High-grade glioma associated immunosuppression does not prevent immune responses induced by vaccination with autologous, tumor-lysate pulsed dendritic cells

Recent advances in immunotherapy have included inhibition of immune checkpoint proteins in the tumor microenvironment and tumor lysate-based vaccination strategies. We combined these approaches in pet dogs with high-grade glioma. Administration of a synthetic peptide targeting the immune checkpoint protein, CD200, enhanced the capacity of antigen-presenting cells to prime T-cells to mediate an anti-glioma response. We found that in canine spontaneous gliomas, local injection of a canine-specific, CD200-directed peptide before subcutaneous delivery of an autologous tumor lysate vaccine prolonged survival relative to a historical control treated with autologous tumor lysate alone (median survivals of 12.7 months and 6.36 months, respectively). Antigen-presenting cells and T-lymphocytes primed with this peptide suppressed their expression of the inhibitory CD200 receptor, thereby enhancing their ability to initiate immune reactions in a glioblastoma microenvironment replete with the immunosuppressive CD200 protein. These results support consideration of a CD200 ligand as a novel glioblastoma immunotherapeutic agent.

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SCIDOT-51. OVERPOWERING MULTIPLE INHIBITORY IMMUNE CHECKPOINTS WITH A SINGLE PEPTIDE INHIBITOR ENHANCED SURVIVAL IN A SPONTANEOUS HIGH-GRADE GLIOMA CANINE PILOT-TRIAL

Neuro-Oncology ◽

10.1093/neuonc/noz175.1186 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi282-vi282

Author(s):

Michael Olin ◽

Christopher Moertel ◽

G Elisabeth Pluhar

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Pilot Trial ◽

High Grade Glioma ◽

Cns Tumors ◽

Immune Checkpoints ◽

Peptide Ligand ◽

Autologous Tumor ◽

High Grade ◽

Tumor Lysate

Abstract Given the modest effects current immune checkpoint-inhibitors have on patients with CNS tumors, we focused our studies on the novel CD200 immune checkpoint. The CD200 checkpoint suppresses the immune system through binding of the inhibitory CD200 protein to the inhibitory receptor (CD200R1) expressed on immune cells. In addition to CD200R1, the CD200 checkpoint includes activation receptors (CD200AR), which we are targeting with a peptide ligand (CD200AR-L) to reverse the inhibitory effects of the CD200 protein. We showed that spontaneous high-grade glioma dogs receiving a canine specific CD200AR-L in combination with autologous tumor lysate vaccine had an increased median overall survival of 9 months, compared to 6.3 months with lysate alone, resulting in an overall 36-month survival of 21%. However, we have a 45% event-free (progression-free) group of dogs that died of non-tumor related deaths with an extended median survival of 18 months. Six dogs remain on trial, 87% of the dogs receiving tumor lysate only died of tumor recurrence within 6 months. Serum chemistry profiles and physical examinations showed that the peptide did not induce any systemic toxicity. To determine how we obtained these unprecedented results, we focused on the mechanism of CD200AR-L/CD200AR binding. We discovered DAP10/12 signaling pathways and CD200ARs are upregulated, while the inhibitory CD200R1 is downregulated. We discovered the molecular connection between CD200, PD-1 and CTLA4. We demonstrated that our murine and human CD200AR-L downregulates the inhibitory PD-1 and PD-L1 and inhibits the upregulation of CTLA4. Therefore, we attribute the success of CD200AR-L to the ability to concurrently modulate multiple immune checkpoints. We have now developed human GMP grade CD200AR-L peptides to develop an immunotherapy approach for patients with CNS tumors; we will conduct a Phase I trial utilizing the peptide ligand concomitantly with an allogeneic GBM6-AD cell line as a tumor vaccine and the adjuvant imiquimod.

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Impairment of membrane TNFα expression reduces cytotoxic activity of dendritic cells against autologous tumor cells in high-grade glioma patients

Annals of Oncology ◽

10.1093/annonc/mdx711.067 ◽

2017 ◽

Vol 28 ◽

pp. xi25

Author(s):

T. Tyrinova ◽

O. Leplina ◽

S. Mishinov ◽

M. Tikhonova ◽

A. Kalinovskiy ◽

...

Keyword(s):

Dendritic Cells ◽

Cytotoxic Activity ◽

Tumor Cells ◽

High Grade Glioma ◽

Autologous Tumor ◽

High Grade

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CTIM-06. DENDRITIC CELL VACCINE STUDY FOR RECURRENT, HIGH-GRADE GLIOMA: TISSUE-BASED RNA SEQUENCING AND SERUM CYTOKINE LEVELS AS POTENTIAL BIOMARKERS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.140 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii33-ii34

Author(s):

Macarena De La Fuente ◽

Tulay Koru-Sengul ◽

Deborah Heros ◽

Feng Miao ◽

Alain Fernandez Marrero ◽

...

