Abstract 611: PD-1-based combination immunotherapy reinvigorates CD8+T cells in metastatic pancreatic cancer patients with improved survival

BackgroundWith the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. In this era of combination immunotherapies, we sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer.MethodsTwo different mouse models of pancreatic cancer were used to assess the potential of this combination regimen. Therefore, effects on tumour growth kinetics and survival were charted. Differential effects on immune signatures was investigated using RNA sequencing. Functional immune subset involvement was tested using different immune depletion experiments and multicolour flow cytometry in different relevant immune sites. Immune memory was checked using re-challenge experiments.ResultsWe demonstrated profound reduction in tumour growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented dose reduction of CD40 agonist without losing any efficacy (fig 1). RNA sequencing analysis showed involvement of natural killer cell and T cell mediated anti-tumour responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumours by both cytotoxic T cells and natural killer cells, as well as a striking increase in the ratio of CD8+ T cells over T regulatory cells. We also observed a significant increase in numbers of dendritic cells in tumour draining lymph nodes, particularly CD103+ dendritic cells with cross-presentation potential. A critical role for CD8+ T cells and involvement of natural killer cells in the anti-tumour effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin-15 and the CD40 agonist were combined.Abstract 453 Figure 1Tumour kinetics and survival in Panc02 (left) and KPC (right) pancreatic cancer mouse modelsConclusionsWe demonstrated profound synergistic anti-tumour effects upon combination of CD40 agonist and interleukin-15 treatment in mouse models of pancreatic cancer. This preclinical data supports initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.

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Interim data: Phase I/IIa study of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682 (E-EDV-D682) with immunomodulatory adjuvant EDVs carrying α-galactosyl ceramide (EDV-GC) in patients with recurrent, metastatic pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4632 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4632-4632 ◽

Cited By ~ 1

Author(s):

Joanne Lundy ◽

Gavin M. Marx ◽

Jennifer MacDiarmid ◽

Himanshu Brahmbhatt ◽

Vinod Ganju

Keyword(s):

Pancreatic Cancer ◽

Immune Response ◽

T Cells ◽

Phase I ◽

Cd8 T Cells ◽

Advanced Pancreatic Cancer ◽

Cytotoxic Drug ◽

Metastatic Pancreatic Cancer ◽

Adaptive Immune ◽

Galactosyl Ceramide

4632 Background: Targeted EDV nanocells loaded with doxorubicin and microRNA16a have shown excellent safety profiles in Phase I trials in recurrent glioma and mesothelioma. This planned safety analysis of an ongoing first-in-human, open label Phase I/IIa study in patients with treatment-refractory metastatic pancreatic cancer, assesses safety, biologic and clinical activity of EGFR-targeted EDV nanocells carrying cytotoxic drug PNU-159682, designed to overcome drug resistance, combined with EDV nanocells carrying immunomodulatory adjuvant α-galactosyl ceramide, designed to stimulate anti-tumour immune response. Methods: 9 patients with advanced pancreatic cancer enrolled in the dose escalation phase to evaluate safety of the EDV combination. Doses gradually escalated from 2 x 109 EDVs/dose to a maximum of 7 x 109 EDVs/dose in Week 7, with subsequent dosing at the maximum dose achieved in Cycle 1. iRECIST criteria was used to assess tumour response after each cycle, and blood was collected each cycle for cytokine and PBMC analysis. Results: Combination EDVs were well tolerated with no DLTs, and no drug related SAEs. A minority of patients experienced G1 infusion reactions, which responded promptly to supportive treatment. PR or SD was achieved at 8 weeks in 8/9 patients (CBR 89%), with responses confirmed at 4 months in 4/5 evaluable patients (80%), with 2 durable responses seen beyond 6 months. Exploratory analyses have revealed elevation of IFN-α and IFN-γ in almost all evaluable patients (6/8). In addition, we observed elevated CD8+ T cells (2/8), iNKT, dendritic and NK cells (3/8), and a reduction in exhausted CD8+ T cells (3/8), suggesting activation of both innate and adaptive immune responses. Conclusions: EDVs carrying the cytotoxic drug and immune adjuvant are safe and well tolerated. Early signals point to durable responses, possibly related to the development of an innate and adaptive immune response along with cytotoxic effects on drug resistant tumour cells. The Phase IIa study plans to enrol an additional 35 patients to further evaluate safety and anti-tumour efficacy. Clinical trial information: ACTRN12619000385145 .

