scholarly journals IMMU-31. PNOC007: H3.3K27M SPECIFIC PEPTIDE VACCINE COMBINED WITH POLY-ICLC FOR THE TREATMENT OF NEWLY DIAGNOSED HLA-A2+ H3.3K27M DIFFUSE MIDLINE GLIOMAS (DMG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii366-iii366
Author(s):  
Sabine Mueller ◽  
Jared Taitt ◽  
Erin Bonner ◽  
Rishi Lulla ◽  
Stewart Goldman ◽  
...  
Keyword(s):  
Immune Cell ◽  
Peptide Vaccine ◽  
Median Number ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Immune Monitoring ◽  
Effector Memory ◽  
Newly Diagnosed ◽  
High Throughput Analysis ◽  
Peripheral Blood Mononuclear ◽  
Specific Peptide

Abstract OBJECTIVE To assess safety and efficacy within a multi-center trial the H3.3K27M specific peptide vaccine with poly-ICLC in HLA-A02.01+ patients diagnosed with H3.3K27M+ DMGs. METHODS After focal radiation therapy, participants 3–21 years of age were enrolled into two strata. Stratum A: newly diagnosed diffuse intrinsic pontine glioma (DIPG); Stratum B: other DMGs. H3.3K27M vaccine was administered with poly-ICLC IM every 3 weeks for 8 doses followed by every 6 weeks for a total of 96 weeks. Immuno-monitoring of peripheral blood mononuclear cell (PBMC) and imaging occurred every 3 months. Modified iRANO criteria were applied. PBMC samples were evaluated by mass cytometry. RESULTS From November 2016 until March 2019, 19 eligible patients (median age 11, range 5–17 yrs; 53 % female) were enrolled in Stratum A and 10 eligible patients (median age 13, range 7–18 yrs; 60 % female) in Stratum B. Treatment was well tolerated (7 grade 3; 0 grade 4 related toxicities). Median number of vaccines per participant was 6 (range 1–11). Overall survival at 12 months was 40% (95% CI 22–73%) for Stratum A and 39% (95% CI 16–93%) for Stratum B. Among the 19 subjects with longitudinal immune cell assessments, 7 exhibited an expansion of K27M-reactive CD8+ effector memory T-cells correlating with prolonged survival (p=0.028). CONCLUSION H3.3K27M specific vaccine in combination with poly-ICLC is well tolerated. CyTOF-based immune monitoring of PBMCs facilitates sensitive high-throughput analysis. Further investigation is warranted to determine if this may be predictive of clinical outcomes.

scholarly journals PDCT-17 (LTBK-11). PNOC007: H3.3K27M SPECIFIC PEPTIDE VACCINE COMBINED WITH POLY-ICLC FOR THE TREATMENT OF NEWLY DIAGNOSED HLA-A2+ H3.3K27M MIDLINE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi284-vi285 ◽  
Author(s):  
Sabine Mueller ◽  
Rishi Lulla ◽  
Stewart Goldman ◽  
Anu Banerjee ◽  
Susan Chi ◽  
...  
Keyword(s):  
Peptide Vaccine ◽  
Injection Site Reaction ◽  
Suppressor Cells ◽  
Inverse Correlation ◽  
Disease Status ◽  
P Value ◽  
Newly Diagnosed ◽  
Mass Cytometry ◽  
Peripheral Blood Mononuclear ◽  
Specific Peptide