Keyword(s):

Dendritic Cells ◽

Rna Sequencing ◽

Tumor Antigens ◽

High Grade Glioma ◽

Treatment Discontinuation ◽

Sequencing Analysis ◽

High Grade ◽

Who Grade ◽

Cytokine Levels ◽

Grade 3

Abstract BACKGROUND Glioblastoma is the most common primary malignant brain tumor. Despite multimodality treatment approach, median progression-free survival (PFS) is only 8 months, median overall-survival (OS) 14 months and 5-year survival rate of under 10%. Dendritic cells (DCs) are the professional antigen presenting cells of the immune system. The rationale for sensitizing dendritic cells to a pool of non-selected tumor antigens is based on the marked heterogeneity present within glioblastoma tumor cells. METHODS Phase 1/feasibility study of DC vaccine for recurrent high-grade glioma was conducted. Pooled, non-selected tumor antigens collected via tumor cell lysate were used for DC sensitization. RNA sequencing analysis was performed on all tumor samples. Cytokine levels in serum were detected using a Luminex cytokine panel. RESULTS A total of 20 patients were enrolled onto this study (median age 58yrs, range: 39–74, 65% male). Pathology showed WHO grade IV glioblastoma in 14 (70%) and grade III anaplastic astrocytoma in 6 (30%) patients. IDH wild type in 19 (95%) patients. Treatment emergent adverse events (all grades, regardless of attribution) occurred in more than 15% of the patients (20% fatigue, 15% dizziness, 15% headache, none leading to treatment discontinuation). There were five grade 3–4 and none grade 5 events. One grade 4 event (seizure) probable related to investigational treatment leading to treatment discontinuation. Four grade 3 events (dysphasia, possible related; intracranial hemorrhage unrelated; muscle weakness, unlikely related and hematoma, unrelated). Median PFS was 3.8 months. Median OS was 11 months. RNA sequencing in tumor samples and correlation with cytokine levels in serum is currently been analyzed. CONCLUSION Tumor lysate pulsed DC vaccination demonstrates acceptable safety and tolerability in high-grade glioma patients. Evaluations of integrating molecular profiling RNA sequencing information and cytokine levels to identify potential subset of patients with significant clinical benefit will be provided.

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Abstract 2839: NK cell response and tumor debulking are associated to prolonged survival in recurrent glioblastoma treated by dendritic cells loaded with autologous tumor lysate.

10.1158/1538-7445.am2013-2839 ◽

2013 ◽

Author(s):

Serena Pellegatta ◽

Marica Eoli ◽

Simona Frigerio ◽

Carlo Antozzi ◽

Maria Grazia Bruzzone ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Response ◽

Nk Cell ◽

Recurrent Glioblastoma ◽

Prolonged Survival ◽

Autologous Tumor ◽

Tumor Lysate ◽

Tumor Debulking

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Individual Patient-Specific Immunity against High-Grade Glioma after Vaccination with Autologous Tumor Derived Peptides Bound to the 96 KD Chaperone Protein

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-11-3358 ◽

2012 ◽

Vol 19 (1) ◽

pp. 205-214 ◽

Cited By ~ 95

Author(s):

Courtney A. Crane ◽

Seunggu J. Han ◽

Brian Ahn ◽

Jessica Oehlke ◽

Valerie Kivett ◽

...

Keyword(s):

High Grade Glioma ◽

Patient Specific ◽

Autologous Tumor ◽

High Grade ◽

Specific Immunity ◽

Chaperone Protein

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Induction of T cell precursors in advanced melanoma treated with autologous tumor lysate loaded dendritic cells

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.90140.2623 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 2623-2623

Author(s):

T. S. Crocenzi ◽

C. G. Tretter ◽

J. Fisher ◽

N. Crosby ◽

D. Truman ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Advanced Melanoma ◽

Autologous Tumor ◽

Tumor Lysate

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Allogeneic partially HLA-matched dendritic cells (DC) as a vaccine in metastatic renal cell cancer (mRCC): Final analysis of a clinical phase I/II study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15053 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15053-e15053 ◽

Cited By ~ 1

Author(s):

Anne Flörcken ◽

Joachim Kopp ◽

Kamran Movassaghi ◽

Antje van Lessen ◽

Anna Takvorian ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Clinical Response ◽

