CTIM-08. COMBINATION OF THE IMA950/POLY-ICLC MULTIPEPTIDE VACCINE WITH PEMBROLIZUMAB IN RELAPSING GLIOBLASTOMA PATIENTS

Abstract The IMA950 peptide vaccine is composed of 9 HLA-A2-restricted peptides eluted from the surface of GBM samples and of two HLA class II-binding peptides1. It was tested in combination with poly-ICLC in patients with newly diagnosed GBM, demonstrating safety. The vaccine was able to elicit CD4 and CD8 T cell responses in the peripheral blood in the majority of patients, with however an overall low magnitude of T cell responses and suboptimal migration of elicited T cells to the brain, probably limiting clinical efficacy2,3. With the aim to improve homing of vaccine-specific T cell to the tumor, we are conducting a phase II clinical trial in patients with recurrent GBM testing the IMA950/poly-ICLC multipeptide vaccine with or without the anti-PD1 antibody pembrolizumab (NCT03665545). 24 patients will be included (12 patients in each arm) and pre- and post-vaccination tumor sample will be available, allowing assessing effect of the vaccine at the tumor site. The primary objective of this trial is safety of IMA950/poly-ICLC given together with pembrolizumab. Secondary objectives include (i) estimation of 6, 9 and 12-month progression-free survival (PFS), (ii) overall survival, (iii) analysis of patient quality of life and (iv) of the synergy/immunogenicity of IMA950/poly-ICLC and pembrolizumab. Immunomonitoring will include measure of vaccine-induced immune responses, IHC for immune cell markers, RNA/TCR sequencing and methylome analysis, to assess vaccine-induced T cell responses, immune modulation and potential signatures predictive of response. Thus far, 6 patients have been included (3 in each arm). Preliminary results show CD4 and CD8 T cell responses to the vaccine are detected in both groups in the peripheral blood. Analysis at the tumor site and comparison between arms will be performed once all patients have been included. 1. Dutoit, V. et al. Brain (2012); 2. Migliorini, D. et al. Neuro Oncol (2019); 3. Rampling, R. et al. Clin Cancer Res(2016)

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Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response

10.1101/2020.12.15.422827 ◽

2020 ◽

Author(s):

Anastasia Gangaev ◽

Elisa A Rozeman ◽

Maartje W Rohaan ◽

Daisy Philips ◽

Sanne Patiwael ◽

...

Keyword(s):

T Cell ◽

Mechanism Of Action ◽

Peripheral Blood ◽

Cell Response ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Tumor Site ◽

Cell Responses ◽

Melanoma Patients

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If activation of circulating tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses towards 71 melanoma associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the melanoma-reactive CD8 T cell response in peripheral blood was unaltered upon PD-1 blockade. In contrast, a broadening of the melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. On the basis of these results, we conclude that PD-1 and CTLA-4 blockade impact the tumor-reactive CD8 T cell response in a distinct manner. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.

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Abstract 1524: Peripheral blood mononuclear cells engineered via microfluidic Cell Squeeze® technology to generate APCs that drive mutant-KRas-specific CD8+ T cell responses

10.1158/1538-7445.am2021-1524 ◽

2021 ◽

Author(s):

Defne Yarar ◽

Carolyne Smith ◽

Amritha Ramakrishnan ◽

Scott Loughhead ◽

Armon Sharei ◽

...

Keyword(s):

T Cell ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Peripheral Blood Mononuclear ◽

Cell Responses ◽

Blood Mononuclear Cells

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TriMix and tumor antigen mRNA electroporated dendritic cell vaccination plus ipilimumab: link between T-cell activation and clinical responses in advanced melanoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000329 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000329 ◽

Cited By ~ 3

Author(s):

Brenda De Keersmaecker ◽

Sofie Claerhout ◽

Javier Carrasco ◽

Isabelle Bar ◽

Jurgen Corthals ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Clinical Response ◽

