Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8<sup>+</sup>T cells

Hanoteau, Aurélie; Henin, Coralie; Švec, David; Donnet, Charlotte Bisilliat; Denanglaire, Sébastien; Colau, Didier; Romero, Pedro; Léo, Oberdan; Eynde, Benoı̂t J. Van den; Moser, Muriel

doi:10.1080/2162402x.2017.1318234

Cited by 14 publications

(13 citation statements)

References 35 publications

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“…However, we evidenced that the combined chemo-immunotherapy expanded dominant clonotypes with high avidity and anti-tumor activity (Figure 2░C-E), confirming that DNA-targeting drugs such as DTIC strongly influence the anti-tumor specific T-cell response. 16 , 18 , 20 , 40–42 …”

Section: Discussionmentioning

confidence: 99%

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

et al. 2018

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We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8+ Melan-A-specific T-cell functionality, enlarges the Melan-A+ TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8+ T cells, in the same patients previously analyzed for Melan-A. We found that T-cell clones isolated from patients treated with vaccination alone possessed an Early/intermediate differentiated phenotype, whereas T cells isolated after DTIC plus vaccination were late-differentiated. Sequencing analysis of the TCRBV chains of 29 treatment-driven gp100-specific CD8+ T-cell clones revealed an oligoclonal TCR repertoire irrespective of the treatment schedule. The high anti-tumor activity observed in T cells isolated after chemo-immunotherapy was associated with low PD-1 expression. Differently, T-cell clones isolated after peptide-vaccination alone expressed a high level of PD-1, along with LAG-3 and TIM-3, and were neither tumor-reactive nor polyfunctional. Blockade of PD-1 reversed gp100-specific CD8+ T-cell dysfunctionality, confirming the direct role of this co-inhibitory molecule in suppressing anti-tumor activity, differently from what we have previously observed for Melan-A+CD8+ T cells, expressing PD-1 but highly functional. These findings indicate that the functional advantage induced by combined chemo-immunotherapy is determined by the tumor antigen nature, T-cell immune-checkpoints phenotype, TCR repertoire diversity and anti-tumor T-cell quality and highlights the importance of integrating these parameters to develop effective immunotherapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

et al. 2018

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“…2002; Hanoteau et al. 2017). Therefore, we can speculate that by increasing the rate at which the oncolytic virus infects the tumour cells (e.g., by focusing on the reduction of physical barriers inside the tumour, which allows for better virus spread (Alzahrani et al.…”

Section: Resultsmentioning

confidence: 99%

Investigating Macrophages Plasticity Following Tumour–Immune Interactions During Oncolytic Therapies

Eftimie

2019

Acta Biotheor

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Over the last few years, oncolytic virus therapy has been recognised as a promising approach in cancer treatment, due to the potential of these viruses to induce systemic anti-tumour immunity and selectively killing tumour cells. However, the effectiveness of these viruses depends significantly on their interactions with the host immune responses, both innate (e.g., macrophages, which accumulate in high numbers inside solid tumours) and adaptive (e.g., T cells). In this article, we consider a mathematical approach to investigate the possible outcomes of the complex interactions between two extreme types of macrophages (M1 and M2 cells), effector T cells and an oncolytic Vesicular Stomatitis Virus (VSV), on the growth/elimination of B16F10 melanoma. We discuss, in terms of VSV, and macrophages levels, two different types of immune responses which could ensure tumour control and eventual elimination. We show that both innate and adaptive anti-tumour immune responses, as well as the oncolytic virus, could be very important in delaying tumour relapse and eventually eliminating the tumour. Overall this study supports the use mathematical modelling to increase our understanding of the complex immune interaction following oncolytic virotherapies. However, the complexity of the model combined with a lack of sufficient data for model parametrisation has an impact on the possibility of making quantitative predictions.

