Immunotherapy with subcutaneous immunogenic autologous tumor lysate increases murine glioblastoma survival

Abstract

Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether ‘targeting’ in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas.

Immune phenotyping of diverse syngeneic murine brain tumors identifies immunologically distinct types

“…Based on TCGA (The Cancer Genome Atlas) data for gene expression profiling and mutational spectrum that revealed immune phenotypic differences in different GBM subtypes 17,18 , we hypothesized that the tumor models generated from mouse tumor lines with distinct background would have differences in their immune profiles. This is further strengthened by previous findings showing that immunotherapy with autologous tumor lysates of GL261 and CT2A has a differential response with better efficacy in CT2A tumors 11 .…”

“…In this study, we report a plethora of immune-phenotypic data that can be utilized to make better choices of the mouse model to be used for testing various antitumor therapies. We report higher frequency of Ly6C+ macrophages in CT2A that mediate efferocytosis and cross presentation of antigens that can explain why CT2A responds better to vaccination with autologous lysate, as compared to GL261 tumors 57 .…”

Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses

“…To determine whether monocyte vaccination would be efficacious in more aggressive tumors, we examined a model of glioblastoma (GBM) in which mice were injected intracranially (IC) with CT-2A astrocytoma tumor cells. To our knowledge, no vaccine has been shown to prolong survival in this model (37). Because TRP2 is an antigenic target in human GBM (38), we injected TRP2transfected CT-2A cells and treated mice with dose-matched IV TRP2-monocytes, IV TRP2-DCs, or SQ TRP2-DCs, beginning 2 days after tumor inoculation.…”

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

“…GBM is located in the immune-privileged CNS together with an array of immunosuppressive defense mechanisms that make it a challenging target for immunotherapy [2,40]. Despite these challenges, vaccines have shown activity against high-grade gliomas [15,18]. Preclinical and early clinical data reinforce the notion that long-lasting remission is possible with immunotherapy [41,42].…”

“…Active immunotherapeutic strategies are being evaluated to direct the adaptive immune system to target residual GBM cells remaining after standard treatment [7]. Whole cell vaccine-based immunotherapy as monotherapy or in combination with irradiation or immunomodulatory substances has shown efficacy in experimental gliomas [11][12][13][14][15][16] and has been tested in patients with malignant gliomas, with partial clinical responses [17,18]. Immunotherapeutic strategies can potentially generate a cellular antitumor immune response against different neo-antigens on tumor cells even in their non-dividing stage, with a relatively low risk of side effects [19].…”