T Cell Activation ◽

Peripheral Blood ◽

T Cell Responses ◽

Cd8 T Cell ◽

Advanced Melanoma ◽

Dendritic Cell Vaccination ◽

Cell Responses

BackgroundWe previously reported that dendritic cell-based mRNA vaccination plus ipilimumab (TriMixDC-MEL IPI) results in an encouraging rate of tumor responses in patients with pretreated advanced melanoma. Here, we report the TriMixDC-MEL IPI-induced T-cell responses detected in the peripheral blood.MethodsMonocyte-derived dendritic cells electroporated with mRNA encoding CD70, CD40 ligand, and constitutively active TLR4 (TriMix) as well as the tumor-associated antigens tyrosinase, gp100, MAGE-A3, or MAGE-C2 were administered together with IPI for four cycles. For 18/39 patients, an additional vaccine was administered before the first IPI administration. We evaluated tumor-associated antigen specific T-cell responses in previously collected peripheral blood mononuclear cells, available from 15 patients.ResultsVaccine-induced enzyme-linked immunospot assay responses detected after in vitro T-cell stimulation were shown in 12/15 patients. Immune responses detected in patients with a complete or partial response were significantly stronger and broader, and exhibited a higher degree of multifunctionality compared with responses in patients with stable or progressive disease. CD8+ T-cell responses from patients with an ongoing clinical response, either elicited by TriMixDC-MEL IPI or on subsequent pembrolizumab treatment, exhibited the highest degree of multifunctionality.ConclusionsTriMixDC-MEL IPI treatment results in robust CD8+ T-cell responses in a meaningful portion of stage III or IV melanoma patients, and obviously in patients with a clinical response. The levels of polyfunctional and multiantigen T-cell responses measured in patients with a complete response, particularly in patients evidently cured after 5+ years of follow-up, may provide a benchmark for the level of immune stimulation needed to achieve a durable clinical remission.Trial registration numberNCT01302496.

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Comparison of Human Memory CD8 T Cell Responses to Adenoviral Early and Late Proteins in Peripheral Blood and Lymphoid Tissue

PLoS ONE ◽

10.1371/journal.pone.0020068 ◽

2011 ◽

Vol 6 (5) ◽

pp. e20068 ◽

Cited By ~ 2

Author(s):

Amita Joshi ◽

Biwei Zhao ◽

Cara Romanowski ◽

David Rosen ◽

Phyllis Flomenberg

Keyword(s):

T Cell ◽

Peripheral Blood ◽

Lymphoid Tissue ◽

T Cell Responses ◽

Cd8 T Cell ◽

Human Memory ◽

Cell Responses ◽

Memory Cd8 T Cell

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Rapid whole blood analysis of virus-specific CD4 and CD8 T cell responses in persistent HIV infection

AIDS ◽

10.1097/00002030-200012010-00004 ◽

2000 ◽

Vol 14 (17) ◽

pp. 2653-2660 ◽

Cited By ~ 23

Author(s):

Martina Sester ◽

Urban Sester ◽

Hans Köhler ◽

Thomas Schneider ◽

Ludwig Deml ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

Whole Blood ◽

T Cell Responses ◽

Cd8 T Cell ◽

Blood Analysis ◽

Cell Responses ◽

Whole Blood Analysis

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The Breadth of Synthetic Long Peptide Vaccine-Induced CD8+ T Cell Responses Determines the Efficacy against Mouse Cytomegalovirus Infection

PLoS Pathogens ◽

10.1371/journal.ppat.1005895 ◽

2016 ◽

Vol 12 (9) ◽

pp. e1005895 ◽

Cited By ~ 10

Author(s):

Eleni Panagioti ◽

Anke Redeker ◽

Suzanne van Duikeren ◽

Kees LMC Franken ◽

Jan Wouter Drijfhout ◽

...

Keyword(s):

T Cell ◽

Cytomegalovirus Infection ◽

Peptide Vaccine ◽

T Cell Responses ◽

Cd8 T Cell ◽

Mouse Cytomegalovirus ◽

Cell Responses

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P03.06 Deciphering vaccine-induced neoepitope-specific T cell responses in a patient with H3K27M-mutant midline glioma WHO grade 4

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-itoc8.28 ◽

2021 ◽

Vol 9 (Suppl 1) ◽

pp. A15.1-A15

Author(s):

K Lindner ◽

K Kromer ◽

K Jähne ◽

L Bunse ◽

C Tan ◽

...

