To ablate or not to ablate? HSCs in the T cell driver’s seat

Anasetti, Claudio; Mulé, James J.

doi:10.1172/jci30973

Cited by 14 publications

(11 citation statements)

References 58 publications

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“…Given that the effectiveness of immunotherapy is enhanced by a lymphodepleting regimen and transfer of hematopoietic stem cells (17), we tested the hypothesis that the efficiency of adoptively transferred Tc1 or Tc17 cells would be enhanced by myeloablative TBI and syngeneic BMT. We injected B16-F10 cells i.v.…”

Section: Resultsmentioning

confidence: 99%

“…The improved effectiveness of ACT following a non-myeloablative lymphodepletion provides the rational basis for the evaluation of more intensive conditioning regimens such as a myeloablative regimen in conjunction with BMT. In fact, more recent studies have indicated that hematopoietic stem cells promote the expansion and function of anti-tumor CD8 + T cells after ACT into tumor-bearing hosts (16, 17). …”

Section: Introductionmentioning

confidence: 99%

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Adoptive Transfer of Tc1 or Tc17 Cells Elicits Antitumor Immunity against Established Melanoma through Distinct Mechanisms

Cho

Wang

et al. 2013

The Journal of Immunology

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Adoptive cell transfer (ACT) of ex vivo activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that Th17/Tc17 cells may exhibit potent anti-tumor activity, but the specific mechanisms have not been completely defined. In the present study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized Tc1 or Tc17 cells combined with autologous BMT after total TBI. BMT combined with ACT of anti-tumor (gp100-specific) Tc17 cells significantly suppressed the growth of established melanoma, whereas Tc1 cells induced long-term tumor regression. After ACT, Tc1 cells maintained their phenotype to produce IFNγ but not IL-17. However, although Tc17 cells largely preserved their ability to produce IL-17, a subset secreted IFNγ or both IFNγ and IL-17, indicating the plasticity of Tc17 cells in vivo. Furthermore, after ACT the Tc17 cells had a long-lived effector T cell phenotype (CD127hi/KLRG-1low) as compared to Tc1 cells. Mechanistically, Tc1 cells mediated anti-tumor immunity primarily through the direct effect of IFNγ on tumor cells. In contrast, despite the fact that some Tc17 cells also secreted IFNγ, Tc17-mediated anti-tumor immunity was independent of the direct effects of IFNγ on the tumor. Nevertheless, IFNγ played a critical role by creating a microenvironment that promoted Tc17-mediated anti-tumor activity. Taken together, these studies demonstrate that both Tc1 and Tc17 cells can mediate effective anti-tumor immunity through distinct effector mechanisms, but Tc1 cells are superior to Tc17 cells in mediating tumor regression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adoptive Transfer of Tc1 or Tc17 Cells Elicits Antitumor Immunity against Established Melanoma through Distinct Mechanisms

Cho

Wang

et al. 2013

The Journal of Immunology

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“…The drugs have multiple effects that seem to promote the antitumor effects of the adoptively transferred T cells. There is evidence for numerous effects, including killing of host Tregs that suppress antitumor immune responses; creating "space" in the host so that the adoptively transferred T cells can engraft (93); and perhaps enhancing cross-priming of tumor antigens. Curti and colleagues (94), have studied the optimal time to harvest autologous CD4 + T cells in relation to the timing of cyclophosphamide administration in patients with advanced cancers.…”

