scholarly journals Strategies in Developing Immunotherapy for Pancreatic Cancer: Recognizing and Correcting Multiple Immune “Defects” in the Tumor Microenvironment

2019 ◽  
Vol 8 (9) ◽  
pp. 1472 ◽  
Author(s):  
Sireesha Upadhrasta ◽  
Lei Zheng
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Types ◽  
Cancer Immunotherapies ◽  
Immune Defects ◽  
Made In

With the advent of cancer immunotherapies, significant advances have been made in the treatment of many tumor types including melanoma, lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, bladder cancer, etc. However, similar success has not been observed with the treatment of pancreatic cancer and all other immunogenic “cold” tumors. This prompts the need for a better understanding of the complexity of the cold tumor microenvironment (TME) of pancreatic cancer and what are truly the “defects” in the TME making the cancer unresponsive to immune checkpoint inhibitors. Here we discuss four major immune defects that can be recognized in pancreatic cancer, including lack of high-quality effector intratumoral T cells, heterogeneous dense stroma as a barrier to effector immune cells infiltrating into the tumor, immunosuppressive tumor microenvironment, and failure of the T cells to accomplish tumor elimination. We also discuss potential strategies for pancreatic cancer treatment that work by correcting these immune defects.

Adoptive CD8+T-cell grafted with liposomal immunotherapy drugs to counteract the immune suppressive tumor microenvironment and enhance therapy for melanoma

Nanoscale ◽  
2021 ◽  
Author(s):  
Simeng Liu ◽  
Huimin Liu ◽  
Xiaoshuang Song ◽  
Ailing Jiang ◽  
Yuchuan Deng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Viability ◽  
Tumor Targeting ◽  
Cd8 T Cell ◽  
Targeting Delivery ◽  
Immunosuppressive Tumor Microenvironment

Efficient tumor-targeting delivery of CpG or BMS-202 by adoptive T-cells coupled with drug loaded liposomes reversed the immunosuppressive tumor microenvironment, restoring T cell viability and effectively inhibiting the growth of melanoma.

Preliminary data from QUILT 3.055: A phase 2 multi-cohort study of N803 (IL-15 superagonist) in combination with checkpoint inhibitors (CPI).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2596-2596
Author(s):  
John M. Wrangle ◽  
Mark M. Awad ◽  
Firas Benyamine Badin ◽  
Mark P Rubinstein ◽  
Paul Bhar ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Stable Disease ◽  
Preliminary Data ◽  
Checkpoint Inhibitors ◽  
Killer Cell ◽  
Injection Site Reaction ◽  
Initial Response ◽  
Multiple Tumor ◽  
Grade 3 ◽  
Tumor Types

2596 Background: There is currently a paucity of treatment options for checkpoint relapsed patients who have had an initial response but subsequently progress. N803, a novel IgG1 Fc-engineered IL-15-complexed protein may rescue checkpoint activity in a checkpoint independent manner via its selective enhancement of natural killer cell (NK) and CD8+ T cell number and function, without stimulation of T regs and MDSCs. Methods: QUILT 3.055, (NCT03228667) a phase 2b study of N803 plus investigator choice CPI in 11 tumor types: NSCLC, SCLC, Urothelial carcinoma, HNSCC, Merkel cell carcinoma, Melanoma (single PD-1/PD-L1 CPI or w/ ipilimumab), Renal cell carcinoma (RCC), Gastric cancer, Cervical cancer, Hepatocellular carcinoma, Microsatellite instability-high (MSI-H)/ mismatch repair deficient (dMMR) solid tumors, with a heterogeneous mix of prior therapies. We present interim data for 135 patients treated with CPI alone or in combination with chemotherapy as their most recent prior therapy. Trial inclusion required investigator assessed progression on last line of therapy, patients had either CR with relapse or partial response or stable disease for 6 months with progression as their most recent result of checkpoint therapy. Patients with hyperprogression or best initial response of progression were excluded. Subjects received N803 15mck/kg SC q 3 weeks in combination with the same checkpoint inhibitor on which they had their most recent progression. Results: Preliminary data from 135 patients (60% NSCLC) with treatment with checkpoint and N-803 following progression on the same checkpoint show CR 0%, PR 8%, Stable Disease 51%, Progression 29%, response unevaluable 12% to date. A PR or SD was seen in all subgroups. Median PFS 3.9 months (95% CI: 2.6,5.0). Median OS 13.8 months (95% CI: 11.8, 16.3) N-803 is well tolerated with grade 1-2 common N-803 treatment related adverse events (TRAE) were injection site reaction (68%), chills (32%) fatigue (26%), pyrexia (26%), flu-like illness (14%), nausea (12%) and no other individual AE > 10%. Grade 3 N-803 TRAE were 12% but no individual grade 3 AEs were greater than 5%. Conclusions: N803 demonstrates low toxicity in patients previously treated with CPI and promising efficacy of cessation of progression and induction of response and durable stable disease in patients who had previously progressed on a CPI containing regimen in multiple tumor types and different CPIs. Clinical trial information: NCT03228667.