Keyword(s):

T Cell ◽

Intellectual Property ◽

Peripheral Blood ◽

Cancer Vaccines ◽

Stock Options ◽

Peptide Vaccine ◽

T Cell Responses ◽

Who Grade ◽

Cell Responses ◽

Anti Cancer

BackgroundK27M-mutant histone-3 (H3K27M) defines a clinically and molecularly distinct entity of diffuse midline gliomas WHO grade 4 with an unfavorable prognosis. From an immunological perspective, H3K27M constitutes a cancer neoepitope: in a syngeneic MHC-humanized mouse model, an H3K27M-specific long peptide vaccine induced mutation-specific T cells responses capable of inhibiting growth of H3K27M-expressing tumors.Materials and MethodsHere, we describe clinical response of a patient diagnosed with H3K27M-mutant midline gliomas to H3K27M-specific peptide vaccination and exploit vaccine-induced T cell phenotypes.ResultsRepeated peptide vaccinations were well tolerated and resulted in long-term response after pseudoprogression. Longitudinal immune monitoring showed induction of H3K27M-specific CD4-driven T cell responses in the peripheral blood. Within the cerebrospinal fluid, expansion of HLA-specific vaccine-induced T cell receptor (TCR) clones was observed and associated with distinct HLA types.ConclusionsIdentification of vaccine-induced TCR clones within the peripheral blood and CSF of patients with H3K27M-mutant midline glioma may be used to prioritize TCRs for adoptive T cell therapy.Disclosure InformationK. Lindner: None. K. Kromer: None. K. Jähne: None. L. Bunse: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Patent: US20180155403A1 (Histone Anti-Cancer Vaccines). C. Tan: None. I. Poschke: None. E. Green: None. J.M. Lindner: None. M. Platten: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; Roche. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Patent: US20180155403A1 (Histone Anti-Cancer Vaccines). K. Sahm: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Patent: US20180155403A1 (Histone Anti-Cancer Vaccines).

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Immunogenicity and Efficacy of a Novel Multi-Antigenic Peptide Vaccine Based on Cross-Reactivity between Feline and Human Immunodeficiency Viruses

Viruses ◽

10.3390/v11020136 ◽

2019 ◽

Vol 11 (2) ◽

pp. 136 ◽

Cited By ~ 2

Author(s):

Bikash Sahay ◽

Alek Aranyos ◽

Meerambika Mishra ◽

Andrew McAvoy ◽

Marcus Martin ◽

...

Keyword(s):

T Cell ◽

Mononuclear Cells ◽

Peptide Vaccine ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Cell Immunity ◽

Evolutionarily Conserved ◽

Human Immunodeficiency Viruses ◽

Hiv 1

For the development of an effective HIV-1 vaccine, evolutionarily conserved epitopes between feline and human immunodeficiency viruses (FIV and HIV-1) were determined by analyzing overlapping peptides from retroviral genomes that induced both anti-FIV/HIV T cell-immunity in the peripheral blood mononuclear cells from the FIV-vaccinated cats and the HIV-infected humans. The conserved T-cell epitopes on p24 and reverse transcriptase were selected based on their robust FIV/HIV-specific CD8+ cytotoxic T lymphocyte (CTL), CD4+ CTL, and polyfunctional T-cell activities. Four such evolutionarily conserved epitopes were formulated into four multiple antigen peptides (MAPs), mixed with an adjuvant, to be tested as FIV vaccine in cats. The immunogenicity and protective efficacy were evaluated against a pathogenic FIV. More MAP/peptide-specific CD4+ than CD8+ T-cell responses were initially observed. By post-third vaccination, half of the MAP/peptide-specific CD8+ T-cell responses were higher or equivalent to those of CD4+ T-cell responses. Upon challenge, 15/19 (78.9%) vaccinated cats were protected, whereas 6/16 (37.5%) control cats remained uninfected, resulting in a protection rate of 66.3% preventable fraction (p = 0.0180). Thus, the selection method used to identify the protective FIV peptides should be useful in identifying protective HIV-1 peptides needed for a highly protective HIV-1 vaccine in humans.

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