TCR Sequencing Can Identify and Track Glioma- Infiltrating T Cells after DC Vaccination

Hsu, MS; Sedighim, S; Wang, T; Antonios, JP; Everson, R. Garth; Am, Tucker; Du, L; Emerson, RO; Yusko, E; Sanders, C; Robins, HS; Yong, WH; Davidson, TB; Li, G; :Liau, LM; Prins, RM

doi:10.21417/b7d59f

Cited by 14 publications

(16 citation statements)

References 21 publications

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“…Thus various techniques that can amplify dendritic cell based, tumor specific, immune response, are currently under investigation. Targeted patient selection (pSTAT signaling, mesenchyman gene expression signature, TCR), 47,48 administration of adjuvant treatments (tetanus, polyICLC, imiquimod), 26,49 as well as novel tumor antigen generation and delivery strategies (CMV RNA, cocktail of peptides) 50,51 are being trialed aiming to improve the specificity and the efficiency of the technique.…”

Section: Discussionmentioning

confidence: 99%

Immune infiltration of tumor microenvironment following immunotherapy for glioblastoma multiforme

Sokratous

Polyzoidis

Ashkan

2017

Human Vaccines & Immunotherapeutics

109

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Autologous dentritic cell immunotherapy has been proven effective in treating tumors outside the central nervous system. Current evidence from phase I and II trials suggest a similar efficacy for central nervous system tumors as well and that an active immune response against these tumors can be generated. We aim to review the literature to identify the types of immune responses against gliomas found to be generated by dendritic cell vaccinations and the types of immune cells subsequently infiltrating the glioma microenvironment. A systematic review of the literature was performed by searching the online databases PubMEd, Google Scholar, and EMBASE with use of the keywords intratumoral, infiltration, lymphocytic, vaccination and gliomas. Seven studies reporting lymphocytic infiltration of gliomas microenvironment were identified. Three studies (42.8%) reported presence of tumor infiltrating lymphocytes in 50%, 50% and 28.6% of included patients respectively in the post-vaccination specimens that were not present in the pre-vaccination samples. The remaining 4 (57.2%) reported an up to 6-fold increase in the number of pre-existing lymphocytes following vaccination. Present data indicate that tumor infiltration by lymphocytes can be induced by dentritic cell immunotherapy and that this may positively affect clinical outcome. It still remains unclear which factors influence the above reaction and therefore prediction of response to treatment is still not possible.

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Section: Discussionmentioning

confidence: 99%

Immune infiltration of tumor microenvironment following immunotherapy for glioblastoma multiforme

Sokratous

Polyzoidis

Ashkan

2017

Human Vaccines & Immunotherapeutics

109

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“…We extracted genomic DNA from sorted CD3 þ PD-1 þ and CD3 þ PD-1 À T cells from malignant glioma patient TILs and PBMCs and from healthy donor PBMCs using DNeasy Blood & Tissue Kit (Qiagen catalog no. 69504) and sequenced DNA at the T-cell receptor (TCR) V-b CDR3 region using high-throughput sequencing in collaboration with Adaptive Biotechnologies, as we have recently published (24).…”

Section: Tcr V-b Sequencingmentioning

confidence: 99%

Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation

Davidson

Lee

Hsu

et al. 2019

Clinical Cancer Research

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Purpose: Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Our recent preclinical work has suggested that PD-1/PD-L1 plays an important immunoregulatory role to limit effective antitumor T-cell responses induced by active immunotherapy. However, little is known about the functional role that PD-1 plays on human T lymphocytes in patients with malignant glioma. Experimental Design: In this study, we examined the immune landscape and function of PD-1 expression by T cells from tumor and peripheral blood in patients with malignant glioma. Results: We found several differences between PD-1 þ tumor-infiltrating lymphocytes (TIL) and patient-matched PD-1 þ peripheral blood T lymphocytes. Phenotypically, PD-1 þ TILs exhibited higher expression of markers of activation and exhaustion than peripheral blood PD-1 þ T cells, which instead had increased markers of memory. A comparison of the T-cell receptor variable chain populations revealed decreased diversity in T cells that expressed PD-1, regardless of the location obtained. Functionally, peripheral blood PD-1 þ T cells had a significantly increased proliferative capacity upon activation compared with PD-1 À T cells. Conclusions: Our evidence suggests that PD-1 expression in patients with glioma reflects chronically activated effector T cells that display hallmarks of memory and exhaustion depending on its anatomic location. The decreased diversity in PD-1 þ T cells suggests that the PD-1-expressing population has a narrower range of cognate antigen targets compared with the PD-1 nonexpression population. This information can be used to inform how we interpret immune responses to PD-1-blocking therapies or other immunotherapies.

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“…glioblastoma | PET | MRI | immunotherapy | checkpoint blockade G lioblastoma (GBM), the most common primary malignancy of the brain, occurs in both the young and the elderly, with swift and devastating outcomes. While advances in immunotherapy are beginning to reach clinical relevance in GBM (1-4), a corresponding improvement in effective monitoring of the immune response is lacking (5)(6)(7). T lymphocytes are the most critical immune cell type for immune surveillance of cancer.…”

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confidence: 99%

Detection of immune responses after immunotherapy in glioblastoma using PET and MRI

Antonios

Soto

Everson

et al. 2017

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

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Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast-enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [18F]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [18F]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [18F]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [18F]-clofarabine ([18F]-CFA), that may be more clinically relevant. Enhanced [18F]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors.

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TCR Sequencing Can Identify and Track Glioma- Infiltrating T Cells after DC Vaccination

Cited by 14 publications

References 21 publications

Immune infiltration of tumor microenvironment following immunotherapy for glioblastoma multiforme

Immune infiltration of tumor microenvironment following immunotherapy for glioblastoma multiforme

Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation

Detection of immune responses after immunotherapy in glioblastoma using PET and MRI

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