Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma

Schalper, Kurt A.; Rodríguez-Ruiz, María E.; Díez-Valle, Ricardo; López-Janeiro, Álvaro; Porciuncula, Angelo; Idoate, Miguel A.; Inogés, Susana; Andrea, Carlos de; Cerio, Ascensión López‐Díaz de; Tejada, Sonia; Berraondo, Pedro; Villarroel‐Espíndola, Franz; Choi, Jungmin; Gúrpide, Alfonso; Giráldez, Miriam; Goicoechea, Iosune; Pérez-Larraya, Jaime Gállego; Sanmamed, Miguel F.; Perez-Gracia, José Luis; Melero, Ignacio

doi:10.1038/s41591-018-0339-5

Cited by 477 publications

(350 citation statements)

References 36 publications

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“…The authors proposed that this led to systemic priming of T cells and therefore the effective production of anti‐tumor T‐cell clones. Similar results have been found by others using neoadjuvant nivolumab . In the latter study, neoadjuvant nivolumab did not appear to result in prolonged survival of the treated patients; however, their results suggested that combined immunotherapies may be more efficacious …”

Section: Discussionsupporting

confidence: 86%

“…Similar results have been found by others using neoadjuvant nivolumab. 21 In the latter study, neoadjuvant nivolumab did not appear to result in prolonged survival of the treated patients; however, their results suggested that combined immunotherapies may be more efficacious. 22 Our preliminary studies in patients from our phase I study suggested that there are differences between patients who displayed long-term survival compared with those who did not.…”

Section: Discussionmentioning

confidence: 88%

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

et al. 2019

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Objectives Clinical response to antibody‐based immunotherapies targeting checkpoint inhibitors is critically dependent on the tumor immune microenvironment (TIME). However, the precise impact of the TIME on adoptive cellular immunotherapy remains unexplored. Here we have conducted a long‐term follow‐up analysis of patients with recurrent glioblastoma multiforme (GBM) who were treated with autologous CMV‐specific T‐cell therapy to delineate the potential impact of the TIME on their clinical response. Methods Multiplexed immunohistochemical analysis of CD3, PD‐L1 and Sox‐2 in GBM tissue biopsies obtained before autologous T‐cell therapy was carried out and correlated with long‐term survival of GBM patients adoptively treated with T‐cell therapy. Results Tumor microenvironment analyses revealed that the pre‐treatment cellular composition of the tumor tissue may influence the subsequent response to adoptive T‐cell therapy. GBM patients who showed prolonged overall survival following T‐cell therapy had a significantly lower number of tumor‐infiltrating CD3+ T cells in recurrent tumors than that in patients with short‐term survival. Furthermore, long‐term surviving patients showed low or undetectable PD‐L1 expression in tumor cells in recurrent GBM biopsies. Conclusion We hypothesise that lack of PD‐L1‐mediated immunosuppression in the TIME may allow efficient immune control following adoptive T‐cell therapy. Future studies combining anti‐PD‐L1 or genetically modified T cells with PD‐1 receptor knockdown could be considered to improve clinical responses in patients who have high PD‐L1 expression in their tumors.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 88%

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

et al. 2019

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“…18 In other trial arms exploring combinations of nivolumab with ipilimumab, the response rate was a disappointing 7%. [20][21][22] Although acute ICI sensitivity of tumors with a high mutation burden, because of mismatch repair deficiency has been described, 23,24 recent data suggest that only 3.5% of primary or recurrent glioblastoma patients had a high somatic tumor mutation burden and so may benefit from ICI therapy. [20][21][22] Although acute ICI sensitivity of tumors with a high mutation burden, because of mismatch repair deficiency has been described, 23,24 recent data suggest that only 3.5% of primary or recurrent glioblastoma patients had a high somatic tumor mutation burden and so may benefit from ICI therapy.…”

Section: Standard Treatment and Prognosismentioning

confidence: 99%

“…19 In three recently reported studies of neoadjuvant anti-PD1 therapy in recurrent glioblastoma patients, although clinical responses were lacking, evidence on surgical resection specimens of persistent T-cell inflammation and pro-inflammatory cytokine profiles tended to favor an improved prognosis and may suggest a rationale for ICI use in conjunction with CAR-T cell therapy. [20][21][22] Although acute ICI sensitivity of tumors with a high mutation burden, because of mismatch repair deficiency has been described, 23,24 recent data suggest that only 3.5% of primary or recurrent glioblastoma patients had a high somatic tumor mutation burden and so may benefit from ICI therapy. 2 Notwithstanding promising case reports, [25][26][27][28] formal testing of the sensitivity of this group of patients to ICI therapy is awaited.…”

Section: Immune Checkpoint Inhibitor (Ici) Therapymentioning

confidence: 99%

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

2019

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Chimeric antigen receptor (CAR)‐T cell therapy is now approved in the United States and Europe as a standard treatment for relapsed/refractory B‐cell malignancies. It has also been approved recently by the Therapeutic Goods Administration in Australia and may soon be publicly reimbursed. This advance has accentuated scientific, clinical and commercial interest in adapting this exciting technology for the treatment of solid cancers where it is widely recognised that the challenges of overcoming a hostile tumor microenvironment are most acute. Indeed, CAR‐T cell technology may be of the greatest value for those cancers that lack pre‐existing immunity because they are immunologically ‘cold’, or have a low somatic tumor mutation load, or both. These cancers are generally not amenable to therapeutic immune checkpoint blockade, but CAR‐T cell therapy may be effective because it provides an abundant supply of autologous tumor‐specific T cells. This is achieved by using genetic engineering to re‐direct autologous T‐cell cytotoxicity towards a tumor‐associated antigen, bypassing endogenous T‐cell requirements for antigen processing, MHC‐dependent antigen presentation and co‐stimulation. One of the most challenging solid cancers is glioblastoma, which has among the least permissive immunological milieu of any cancer, and which is almost always fatal. Here, we argue that CAR‐T cell technology may counter some glioblastoma defences and provide a beachhead for furthering our eventual therapeutic aims of restoring effective antitumor immunity. Although clinical investigation of CAR‐T cell therapy for glioblastoma is at an early stage, we discuss three recently published studies, which feature significant differences in target antigen, CAR‐T cell phenotype, route of administration and tumor response. We discuss the lessons, which may be learned from these studies and which may guide further progress in the field.

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“…Several preclinical studies have shown benefit in blocking PD‐1 or CTLA‐4 in murine glioma models. Importantly, two recent clinical reports have shown benefit for neoadjuvant anti‐PD‐1 immunotherapy in promoting survival and modifying the TME in glioma patients. These promising reports suggest that blocking PD‐1 changes the TME and could synergize with CAR T therapy in improving the survival of glioma patients.…”

Section: Car T Cells and The Suppressive Microenvironment Of Brain Tumentioning

confidence: 99%

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

163

149

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Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

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Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma

Cited by 477 publications

References 36 publications

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

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

Clinical chimeric antigen receptor‐T cell therapy: a new and promising treatment modality for glioblastoma

CAR T cells for brain tumors: Lessons learned and road ahead

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