Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy

Walker, David G.; Shakya, Reshma; Morrison, Beth; Neller, Michelle A.; Matthews, Katherine; Nicholls, John M.; Smith, Corey; Khanna, Rajiv

doi:10.1002/cti2.1088

Cited by 10 publications

(11 citation statements)

References 26 publications

(46 reference statements)

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“…Due to the rapid progression of GBM, early immunotherapeutic intervention in addition to tumor debulking with surgery, radiotherapy, and chemotherapy is likely to provide the most effective means to augment OS in patients. We previously reported the use of autologous CMV-specific ACT in 11 patients with recurrent GBM, and recently provided an update on 4 of these patients who have demonstrated impressive OS of up to 9 years following treatment (24). However, due to the advanced stage of recurrent disease, we were unable to provide treatment for 8 patients recruited to this previous study (18).…”

Section: Discussionmentioning

confidence: 99%

“…Although the role of CMV in GBM remains controversial (19), the presence of foreign CMV antigens within GBM tissue makes this an attractive target for ACT (20)(21)(22)(23). Our initial studies using CMV-specific ACT against recurrent GBM provided encouraging clinical responses, with multiple patients showing prolonged OS (24). To assess whether earlier intervention with ACT improved patient outcomes, we initiated a phase I safety study utilizing CMV-specific ACT to treat GBM following primary resection and chemo/radiotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme

Smith¹,

Lineburg²,

Martins³

et al. 2020

Journal of Clinical Investigation

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BACKGROUND. The recent failure of checkpoint-blockade therapies for glioblastoma multiforme (GBM) in late-phase clinical trials has directed interest toward adoptive cellular therapies (ACTs). In this open-label, first-inhuman trial, we have assessed the safety and therapeutic potential of cytomegalovirus-specific (CMV-specific) ACT in an adjuvant setting for patients with primary GBM, with an ultimate goal to prevent or delay recurrence and prolong overall survival. METHODS. Twenty-eight patients with primary GBM were recruited to this prospective study, 25 of whom were treated with in vitro-expanded autologous CMV-specific T cells. Participants were monitored for safety, progression-free survival, overall survival (OS), and immune reconstitution. RESULTS. No participants showed evidence of ACT-related toxicities. Of 25 evaluable participants, 10 were alive at the completion of follow-up, while 5 were disease free. Reconstitution of CMV-specific T cell immunity was evident and CMVspecific ACT may trigger a bystander effect leading to additional T cell responses to nonviral tumor-associated antigens through epitope spreading. Long-term follow-up of participants treated before recurrence showed significantly improved OS when compared with those who progressed before ACT (median 23 months, range 7-65 vs. median 14 months, range 5-19; P = 0.018). Gene expression analysis of the ACT products indicated that a favorable T cell gene signature was associated with improved long-term survival. CONCLUSION. Data presented in this study demonstrate that CMV-specific ACT can be safely used as an adjuvant therapy for primary GBM and, if offered before recurrence, this therapy may improve OS of GBM patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme

Smith¹,

Lineburg²,

Martins³

et al. 2020

Journal of Clinical Investigation

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“…These data suggest that combining T-cell therapy with PD-1/PD-L1 blockade may improve overall survival of GBM patients. 83 Therefore, quantitative fluorescence multiplexed IHC technology as a platform for diagnostic and prognostic biomarker identification is poised to revolutionise traditional pathological interpretation.…”

Section: Future Clinical Applications Of Mfihcmentioning

confidence: 99%

“…While the long‐term survivors had significantly reduced number of CD3 + T cells in comparison with short‐term survivors, a proportion of short‐term survivors displayed higher PD‐L1 expression. These data suggest that combining T‐cell therapy with PD‐1/PD‐L1 blockade may improve overall survival of GBM patients 83 . Therefore, quantitative fluorescence multiplexed IHC technology as a platform for diagnostic and prognostic biomarker identification is poised to revolutionise traditional pathological interpretation.…”