Abstract OBJECTIVE To assess within a multi-center trial the safety of H3.3K27M specific peptide vaccine in combination with poly-ICLC in HLA-A02.01+ patients diagnosed with H3.3K27M+ diffuse midline gliomas. METHODS Subjects 3–21 years of age with CLIA confirmed H3.3K27 mutation status were eligible. Patients were enrolled after completion of focal radiation therapy. The trial enrolled two strata: Stratum A included newly diagnosed patients with diffuse intrinsic pontine glioma (DIPG) (n=19); Stratum B included non-DIPG midline glioma patients including spinal cord tumors as an exploratory strata (n=10). The H3.3K27M vaccine was administered in combination with poly-ICLC every 3 weeks for a total of 8 doses followed by every 6 weeks for a maximum of 96 weeks of therapy. Immuno-monitoring and imaging occurred every 3 months. Modified iRANO criteria are used for ongoing assessment of disease status. Patients’ peripheral blood mononuclear cell (PBMC) samples were evaluated by mass cytometry. RESULTS From November 2016 until March 2019, 19 eligible patients (median age 11, range 5–17 yrs; 53 % female) were enrolled in Stratum A and 10 eligible patients (median age 13, range 7–18 yrs; 60 % female) in Stratum B. Treatment was well tolerated with 7 grade 3 and 0 grade 4 treatment related toxicities. The most common related side effect included injection site reaction. Median number of vaccine administrations per patient was 6 (range 1–11). Overall survival at 12 months was 40% (95% CI 22–73%) for Stratum A and 39% (95% CI 16–93%) for Stratum B. A mass cytometry-based analysis of patient PBMCs (n = 16) revealed a trend towards an inverse correlation between polymorphonuclear myeloid-derived suppressor cells and the expansion of H3.3K27M-specific CD8+ T-cells (p-value = 0.154). CONCLUSION H3.3K27M specific vaccine in combination with poly-ICLC is well tolerated. Further evaluation will include a combination with checkpoint inhibitor nivolumab.

scholarly journals CTIM-21. PEPTIDE VACCINE DIRECTED TO CMV pp65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii37-ii37
Author(s):  
Eric Thompson ◽  
Daniel Landi ◽  
Eric Thompson ◽  
Eric Lipp ◽  
Bea Balajonda ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase I ◽  
Malignant Glioma ◽  
Phase I Trial ◽  
Peptide Vaccine ◽  
Median Number ◽  
Immune Monitoring ◽  
Preliminary Results ◽  
Treatment Regimens ◽  
Children And Young Adults

Abstract INTRODUCTION The cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma. METHODS Vaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly. RESULTS To date, 17 patients have been enrolled. Diagnoses include medulloblastoma (n=1), glioblastoma (n=9), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=2), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 41% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 0.8, not estimable) and median OS is 6.5 months (95% CI 1.8, not estimable). Interim analysis of immune monitoring bloodwork and perfusion MRI to quantify responses to PEP-CMV has been delayed due to COVID-19. However, adults with GBM who received PEP-CMV (NCT02864368) had significant (p≤0.05) increases in GCSF, GM-CSF, IFN-γ, IL-10, IL-2, IL-8, MIP1-α, and TNF-α levels. CONCLUSIONS Preliminary results demonstrate that PEP-CMV is feasible and well-tolerated in heavily pretreated, multiply recurrent patients.

scholarly journals IMMU-22. PHASE IB IMMUNOTHERAPY CLINICAL TRIAL WITH THE USE OF AUTOLOGOUS DENDRITIC CELLS PULSED WITH AN ALLOGENIC TUMORAL CELL LINES LYSATE IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii364-iii364
Author(s):  
Andres Morales La Madrid ◽  
Jaume Mora ◽  
Ofelia Cruz ◽  
Vicente Santa-Maria Lopez ◽  
Sara Perez-Jaume ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Tumor Antigens ◽  
Progression Free Survival ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Tumor Lysate ◽  
Pontine Glioma ◽  
Peripheral Blood Mononuclear

