancy. We transduced mouse T cells with a Moloney murine retroviral gene construct and transferred them into congenic mice, which were preconditioned to enhance the engraftment of transferred T cells. Recipients were then observed long-term for evidence of cancer. Transferred T cells persisted in mice throughout life at levels up to 17% with gene copy numbers up to 5.89 Â 10 5 per million splenocytes. Mice receiving gene-modified T cells developed tumors at a similar rate as control mice that did not receive T cells, and tumors in both groups of mice were of a similar range of histologies. Hematological malignancies comprised approximately 60% of cancers, and the remaining cancers consisted largely of carcinomas. Importantly, the incidence of lymphomas was similar in both groups of mice, and no lymphomas were found to be of donor T-cell origin. This study indicates that the use of retroviral vectors to transduce T cells does not lead to malignant transformation.

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Section: Discussionmentioning

confidence: 99%

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Westwood

Murray²,

Trivett³

et al. 2008

Gene Ther

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show abstract

“…[1][2][3][4] Patient-derived T cells are retrovirally engineered ex vivo to express a recombinant T-cell receptor or, alternatively, a chimeric antigen receptor (CAR, immunoreceptor), amplified and re-infused to recognize and to destroy tumour lesions by their cytolytic capacities. In contrast to recombinant T-cell receptors, CARs consist of a single polypeptide chain with an antibody-derived single chain fragment (scFv) in the extracellular moiety for binding and the CD3z or combined CD28-CD3z signalling domain in the intracellular moiety for T-cell activation.…”

Section: Introductionmentioning

confidence: 99%

Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response

2010

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“…10 Both sustained survival and increased amplification result in a prolonged redirected T-cell response and in an improved antitumor attack, making second-generation CARs favorable for clinical use. [11][12][13] In physiological activation of naïve T cells, CD28 recruitment by B7 engagement sustains formation of the immunological synapse, thereby lowering the antigen threshold and increasing T-cell activation. In physiological T-cell activation, the activation efficiency correlates with the T-cell receptor (TCR) avidity to the cognate peptide-major histocompatibility complex (MHC) complex.…”

Section: Introductionmentioning

confidence: 99%

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

2010

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Adoptive immunotherapy of cancer using chimeric antigen receptor (CAR)-engineered T cells with redirected specificity showed efficacy in recent trials. In preclinical models, 'second-generation' CARs with CD28 costimulatory domain in addition to CD3z performed superior in redirecting T-cell effector functions and survival. Whereas CD28 costimulation sustains physiological T-cell receptor (TCR)-CD3 activation of naïve T cells, the impact of CD28 cosignalling on the threshold of CAR-mediated activation of pre-stimulated T cells without B7-CD28 recruitment remained unclear. Using CARs of different binding affinities, but same epitope specificity, we demonstrate that CD28 cosignalling neither lowered the antigen threshold nor the binding affinity for redirected T-cell activation. 'Affinity ceiling' above which increase in affinity does not increase T-cell activation was not altered. Accordingly, redirected tumor cell killing depended on the binding affinity but was likewise effective for CD3z and CD28-CD3z CARs. In contrast to CD3z, CD28-CD3z CAR-driven activation was not increased further by CD28-B7 engagement. However, CD28 cosignalling, which is required for interleukin-2 induction could not be replaced by high-affinity CD3z CAR binding or high-density antigen engagement. We conclude that CD28 CAR cosignalling does not alter the activation threshold but redirects T-cell effector functions.

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A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer

Cited by 1,057 publications

References 31 publications

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

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