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Abstract 4491: Association of intratumoral immunologic profile with overall survival in metastatic pancreatic cancer patients treated with combination immunotherapy with or without PD-1 blockade

10.1158/1538-7445.am2019-4491 ◽

2019 ◽

Author(s):

Annie A. Wu ◽

Takahiro Tsujikawa ◽

Gina Choe ◽

Teresa Beechwood ◽

Lisa M. Coussens ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Metastatic Pancreatic Cancer ◽

Combination Immunotherapy ◽

Immunologic Profile

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Abstract PR-004: Systemic and intratumoral immune profiling in metastatic pancreatic cancer patients who received front-line FOLFIRINOX and were treated with combination immunotherapy with CTLA-4 blockade in the maintenance setting

10.1158/1538-7445.panca20-pr-004 ◽

2020 ◽

Author(s):

Annie A. Wu ◽

Katherine M. Bever ◽

Won Jin Ho ◽

Elana J. Fertig ◽

Nan Niu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Metastatic Pancreatic Cancer ◽

Combination Immunotherapy ◽

Front Line ◽

Immune Profiling

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Abstract 4491: Association of intratumoral immunologic profile with overall survival in metastatic pancreatic cancer patients treated with combination immunotherapy with or without PD-1 blockade

10.1158/1538-7445.sabcs18-4491 ◽

2019 ◽

Author(s):

Annie A. Wu ◽

Takahiro Tsujikawa ◽

Gina Choe ◽

Teresa Beechwood ◽

Lisa M. Coussens ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Metastatic Pancreatic Cancer ◽

Combination Immunotherapy ◽

Immunologic Profile

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Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003019 ◽

2021 ◽

Vol 9 (7) ◽

pp. e003019

Author(s):

Robert H Vonderheide ◽

Kimberly A Kraynyak ◽

Anthony F Shields ◽

Autumn J McRee ◽

Jennifer M Johnson ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Cd8 T Cells ◽

Plasmid Dna ◽

Phase 1 ◽

Dna Encoding ◽

Cancer Types ◽

Ifn Γ ◽

Human Telomerase ◽

Disease Free

BackgroundHuman telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types.MethodsA phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type.ResultsOf the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival.ConclusionsPlasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.

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The Neutrophil/Lymphocyte Ratio at Diagnosis Is Significantly Associated with Survival in Metastatic Pancreatic Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms18040730 ◽

2017 ◽

Vol 18 (4) ◽

pp. 730 ◽

Cited By ~ 24

Author(s):

Matteo Piciucchi ◽

Serena Stigliano ◽

Livia Archibugi ◽

Giulia Zerboni ◽

Marianna Signoretti ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Metastatic Pancreatic Cancer ◽

Neutrophil Lymphocyte Ratio ◽

Lymphocyte Ratio

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ILDR1 Is a Prognostic Biomarker and Associated With Immune Inﬁltration in Gastric Cancer

10.21203/rs.3.rs-944596/v1 ◽

2021 ◽

Author(s):

Yanling Ma ◽

WenBo Qi ◽

BaoHong Gu ◽

XueMei Li ◽

ZhenYu Yin ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Dendritic Cells ◽

Cancer Patients ◽

Cd8 T Cells ◽

Immune Cells ◽

Copy Number ◽

Sequencing Data ◽

Number Variation ◽

Gastric Cancer Patients

Abstract Objective: To investigate the association between ILDR1 and prognosis and immune infiltration in gastric cancer. Methods: We analyzed the RNA sequencing data of 9736 tumor tissues and 8587 normal tissues in the TCGA and GTEx databases through the GEPIA2 platform. The expression of ILDR1 in gastric cancer and normal gastric mucosa tissues with GEPIA and TIMER. Clinical subgroup analysis was made through Kaplan-Meier analysis. Analyzed the correlation between ILDR1 and VEGFA expression in gastric cancer, through the gene sequencing data of gastric cancer in TCGA. Explored the relationship between ILDR1 methylation and the prognosis of gastric cancer patients through the MethSurv database. The correlation between ILDR1 and immune cells and the correlation of copy number variation were explored through the TIMER database. Results: ILDR1-high GC patients had a lower PFS and OS. High ILDR1 expression was significantly correlated with tumor grade. There was a negative correlation between the ILDR1 expression and the abundances of CD8+ T, Macrophages and DC and etc. The methylation level of ILDR1 is associated with a good prognosis of gastric cancer. ILDR1 copy number variation was correlated with immune cells, IDLR1 arm-loss was associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells, and arm-duplication was associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells. Conclusion: The increased expression of ILDR1 is associated with poor prognosis in patients with gastric cancer. ILDR1 can be used as a novel predictive biomarker to provide a new therapeutic target for gastric cancer patients.

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