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a lethal condition, and therefore novel approaches are needed. Monocyte-derived dendritic cells (mDCs) pulsed with tumor antigens, as professional antigen-presenting cells, are a promising strategy for immunotherapy of invasive brain tumors. METHODS Our Ib pilot study explored the use of immunotherapy with mDCs for the treatment of newly diagnosed DIPG. Patient′s mDCs were extracted after irradiation and were primed with an allogenic tumor lysate from five patients with K27M-mutated DIPGs. The principal goal of this study was to establish the feasibility and safety of the intradermic administration of these mDC vaccines in patients with DIPG. In the absence of progression, patients received maintenance boosts of tumor lysate. Additionally, we evaluated the non-specific and antitumoral immune response generated in peripheral blood mononuclear cells (PBMC) and in cerebrospinal fluid (CSF) cells. RESULTS Nine patients were included in the study (2016–2018). Vaccines fabrication was feasible and administered in all cases without grade 3 or 4 toxicities. KLH (9/9 patients) and antitumor (8/9 patients) specific responses were identified in PBMC. Immunological responses were also confirmed in T-lymphocytes from the CSF of two patients. Twenty-four month overall survival and progression free survival was 33.3% (95 % CI 13.2% to 84.0 %) and zero, respectively. DISCUSSION These results demonstrate that mDC vaccination is feasible, safe, and generates a DIPG-specific immune response detected in PBMC and CSF. There was a trend in improved OS when compared to historic controls. This strategy shows a promising immunotherapy backbone for future combination schemas.

scholarly journals IMMU-30. UTILIZING A NOVEL MASS CYTOMETRY-BASED IMMUNOMONITORING PLATFORM FOR THE CHARACTERIZATION OF VACCINE-REACTIVE, EPITOPE-SPECIFIC CD8+ T-CELLS IN HLA-A*0201+ PATIENTS WITH K27M+ DIFFUSE MIDLINE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi125-vi125
Author(s):  
Jared Taitt ◽  
Payal Watchmaker ◽  
Takahide Nejo ◽  
Neil Almeida ◽  
Kaori Okada ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Time Course ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Peptide Vaccine ◽  
Effector Memory ◽  
Mass Cytometry ◽  
Peripheral Blood Mononuclear

Abstract Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. We have identified a novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a pilot clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine and tetanus toxoid (TT) peptide emulsified in Montanide in combination with poly-ICLC every 3 weeks for a total of 24 weeks. Our objective is to characterize vaccine-induced H3.3K27M-specific T-cell subpopulations in peripheral blood mononuclear cells through the evaluation of surface markers correlated with activation, memory, and exhaustion phenotypes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. Through this approach, the temporal expansion of vaccine-reactive CD8+ T-cells was observed in all of patients (n = 4) who completed a minimum of 18 weeks on the study. These T-cells were subsequently stratified into discrete clusters on a tSNE plot using canonical CD8+ T-cell markers. Resultant clusters were further classified by their expression profiles, revealing distinct effector memory and exhausted subpopulations. Chronological monitoring of these groups indicates the time course-dependent development and persistence of vaccine-reactive exhausted and effector memory CD8+ T-cells in 75% of patients analyzed. Furthermore, a comparative analysis of myeloid subpopulations revealed an inverse correlation between the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) and length of enrollment in the trial. Future plans include the analysis of regulatory T-cells (Tregs) and MDSCs of all enrolled patients to solidify the relationship between the length of stay on the study and prevalence of immunosuppressive populations. This methodology offers insight into the progression of vaccine-induced patient immune responses and exhibits promise as a platform that may be extrapolated to other immunotherapies.

scholarly journals DDRE-10. IMMUNE PROFILES ASSOCIATE WITH OUTCOMES IN HLA-A*02:01+, H3.3K27M+ PATIENTS WITH DIFFUSE MIDLINE GLIOMAS TREATED WITH H3.3K27M PEPTIDE VACCINE COMBINED WITH POLY-ICLC: A PNOC REPORT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii63-ii63
Author(s):  
Sabine Mueller ◽  
Jared M Taitt ◽  
Javier Villanueva-Meyer ◽  
Erin R Bonner ◽  
Takahide Nejo ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Peptide Vaccine ◽  
Injection Site Reaction ◽  
Suppressor Cells ◽  
Cd8 T Cell ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Peripheral Blood Mononuclear ◽  
Immunological Responses ◽  
Pre Treatment

