Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell–mediated glioma rejection

Berg, Johannes vom; Vrohlings, Melissa; Haller, Sergio; Haimovici, A; Kulig, Paulina; Śledzińska, Anna; Weller, Michael; Becher, Burkhard

doi:10.1084/jem.20130678

Cited by 171 publications

(89 citation statements)

References 33 publications

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“…Local administration of recombinant IL-12 in combination with inhibition of cytotoxic Tlymphocyte associated antigen 4 (CTLA4), which is believed to be important for the immunosuppressive functions of T regs , led to complete regression of established tumors. This is in line with the notion that a preponderance of T regs contributes to a feeble immune response in glioblastoma [104]. Taken together, these data suggest that IL-12 has marked anti-tumorigenic potential but that the precise mechanism of action seem to vary greatly depending on the type of tumor and the experimental condition.…”

Section: Cancersupporting

confidence: 88%

Interleukin-12: Functional activities and implications for disease

Zundler

Neurath

2015

Cytokine & Growth Factor Reviews

168

131

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Section: Cancersupporting

confidence: 88%

Interleukin-12: Functional activities and implications for disease

Zundler

Neurath

2015

Cytokine & Growth Factor Reviews

168

131

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“…Studies were excluded because of following reasons: (1) not sufficient survival data reported, (2) letters, reviews, commentary, perspectives, case reports, conference abstracts, editorials or expert opinion, (3) studies reporting xenograft results in immunodeficient or humanized mice. Overall these search criteria helped short-list 15 research articles 12,15,16,[50][51][52][53][54][55][56][57][58][59][60][61] mentioned in Box S1.…”

Section: Methodsmentioning

confidence: 99%

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

et al. 2017

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Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also "guide and prioritize" preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression. Based on these analyses, we found that predictive biomarkers of ICI responsiveness exhibited inconsistent patterns in GBM patients, i.e., they either predicted ICI resistance (as compared with typical ICI-responsive cancer-types like melanoma, lung cancer or bladder cancer) or susceptibility to therapeutic targeting of CTLA4 or IDO1. On the other hand, our comprehensive literature meta-analysis and preclinical testing of ICIs using an orthotopic GL261-glioma mice model, indicated significant antitumor properties of anti-PD1 antibody, whereas blockade of IDO1 or CTLA4 either failed or provided very marginal advantage. These trends raise the need to better assess the applicability of ICIs and associated biomarkers for GBM.

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“…Combination therapy with i.t. IL-12 and systemic anti-CTLA-4 led to eradication of murine glioblastoma in mouse [88]. I.t.…”

Section: It Immunotherapy With Cytokinesmentioning

confidence: 98%

Intratumoral immunotherapy for melanoma

Singh

Overwijk

2015

Cancer Immunol Immunother

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Selection of suitable tumor-associated antigens is a major challenge in the development of effective cancer vaccines. Intratumoral (i.t.) immunotherapy empowers the immune system to mount T cell responses against tumor-associated antigens which are most immunogenic. To mediate systemic tumor regression, i.t. immunotherapy must generate systemic T cell responses that can target distant metastases beyond the initially treated tumor mass. Now that promising preclinical results and some initial success in clinical trials have been obtained, we here review i.t. immunotherapy-related preclinical and clinical studies, their mechanisms of action and future prospects.

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Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell–mediated glioma rejection

Abstract: T cells are crucial effectors of glioma rejection induced by local IL-12 application and CTLA-4 blockade.

Cited by 171 publications

References 33 publications

Interleukin-12: Functional activities and implications for disease

Interleukin-12: Functional activities and implications for disease

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

Intratumoral immunotherapy for melanoma

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