Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses

Koya, Richard C.; Mok, Stephen; Comı́n-Anduix, Begoña; Chodon, Thinle; Radu, Caius G.; Nishimura, Michael I.; Witte, Owen N.; Ribas, Antoni

doi:10.1073/pnas.1008300107

Cited by 61 publications

(50 citation statements)

References 23 publications

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“…2A), consistent with prior data from other groups regarding the behavior of effector T cells in tumors and infected tissues (7,24,31,32). The presence of substantial numbers of nonspecific T cells could reduce the efficiency of cognate CTL-target cell contacts by steric hindrance.…”

Section: Discussionsupporting

confidence: 80%

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Ariotti

Beltman

Borsje

et al. 2015

The Journal of Immunology

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It is well established how effector T cells exit the vasculature to enter the peripheral tissues in which an infection is ongoing. However, less is known regarding how CTLs migrate toward infected cells after entry into peripheral organs. Recently, it was shown that the chemokine receptor CXCR3 on T cells has an important role in their ability to localize infected cells and to control vaccinia virus infection. However, the search strategy of T cells for virus-infected targets has not been investigated in detail and could involve chemotaxis toward infected cells, chemokinesis (i.e., increased motility) combined with CTL arrest when targets are detected, or both. In this study, we describe and analyze the migration of CTLs within HSV-1–infected epidermis in vivo. We demonstrate that activated T cells display a subtle distance-dependent chemotaxis toward clusters of infected cells and confirm that this is mediated by CXCR3 and its ligands. Although the chemotactic migration is weak, computer simulations based on short-term experimental data, combined with subsequent long-term imaging indicate that this behavior is crucial for efficient target localization and T cell accumulation at effector sites. Thus, chemotactic migration of effector T cells within peripheral tissue forms an important factor in the speed with which T cells are able to arrive at sites of infection.

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Section: Discussionsupporting

confidence: 80%

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Ariotti

Beltman

Borsje

et al. 2015

The Journal of Immunology

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“…The lentiviral vector pF5-sr39tk expressing the F5 TCR chains and the sr39tk reporter was constructed as previously described (37). The TCR chains and the reporter gene are separated by picornaviral-derived 2A sequences that allow the expression of a polycistronic mRNA and the generation of the three protein products (38).…”

Section: Methodsmentioning

confidence: 99%

Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells

Vatakis

Koya²,

Nixon

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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103

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The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201–restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific naïve CD8 + T-cell population. Following tumor challenge, these transgenic CD8 + T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non–HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.

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“…These gene-engineered lymphocytes hold the promise to treat infectious diseases and cancer, [1][2][3][4][5][6][7][8][9][10] but the appropriate substrate cells to use is understudied, and most current protocols simply transfer genes into "bulk" peripheral blood mononuclear cells (PBMCs). Varieties of data indicate that T cells, and in particular CD8 ϩ T cells, are worthy substrates for gene engineering.…”

Section: Introductionmentioning

confidence: 99%

Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy

Hinrichs

Borman

Gattinoni

et al. 2011

Blood

263

251

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Cluster of differentiation (CD)8 ؉ T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8 ؉ T cells for patient treatments is controversial and understudied. We investigated human CD8 ؉ T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or "exhaustion," maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy. (Blood. 2011;117(3):808-814) IntroductionIt is now possible to genetically engineer human T lymphocytes to express virtually any known gene, including genes encoding T-cell receptors (TCRs) or chimeric antigen receptors (CARs), to provide the desired T-cell specificity. These gene-engineered lymphocytes hold the promise to treat infectious diseases and cancer, 1-10 but the appropriate substrate cells to use is understudied, and most current protocols simply transfer genes into "bulk" peripheral blood mononuclear cells (PBMCs). Varieties of data indicate that T cells, and in particular CD8 ϩ T cells, are worthy substrates for gene engineering. However, CD8 ϩ T cells in peripheral blood are themselves a complex mixture, composed of at least 3 major subsets-naive (T N ), central memory (T CM ), and effector memory (T EM )-each having different functional qualities.The optimal subset to engineer for adoptive immunotherapy is controversial. 8,[11][12][13][14] Memory CD8 ϩ T-cell subsets are more studied than naive cells, because antigen-specific clones can be found at increased frequencies. In a landmark paper, Berger et al 13 have shown in macaques that effector cells derived from T CM rather than T EM possess greater ability to survive and establish immunologic memory after infusion. This finding is consistent with data comparing memory subsets in mice. 15 However, T N cells were not explicitly analyzed in these reports, 12 an omission that might be important given recent findings in mice that naive T cells convey more antitumor activity than memory cells. 12 Short of conducting a series of clinical trials, the decision of which CD8 ϩ T-cell subset to use for clinical protocols will depend on the cell phenotypes that result from transduction of T...

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Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses

Cited by 61 publications

References 23 publications

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Subtle CXCR3-Dependent Chemotaxis of CTLs within Infected Tissue Allows Efficient Target Localization

Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells

Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy

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