Section: Clinical Trialsmentioning

confidence: 99%

Adoptive T cell therapy for cancer in the clinic

2007

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Over the past 50 years, two fundamentally different strategies to stimulate antitumor immunity have been tested in humans: therapeutic vaccination and passive immunization. Passive immunization, herein referred to as adoptive T cell therapy, is the transfusion of autologous or allogeneic T cells into tumor-bearing hosts, i.e., patients. Evidence that T cells can help to control tumor growth has been provided by the analysis of tumor prevalence in immunodeficient mice and humans (1, 2). In the 1970s, Chester Southam and colleagues demonstrated that subcutaneous growth of human tumor autografts to patients bearing advanced cancers was inhibited by cotransfer of autologous leukocytes in about half of the patients (3). This suggested that leukocytes with a specific inhibitory effect on the implantation and growth of cancer cells were present in many patients with advanced cancer and could be used as potential candidates for adoptive immunotherapy. Furthermore, recent evidence indicates that tumor infiltration by human T cells is a powerful predictive biomarker of survival for ovarian and colorectal cancers (4, 5).Therapeutic cancer vaccines are entering the realm of clinical medicine, but despite more than 60 years of research into this therapeutic approach (6), there are currently no FDA-approved adoptive T cell therapies for cancer. However, the recent explosion of knowledge in the fields of T cell and cancer biology has enabled new approaches that might bring adoptive T cell transfer to the routine practice of clinical medicine, with an impact similar to that of the advent of transfusion medicine, which was enabled by blood bank transfusion technology in the first half of the last century. The application of recent lessons from adoptive transfer in lymphodepleted hosts (7), the ability to overcome barriers presented by Tregs (8,9), and the use of improved culture systems (10) have not yet been tested in randomized clinical trials. The intent of this review on the use adoptive T cell therapy for cancer in the clinic is to focus on issues facing the field, with an emphasis on therapy with CTLs, tumor-infiltrating lymphocytes (TILs), engineered T cells, and the use of adoptive T cell transfers to facilitate therapeutic cancer vaccines. CTL therapyAt present, there is a plethora of suitable CTL targets for many tumors (11). Improved CTL cell culture technology (12) has permitted the first clinical tests of adoptive transfer of CTLs, and the approach seems to result in substantial activity in patients with melanoma; CTLs derived from PBLs were used to treat patients with refractory, metastatic melanoma, and 8 of the 20 patients had minor, mixed, or stable antitumor immune responses (13). Furthermore, the infusion of autologous melanoma-associated antigen recognized by T cells 1-specific (MART-1-specific) CD8 + T cells into a patient with metastatic melanoma resulted in T cell infiltration into both the skin and tumor tissue (14). The in vivo efficacy of the infused T cell population was indicated by the destruction of...

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“…Most preclinical models have utilized preparative TBI given at a single non-myeloablating dose (~5Gy), 4, 6, 19 and some studies have used higher doses of preparative TBI (~9Gy) given together with syngeneic BMT. 1, 15, 20 However, these previous experiments have not systematically addressed the impact of preparative TBI given at various doses and fractionation schemes. We sought to evaluate the relationship between the intensity of the lymphodepleting regimen and the effectiveness of ACT-based immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Increased Intensity Lymphodepletion Enhances Tumor Treatment Efficacy of Adoptively Transferred Tumor-specific T Cells

Wrzesinski

Paulos

Kaiser

et al. 2010

Journal of Immunotherapy

227

172

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Lymphodepletion prior to adoptive cell transfer (ACT)-based immunotherapies can enhance anti-tumor responses by augmenting innate immunity, by increasing access to homeostatic cytokines, and by depressing the numbers of regulatory T cells and myeloid-derived suppressor cells. Although it is clear that high-dose total body irradiation (HD-TBI) given together with hematopoietic stem cell (HSC) transplantation effectively enhances ACT, the relationship between the intensity of lymphodepletion and tumor treatment efficacy has not been systematically studied. Using the pmel-1 mouse model of self/tumor-reactive CD8+ T cells, we observed a strong correlation between the intensity of the conditioning regimen and the efficacy of ACT-based treatments using linear regression analysis. This was the case for preparative TBI administered either as a single dose (R2 = 0.97, p < 0.001) or in fractionated doses (R2 = 0.94, p < 0.001). Increased amounts of preparative TBI were directly correlated with progressively more favorable ratios of transferred tumor-reactive CD8+ T cells towards endogenous cells with the potential for inhibitory activity including: CD4+ cells (potentially T regulatory cells); Gr1+ cells (which are capable of functioning as myeloid-derived suppressor cells): and endogenous CD8+ and NK1.1+ cells (that can act as “sinks” for homeostatic cytokines in the post-ablative setting). With increasing ablation, we also observed elevated LPS levels in the sera and heightened levels of systemic inflammatory cytokines. Thus, increased intensity lymphodepletion triggers enhanced tumor treatment efficacy and the benefits of HD-TBI must be titrated against its risks.

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To ablate or not to ablate? HSCs in the T cell driver’s seat

Cited by 14 publications

References 58 publications

Adoptive Transfer of Tc1 or Tc17 Cells Elicits Antitumor Immunity against Established Melanoma through Distinct Mechanisms

Adoptive Transfer of Tc1 or Tc17 Cells Elicits Antitumor Immunity against Established Melanoma through Distinct Mechanisms

Adoptive T cell therapy for cancer in the clinic

Increased Intensity Lymphodepletion Enhances Tumor Treatment Efficacy of Adoptively Transferred Tumor-specific T Cells

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