Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model

Dai, Bailing; Qi, Na; Li, Junchao; Zhang, Guilong

doi:10.1016/j.bbrc.2018.05.064

Cited by 36 publications

(29 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…66 Combining anti-PD-1 with temozolomide, the standard of care for treatment of GBM, produces decreased tumor growth, increased TILs and improved survival when compared with monotherapy. [67][68][69] PD-1 blockade combined with oncolytic viral therapy has also been shown to increase survival in mice. 70 71 DC vaccines in combination with PD-1 inhibitors likewise demonstrate improved murine survival.…”

Section: Ctla-4mentioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

View full text Add to dashboard Cite

Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

show abstract

Section: Ctla-4mentioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…However, as relevant as eliciting the immune system is avoiding to impair its amplification, and here the IMS gains importance. In the GL261 mouse model, TMZ produces a significantly better survival rate when administered in a 6‐d cycle instead of in daily schedule of five consecutive days . Alkylating agents, including TMZ, are known to induce side effects related to the immune system such as leukopenia and neutropenia, when administered daily .…”

Section: Discussionmentioning

confidence: 99%

“…In the GL261 mouse model, TMZ produces a significantly better survival rate when administered in a 6-d cycle 30 instead of in daily schedule of five consecutive days. 43 Alkylating agents, including TMZ, are known to induce side effects related to the immune system such as leukopenia and neutropenia, when administered daily. 44 If TMZ is administered in a continuous schedule, the anti-tumour immune cycle may be hampered due to the inhibition of the proliferation of immune cells, such as primed CD8+ T lymphocytes.…”

Section: Ims-tmz Therapy May Establish Long-term Specific Anti-tumomentioning

confidence: 99%

Anti‐tumour immune response in GL261 glioblastoma generated by Temozolomide Immune‐Enhancing Metronomic Schedule monitored with MRSI‐based nosological images

Calero-Pérez

Villamañan

et al. 2020

NMR in Biomedicine

View full text Add to dashboard Cite

Glioblastomas (GB) are brain tumours with poor prognosis even after aggressive therapy. Improvements in both therapeutic and follow‐up strategies are urgently needed. In previous work we described an oscillatory pattern of response to Temozolomide (TMZ) using a standard administration protocol, detected through MRSI‐based machine learning approaches. In the present work, we have introduced the Immune‐Enhancing Metronomic Schedule (IMS) with an every 6‐d TMZ administration at 60 mg/kg and investigated the consistence of such oscillatory behaviour. A total of n = 17 GL261 GB tumour‐bearing C57BL/6j mice were studied with MRI/MRSI every 2 d, and the oscillatory behaviour (6.2 ± 1.5 d period from the TMZ administration day) was confirmed during response. Furthermore, IMS‐TMZ produced significant improvement in mice survival (22.5 ± 3.0 d for controls vs 135.8 ± 78.2 for TMZ‐treated), outperforming standard TMZ treatment. Histopathological correlation was investigated in selected tumour samples (n = 6) analyzing control and responding fields. Significant differences were found for CD3+ cells (lymphocytes, 3.3 ± 2.5 vs 4.8 ± 2.9, respectively) and Iba‐1 immunostained area (microglia/macrophages, 16.8% ± 9.7% and 21.9% ± 11.4%, respectively). Unexpectedly, during IMS‐TMZ treatment, tumours from some mice (n = 6) fully regressed and remained undetectable without further treatment for 1 mo. These animals were considered “cured” and a GL261 re‐challenge experiment performed, with no tumour reappearance in five out of six cases. Heterogeneous therapy response outcomes were detected in tumour‐bearing mice, and a selected group was investigated (n = 3 non‐responders, n = 6 relapsing tumours, n = 3 controls). PD‐L1 content was found ca. 3‐fold increased in the relapsing group when comparing with control and non‐responding groups, suggesting that increased lymphocyte inhibition could be associated to IMS‐TMZ failure. Overall, data suggest that host immune response has a relevant role in therapy response/escape in GL261 tumours under IMS‐TMZ therapy. This is associated to changes in the metabolomics pattern, oscillating every 6 d, in agreement with immune cycle length, which is being sampled by MRSI‐derived nosological images.

show abstract

“…9 In spite of growing research about the effect of irradiation and chemotherapy on T cell-mediated immunotherapies such as anti-PD1 and anti-CTLA4 Abs, the effect of irradiation or chemotherapy on innate immunemodulator therapeutics such as CD47 blockade Abs has yet to be fully elucidated. 10,11 Here, we evaluated whether irradiation or chemotherapy can enhance anti-CD47 treatment of GBM. We demonstrate that irradiation or TMZ chemotherapy enhanced anti-CD47 treatment by increasing macrophage-mediated phagocytosis of tumor cell in vitro.…”

Section: Introductionmentioning

confidence: 99%

Irradiation or temozolomide chemotherapy enhances anti-CD47 treatment of glioblastoma

et al. 2019

View full text Add to dashboard Cite

Irradiation and temozolomide (TMZ) chemotherapy are the current standard treatments for glioblastoma multiforme (GBM), but they are associated with toxicity and limited efficacy. Recently, these standard therapies have been used to enhance immunotherapy against GBM. Immunotherapy using the anti-CD47 (immune checkpoint inhibitor) treatment has shown promise in treating multiple tumor types, including GBM. The goal of this current work was to test whether irradiation or TMZ chemotherapy could enhance anti-CD47 treatment against GBM. Our results showed that irradiation and TMZ each significantly enhanced anti-CD47-mediated phagocytosis of GBM cells in vitro. Furthermore, mice engrafted with human GBM that received anti-CD47 combined with focal irradiation or TMZ treatment showed a significant increase in the survival rate compared to those that received a single treatment. The tumor growth in mice that received both anti-CD47 and irradiation was significantly less than that of groups that received either anti-CD47 or focal irradiation. The results from this study may support future use of anti-CD47 treatment in combination with irradiation or chemotherapy to enhance the therapeutic efficacy of GBM treatment.

show abstract

Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model

Cited by 36 publications

References 21 publications

T lymphocyte-targeted immune checkpoint modulation in glioma

T lymphocyte-targeted immune checkpoint modulation in glioma

Anti‐tumour immune response in GL261 glioblastoma generated by Temozolomide Immune‐Enhancing Metronomic Schedule monitored with MRSI‐based nosological images

Irradiation or temozolomide chemotherapy enhances anti-CD47 treatment of glioblastoma

Contact Info

Product

Resources

About