Abstract BACKGROUND Patients with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+ H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine. PATIENTS AND METHODS Newly diagnosed patients aged 3–21 years with positive HLA-A*02.01+ and H3.3K27M+ status were enrolled into two strata after completion of radiation therapy: Stratum A for DIPG (n=19); Stratum B for non-pontine DMG (n=10). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry. RESULTS 19 patients enrolled in Stratum A (median age=11 years) and 10 in Stratum B (median age=13 years). There were no grade 4 treatment-related adverse events (TRAE). Injection site reaction was the most commonly reported TRAE. Overall survival (OS) at 12 months was 40% (95% CI, 22% to 73%) for Stratum A and 39% (95% CI, 16% to 93%) for Stratum B. The median OS was 16.1 months in patients exhibiting an expansion of H3.3K27M-reactive CD8+ T-cells compared to 9.8 months for their counterparts (p=0.05). DIPG patients with below-median baseline levels of myeloid-derived suppressor cells had prolonged OS compared to their counterparts (p< 0.1). Immediate pre-treatment dexamethasone administration inversely associated with H3.3K27M-reactive CD8+ T-cell responses. However, neither tumor size or bulk CD8+ T-cell status was significantly associated with OS. CONCLUSION Administration of the H3.3K27M-specific vaccine is well tolerated. Patients with H3.3K27M-specific CD8+ immunological responses demonstrated prolonged OS compared to non-responders.

scholarly journals IMMU-23. A NOVEL MASS CYTOMETRY-BASED MULTI-PARAMETER CHARACTERIZATION OF NEOANTIGEN-REACTIVE CD8+ T-CELLS IN PATIENTS PARTICIPATING IN PNOC007 H3.3K27M PEPTIDE VACCINE CLINICAL TRIAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii364-iii365
Author(s):  
Jared Taitt ◽  
Takahide Nejo ◽  
Payal Watchmaker ◽  
Neil Almeida ◽  
Kaori Okada ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Clinical Outcomes ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Peptide Vaccine ◽  
Effector Memory ◽  
Mass Cytometry ◽  
Peripheral Blood Mononuclear

Abstract BACKGROUND We have identified an HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a multi-center clinical trial of the peptide vaccine through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007) for patients with diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG). We sought to characterize vaccine-reactive CD8+T-cells subpopulations using their precise activation and developmental status to find their associations with clinical outcomes. METHODS Mass cytometry (CyTOF) analysis was performed on patient-derived peripheral blood mononuclear cells collected at baseline as well as pre-specified time points throughout the study. Each cell subtype was characterized via tSNE-clustering based on their expression profiles and quantified as a fraction of total CD45+cells. H3.3K27M-reactive CD8+T-cells were evaluated using an H3.3K27M-HLA-A2 dextramer along with a panel of T-cell and myeloid markers. RESULTS Among all 29 patients enrolled, we analyzed samples from all 19 DIPG and 9 of 10 non-brainstem DMG cases, of which 18 had longitudinal samples available (range: 2–5). Utilizing a novel CyTOF-based immuno-monitoring platform, the expansion of H3.3K27M-reactive CD8+T-cells, defined as a 25% increase at any time-point relative to baseline, was observed in 7 of these 18 patients. Survival analyses indicated that the expansion of H3.3K27M-reactive CD8+T-cells, particularly the effector-memory phenotype, positively correlated with longer overall survival (OS) (median: 16.1 vs 9.7 months, p=0.03), whereas an abundance of early and monocytic myeloid-derived suppressor cells at baseline correlated with shorter OS among DIPG patients (9.5 vs 14.3 months, p=0.002). CONCLUSION Our novel immuno-monitoring approach offers insight into how vaccine-induced immune responses impact clinical outcomes.

Sign in / Sign up

Export Citation Format

Share Document