Section: Future Clinical Applications Of Mfihcmentioning

confidence: 99%

Immune contexture analysis in immuno‐oncology: applications and challenges of multiplex fluorescent immunohistochemistry

et al. 2020

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The tumor microenvironment is an integral player in cancer initiation, tumor progression, response and resistance to anticancer therapy. Understanding the complex interactions of tumor immune architecture (referred to as 'immune contexture') has therefore become increasingly desirable to guide our approach to patient selection, clinical trial design, combination therapies, and patient management. Quantitative image analysis based on multiplexed fluorescence immunohistochemistry and deep learning technologies are rapidly developing to enable researchers to interrogate complex information from the tumor microenvironment and find predictive insights into treatment response. Herein, we discuss current developments in multiplexed fluorescence immunohistochemistry for immune contexture analysis, and their application in immuno-oncology, and discuss challenges to effectively use this technology in clinical settings. We also present a multiplexed image analysis workflow to analyse fluorescence multiplexed stained tumor sections using the Vectra Automated Digital Pathology System together with FCS express flow cytometry software. The benefit of this strategy is that the spectral unmixing accurately generates and analyses complex arrays of multiple biomarkers, which can be helpful for diagnosis, risk stratification, and guiding clinical management of oncology patients.

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“…T cell apoptosis caused by sepsis is now considered to be associated with the programmed death ligand-1 (PD-L1)-programmed death-1 (PD-1) signaling axis, and the increase in PD-L1 expression during sepsis is an important indicator of immunosuppression ( 9 ). Immunotherapy targeting the PD-1/PD-L1 signaling axis is a hot topic in current research, and the tumor microenvironment is an important factor affecting the effect of this immunotherapy for numerous tumors, such as lung tumor, glioblastoma multiforme and colon cancer ( 10 – 12 ). Atezolizumab is an anti-PD-L1 antibody that inhibits binding of PD-L1 to its receptor PD-1, thereby restoring the suppression of T lymphocyte activity ( 13 , 14 ), and has shown efficacy in numerous types of cancer including locally advanced and metastatic urothelial carcinoma, non-small-cell lung cancer and metastatic renal cell carcinoma ( 15 – 17 ).…”

Section: Introductionmentioning

confidence: 99%

Atezolizumab alleviates the immunosuppression induced by PD‑L1‑positive neutrophils and improves the survival of mice during sepsis

Chen

Huang

et al. 2020

Mol Med Rep

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Atezolizumab can reduce immunosuppression caused by T lymphocyte apoptosis in various cancer types. The current study aimed to investigate whether this drug can also alleviate immunosuppression during sepsis. For that purpose, a C57BL/6 mouse sepsis model was generated. Mice were randomly assigned to three groups: Sham, cecal ligation and puncture (CLP) and atezolizumab groups. Atezolizumab was administered in vivo by intraperitoneal injection. The expression of programmed death ligand-1 (PD-L1) on neutrophils and programmed death-1 (PD-1) on T lymphocytes was evaluated, and endotoxin concentration, intestinal permeability, ileum histopathological score and tight junction protein expression were assessed to determine the extent of disease in each group. The rate of T lymphocyte apoptosis was determined to assess the effects of atezolizumab on T lymphocyte apoptosis in vivo and in vitro . Survival times were also recorded to compare mouse prognosis during sepsis. In the CLP group, the proportion of PD-L1 + neutrophils was significantly higher at 48, 72 and 96 h in blood, and at 24, 48, 72 and 96 h in bone marrow, compared with those of the sham group (P<0.05). The proportion of PD-1 + T lymphocytes was also upregulated at 72 h in blood. In the atezolizumab group, endotoxin concentration, intestinal permeability and ileum histopathological score were lower compared with those in the CLP group (P<0.05), whereas the expression of claudin-1 and occludin proteins on ileum was higher compared with that in the CLP group (P<0.05). Both in vivo and in vitro experiments indicated that the rate of T lymphocyte apoptosis following atezolizumab treatment was lower compared with that in the CLP group (P<0.05). Survival analysis demonstrated that mice in the atezolizumab group survived longer compared with those in the CLP group (P<0.05). The current study demonstrated that treatment with atezolizumab may be an effective method for treating immunosuppression induced by sepsis.

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Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy

Cited by 10 publications

References 26 publications

Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme

Autologous CMV-specific T cells are a safe adjuvant immunotherapy for primary glioblastoma multiforme

Immune contexture analysis in immuno‐oncology: applications and challenges of multiplex fluorescent immunohistochemistry

Atezolizumab alleviates the immunosuppression induced by PD‑L1‑positive neutrophils and improves the survival of mice during sepsis

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