NIMG-48. TLR7/8-AGONIST-LOADED NANOPARTICLES REPROGRAM TUMOR-ASSOCIATED MYELOID CELLS FOR EFFECTIVE IMMUNOTHERAPY OF EXPERIMENTAL GLIOMA AND MRI-BASED TREATMENT MONITORING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi139-vi140
Author(s):  
Kira Pfleiderer ◽  
Verena Turco ◽  
Natalie K Horvat ◽  
Jessica Hunger ◽  
Kianush Karimian-Jazi ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Progressive Disease ◽  
Tumor Regression ◽  
Myeloid Cells ◽  
Complete Response ◽  
New Approach ◽  
Splenic Macrophages ◽  
Selective Depletion ◽  
Immunosuppressive Tumor Microenvironment

Abstract Drivers of glioblastoma progression include the immunosuppressive tumor microenvironment (TME), dominated by tumor-associated myeloid cells. Therefore, we investigated a new approach targeting the myeloid compartment to reprogram myeloid cells in the TME using a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the toll-like receptor 7 and 8 (TLR7/8) agonist R848. Biodistribution confirmed specific targeting of CDNP-R848 to tumor-associated macrophages (TAMs) (labeling efficiency: 34.0% ± 22.2%), whereas tumor microglia (5.4% ± 4.4%) and splenic macrophages (13.2% ± 0.7%) revealed less uptake. Interestingly, intravenous application of CDNP-R848 induced strong tumor regression with an overall response rate of 80% (2.5% complete response, 52.5% partial response and 25% stable disease, n=40 mice) in Gl261 syngeneic experimental gliomas, while CDNP vehicle treated animals showed exponential tumor growth (100% progressive disease, n=12 mice). As advanced imaging is essential to monitor intracranial disease and possibly predict response and resistance, we performed high resolution magnetic resonance imaging using ultrasmall iron oxide nanoparticles (USPIO) for macrophage tracking. Increased levels of USPIO uptake in vehicle treated animals compared to CDNP-R848 treated animals were found as an early marker of responding mice (ΔT2*: -11.7 ± 4.2 vs -4.0 ± 2.8 ms, p=0.01). This correlated with an increased influx of myeloid cells into the TME of vehicle treated animals and showed a strong correlation of macrophage recruitment and USPIO uptake (R2: 0.78, p=0.004). Mechanistically, phenotyping of macrophages (CD45high/CD11b+) indicated a pro-inflammatory shift of TAMs with an increased infiltration of pro-inflammatory F4/80+/MHCII+ macrophages during CDNP-R848 treatment. Surprisingly, the anti-tumor effect of CDNP-R848 was independent of CD8+ T cells, CD4+ T cells or NK cells during selective depletion experiments. In summary, this work demonstrates the ability of myeloid-targeted therapies to re-shape the tumor microenvironment for an effective immunotherapy of glioma.

Abstract 4703: Improving CAR T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer

2015 ◽  
Author(s):  
Somala Mohammed ◽  
Sujita Sukumaran ◽  
Pradip Bajgain ◽  
Usanarat Anurathapan ◽  
Helen E. Heslop ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Function ◽  
Car T Cell ◽  
T Cell Function ◽  
Car T ◽  
Immunosuppressive Tumor Microenvironment

The landscape of the tumor-infiltrating B cell and its association with T-cell and tumor microenvironment in human cancers.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 76-76
Author(s):  
Young Kwang Chae ◽  
William Han Bae ◽  
Yeonjoo Choi ◽  
Young Suk Kim ◽  
Jonathan Forrest Anker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tumor Microenvironment ◽  
B Cell ◽  
Cell Carcinoma ◽  
Expression Patterns ◽  
Cell Infiltration ◽  
Inverse Association ◽  
Human Cancers

76 Background: Compared to recent advances in our knowledge of T cell biology with success of immunotherapy, little progress has been made in understanding of the effects of B cells in tumor microenvironment and their interactions with T cells. Preclinical studies reported that B cells may have immune suppressive roles in tumor microenvironment via induction of T cell exhaustion. However, this association has not been shown in human tissues. We explored the landscape of tumor infiltrating B and T cells and their association with tumor microenvironment in various human cancers for which the FDA approved the use of immune checkpoint inhibitors. Methods: Expression patterns for 812 immune related genes from the TCGA database were utilized to define tumor infiltrating cells in 2951 patients with bladder urothelial carcinoma, renal clear cell carcinoma, skin cutaneous melanoma, lung squamous cell carcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma. Odds ratios (ORs) of the numbers of tumors with versus without activated B cell infiltration by the presence of activated CD8T cell infiltration were calculated. Results: Immune landscape of the six human cancers showed a consistent inverse association between tumor infiltrating activated B and CD8 T cells (OR = 0.18, p < 0.001). B cell infiltration was associated with increased expressions of immune checkpoints PD-L1, PD-1 and CTLA-4 and regulatory cytokines TGF-β, IL-10 and IL-35, which are known to be secreted by regulatory B cells. Angiogenic markers, such as angiopoietins, VEGF, MMP-9, CXCL10, CXCL11 and Tie2, showed differential expression patterns between B cell high and low groups. Conclusions: This is the first study that reports the inverse association between tumor infiltrating B and CD8 T cells in human tissues. The strong associations between B cell infiltration and increased expressions of suppressive cytokines and immune checkpoints suggest regulatory B cells may play a role in the T cell suppression in tumor microenvironment. Our results implicate that depleting B cells, leading to possible disinhibition of T cell activation, may be a future therapeutic option in potentiating T cell mediated immunity.

scholarly journals CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment

2016 ◽  
Vol 5 (11) ◽  
pp. e1238541 ◽  
Author(s):  
Evelina Martinenaite ◽  
Shamaila Munir Ahmad ◽  
Morten Hansen ◽  
Özcan Met ◽  
Marie Wulff Westergaard ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Immunosuppressive Tumor Microenvironment
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