Cell Cancer ◽

T Cell Responses ◽

T Cell Response ◽

Delayed Type Hypersensitivity ◽

Autologous Tumor ◽

Tumor Lysate ◽

Cell Responses

e15053 Background: Despite novel kinase inhibitors, prognosis of metastatic RCC remains poor and new experimental approaches are warranted. Our aim was to evaluate a DC-based vaccine, which exploits alloreactivity as a means to amplify specific anti-tumor immune responses. Methods: Allogeneic, partially HLA-matched DC were generated in our GMP facility. DC were loaded with autologous tumor lysate. 8 patients with progressive mRCC were included, 7 patients were immunized repetitively with 107 DC s.c. over 20 weeks. Low-dose IL-2 (3 Mio U s.c. qd) was used concomitantly. Endpoints of the study were feasibility, safety, immunological and clinical responses. T cell responses against HLA-A2-restricted RCC-associated antigens were evaluated by proliferation assays, ELISpot and cytokine bead array (CBA). T cell repertoire was analysed by T cell receptor γ and –β PCR. Results: Vaccination was feasible and safe, no treatment-related grade 3/4 toxicity or clinically relevant autoimmunity was observed. No objective responses were observed, however, 2/7 patients showed stable disease, one a minimal clinical response. The mean TTP was 24.6 weeks (range 5 to 96). Delayed-type hypersensitivity was detected in 3/7 and HLA antibodies were induced in 3/7 patients. In 3/7 patients T cell responses against RCC-associated antigens such as TYMS, G250, vimentin, surviving and cyclin-D1 were induced by vaccination. These antigen-specific T cells showed a predominant TH1-cytokine profile. Interestingly, a clonally expanded T cell population could be detected by γ- and –β PCR in one patient with both a minimal clinical response and a T cell response. This clone is currently persisting for more than 80 months, its specificity is under investigation. Conclusions: Vaccination with allogeneic tumor-lysate-loaded DC was feasible, safe and was able to induce TH1-polarized immune responses against RCC-associated antigens. Tumor vaccination might be a promising approach in minimal residual disease, possibly in combination with antibodies against CTLA-4 or PD-1.

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A prospective, randomized, blinded, placebo-controlled, phase IIb trial of an autologous tumor lysate + yeast cell wall particles (YCWP) + dendritic cells (DC) vaccine vs unloaded YCWP + DC and embedded phase I/IIa trial with tumor lysate particle only (TLPO) vaccine in stage III and stage IV (resected) melanoma to prevent recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.tps201 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. TPS201-TPS201 ◽

Cited By ~ 1

Author(s):

John W Myers ◽

Garth S Herbert ◽

Guy T Clifton ◽

Timothy J Vreeland ◽

Tommy A Brown ◽

...

Keyword(s):

Cell Wall ◽

Dendritic Cells ◽

High Risk ◽

Yeast Cell ◽

Yeast Cell Wall ◽

Stage Iii ◽

Autologous Tumor ◽

Tumor Lysate ◽

Risk Of Recurrence ◽

Disease Free

TPS201 Background: Melanoma is a potentially lethal skin malignancy; patients with stage III/IV resected disease have a recurrence rate of 50-90%. Adjuvant checkpoint inhibitor immunotherapy decreases the risk of recurrence but also causes significant immune-related toxicity. Vaccines are a promising strategy for patients with high risk melanoma. The optimal time to intervene may be in the adjuvant setting after attaining a disease-free state through standard of care therapies. Our strategy uses autologous tumor lysate (TL) in a yeast cell wall particle (YCWP) to load dendritic cells (DC) ex vivo. The tumor lysate particle loaded dendritic cell (TLPLDC) vaccine is then given to prevent melanoma recurrences. An alternate vaccine delivery method that we are evaluating utilizes the tumor lysate particle-only (TLPO) technique, in which tumor lysate is loaded into capped YCWP and injected intradermally, allowing an in vivo uptake by the patient’s dendritic cells. Methods: We are performing a prospective, randomized, blinded, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma who have been rendered disease-free but remain at high risk of recurrence. The study will utilize the TLPLDC strategy vs placebo (2:1) in 120 patients, followed by a bridging study of TLPO vs TLPLDC (2:1) in 60 patients. Both TLPLDC and TLPO inoculations will be monthly x3, followed by boosters at 6, 12, and 18 months. Primary endpoints will be disease free survival (DFS) at 24 months in the TLPLDC arm, and overall safety in the TLPO arm. We have completed enrollment in the phase IIb portion of the study. Clinical trial information: NCT02301611.

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