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“…[196][197][198] In this context, 9 GBM patients refractory to standard-of-care temozolomide-based chemotherapy, 199 radiation therapy, surgery or targeted therapy with bevacizumab 200,201 received Gliovac plus recombinant GM-CSF following a T REG -depleting course of cyclophosphamide, 202 resulting in superior survival rates as compared to historical controls. [203][204][205] As the treatment was associated with limited toxicity, a Phase II study has been initiated to evaluate this immunotherapeutic approach in a larger cohort of GBM patients including bevacizumab-na€ ıve individuals (NCT01903330). Along similar lines, Rampling and colleagues (from the Beatson West of Scotland Cancer Centre, Glasgow, UK) evaluated a peptide-based vaccine (IMA950) 206,207 plus recombinant GM-CSF along with standard chemoradiotherapy and adjuvant temozolomide for the treatment of patients with newly-diagnosed GBM.…”

Section: Completed Clinical Studiesmentioning

confidence: 99%

“…The therapeutic profile of IFN-a2a is being assessed: (1) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma following tumor resection (NCT03253250); (2) in subjected with RCC concomitantly receiving bevacizumabbased therapy (NCT02627144); (3) in individuals with neuroendocrine tumors in the context of chemotherapy with metronomic cyclophosphamide 203,[268][269][270][271] (NCT02838342); and (4) in patients with advanced tumors previously responding to IFN-a2a, in the context of maintenance therapy (NCT02829775). The safety and preliminary efficacy of IFN-a2b are being assessed: (1) in patients with human T-cell lymphotropic virus type I (HTLV-I)-derived adult T-cell leukemia/lymphoma concomitantly receiving belinostat (an FDA-approved histone deacetylase inhibitor) 272,273 and zidovudine (an antiretroviral agent) 274 (NCT02737046); (2) in women with breast cancer in the context of targeted immunotherapy plus metronomic cyclophosphamide (NCT03066947; NCT03328026); (3) in patients with hematological malignancies including CML, as a standalone immunotherapeutic intervention for maintenance purposes (NCT03117816; NCT02634294); (4) in individuals with cholangiocarcinoma receiving pembrolizumab (NCT02982 720); (5) in subjects with hepatocellular carcinoma receiving capecitabine-based chemotherapy 275,276 (NCT02576964); (6) in patients with soft tissue sarcoma receiving microdosed IFN-a2b together with multiple other therapeutic agents via a specific delivery device (NCT03056599); and (6) in women with gynecological tumors, as an intraperitoneal infusion combined with recombinant IFN-g 277,278 and autologous monocytes (NCT02948426).…”

Section: Recently Initiated Clinical Trialsmentioning

confidence: 99%

Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy

et al. 2018

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Cytokines regulate virtually aspects of innate and adaptive immunity, including the initiation, execution and extinction of tumor-targeting immune responses. Over the past three decades, the possibility of using recombinant cytokines as a means to elicit or boost clinically relevant anticancer immune responses has attracted considerable attention. However, only three cytokines have been approved so far by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, namely, recombinant interleukin (IL)-2 and two variants of recombinant interferon alpha 2 (IFN-α2a and IFN-α2b). Moreover, the use of these cytokines in the clinics is steadily decreasing, mostly as a consequence of: (1) the elevated pleiotropism of IL-2, IFN-α2a and IFN-α2b, resulting in multiple unwarranted effects; and (2) the development of highly effective immunostimulatory therapeutics, such as immune checkpoint blockers. Despite this and other obstacles, research in the field continues as alternative cytokines with restricted effects on specific cell populations are being evaluated. Here, we summarize research preclinical and clinical developments on the use of recombinant cytokines for immunostimulation in cancer patients.

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Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8⁺T cells

Cited by 14 publications

References 35 publications

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

Investigating Macrophages Plasticity Following Tumour–Immune Interactions During Oncolytic Therapies

Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy

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Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8+T cells

Cited by 14 publications

References 35 publications

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

Investigating Macrophages Plasticity Following Tumour–Immune Interactions During Oncolytic Therapies

Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy

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Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8⁺T cells