Phase 2 trial of SL-701 in relapsed/refractory (r/r) glioblastoma (GBM): Correlation of immune response with longer-term survival.

Peereboom, David M.; Nabors, Louis B.; Kumthekar, Priya; Badruddoja, Michael; Fink, Karen; Lieberman, Frank S.; Phuphanich, Surasak; Dunbar, Erin; Walbert, Tobias; Schiff, David; Tran, David; Ashby, Lynn S.; Butowski, Nicholas; Iwamoto, Fábio M.; Lindsay, Ross; Bullington, J.; Schulder, Michael; Sherman, Jonathan H.; Goswami, Trishna; Reardon, David A.

doi:10.1200/jco.2018.36.15_suppl.2058

Cited by 11 publications

(5 citation statements)

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“…For examples, we identified in HROG02 cells three HLA-A∗02:01 immunogenic epitopes that have been included in the IMA950 vaccine, TMLARASA from CDPG4, KIQEILTQV from IGF2BP3, and AMTQLLAGV from TNC ( 60 , 61 ). Importantly, we identified 279 HLA-II peptides that have not yet been reported to be presented on GBM cells that are derived from known GBM-associated tumor-antigens that have been used previously as sources for short or long-peptide-based vaccine trials in GBM ( 23 , 24 , 25 , 61 , 71 ). If shown to be immunogenic, novel immunotherapeutic approaches could be developed in the future to target them.…”

Section: Discussionmentioning

confidence: 99%

CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens

Forlani

Michaux

Pak

et al. 2021

Molecular & Cellular Proteomics

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CD4+ T cell responses are crucial for inducing and maintaining effective anti-cancer immunity, and the identification of human leukocyte antigen class II (HLA-II) cancer-specific epitopes is key to the development of potent cancer immunotherapies. In many tumor types, and especially in glioblastoma (GBM), HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in GBM. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed and sensitive mass spectrometry based immunopeptidomics analysis, we here uncovered a remarkable breadth of the HLA-ligandome in HROG02, HROG17 and RA GBM cell lines. The effect of CIITA expression on the induction of the HLA-II presentation machinery was striking in each of the three cell lines, and it was significantly higher compared to interferon gamma (IFNɣ) treatment. In total, we identified 16,123 unique HLA-I peptides and 32,690 unique HLA-II peptides. In order to genuinely define the identified peptides as true HLA ligands, we carefully characterized their association with the different HLA allotypes. In addition, we identified 138 and 279 HLA-I and HLA-II ligands, respectively, most of which are novel in GBM, derived from known GBM-associated tumor-antigens that have been used as source proteins for a variety of GBM vaccines. Our data further indicate that CIITA-expressing GBM cells acquired an antigen presenting cell-like phenotype as we found that they directly present external proteins as HLA-II ligands. Not only that CIITA-expressing GBM cells are attractive models for antigen discovery endeavors, but also such engineered cells have great therapeutic potential through massive presentation of a diverse antigenic repertoire.

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Section: Discussionmentioning

confidence: 99%

CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens

Forlani

Michaux

Pak

et al. 2021

Molecular & Cellular Proteomics

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“…One difficulty in testing new therapies is the relative few number of patients that present with GBM in comparison to the total number of therapies on trial. To remedy this, many trials have begun to use historical control groups and may combine clinical phase I and II or phase II and III testing in certain cases (40)(41)(42)(43).…”

Section: Current Immunotherapies For Gbmmentioning

confidence: 99%

“…SL-701 is a vaccine therapy with adjuvants GM-CSF and imiquimod that has completed phase 2 testing. This vaccine is comprised of synthetic peptides designed to elicit an immune response against interleukin-13 receptor alpha-2, ephrinA2 and survivin ( 40 ). Although an initial report suggested a possible survival tail in refractory GBM patients, full data has not been released.…”

Section: Synergy In Immunotherapy and Antiangiogenic Agents In Gbmmentioning

confidence: 99%

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

2022

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Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

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“…(for n = 15) ( P = N/A) [ 69 ] DCVax-L NCT00045968 1) DCVax-L (tumor lysate-pulsed DC vaccine) 2) PBMC (control) III ( n = 348) Newly diagnosed GBM mOS: 23.1 mos. (95% CI 21.2–25.4; P = N/A) [ 70 ] NCT02078648 SL701/GM-CSF + poly-ICLC and bevacizumab I/II ( n = 74) HLA-A2 + recurrent GBM Stage 1 OS-12: 37% Stage 2 OS-12: 43% ( P = N/A) [ 71 ] I-ATTAC NCT03927222 CMV pp65-LAMP mRNA-pulsed DCs/GM-CSF/Td + TMZ II ( n = 48) Newly diagnosed, CMV + MGMT unmethylated GBM Recruiting ACTION NCT03334305 TTRNA (tumor RNA) pulsed DCs/GM-CSF/Td ± HSCs I ( n = 8) HGG Recruiting NCT01204684 Tumor lysate-pulsed DCs ± resiquimod or poly-ICLC II ( n = 60) New or recurrent HGG Active NCT03382977 VBI-1901/GM-CSF I/II ( n = 38) Recurrent, IDH-1/2 wildtype GBM Recruiting GBM: Checkpoint inhibitors CheckMate 143 NCT02017717 1) Nivolumab 2) Bevacizumab III ( n = 626) Newly diagnosed, first recurrence, or MGMT unmethylated GBM 1) mOS: 9.8 mos. 2) mOS: 10.0 mos.…”

Section: Recent Advances In Immunotherapymentioning

confidence: 99%

Current Advances in Immunotherapy for Glioblastoma

et al. 2021

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Purpose of Review This review seeks to inform oncology clinicians and researchers about the development of novel immunotherapies for the treatment of glioblastoma. An enumeration of ongoing and recently completed clinical trials will be discussed with special attention given to current technologies implemented to overcome central nervous system–specific challenges including barriers to the peripheral immune system, impaired antigen presentation, and T cell dysfunction. Recent Findings The success of immunotherapy in other solid cancers has served as a catalyst to explore its application in glioblastoma, which has limited response to other treatments. Recent developments include multi-antigen vaccines that seek to overcome the heterogeneity of glioblastoma, as well as immune checkpoint inhibitors, which could amplify the adaptive immune response and may have promise in combinatorial approaches. Additionally, oncolytic and retroviruses have opened the door to a plethora of combinatorial approaches aiming to leverage their immunogenicity and/or ability to carry therapeutic transgenes. Summary Treatment of glioblastoma remains a serious challenge both with regard to immune-based as well as other therapeutic strategies. The disease has proven to be highly resistant to treatment due to a combination of tumor heterogeneity, adaptive expansion of resistant cellular subclones, evasion of immune surveillance, and manipulation of various signaling pathways involved in tumor progression and immune response. Immunotherapeutics that are efficacious in other cancer types have unfortunately not enjoyed the same success in glioblastoma, illustrating the challenging and complex nature of this disease and demonstrating the need for development of multimodal treatment regimens utilizing the synergistic qualities of immune-mediated therapies.

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Phase 2 trial of SL-701 in relapsed/refractory (r/r) glioblastoma (GBM): Correlation of immune response with longer-term survival.

Cited by 11 publications

References 0 publications

CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens

CIITA-Transduced Glioblastoma Cells Uncover a Rich Repertoire of Clinically Relevant Tumor-Associated HLA-II Antigens

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

Current Advances in Immunotherapy for Glioblastoma

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