206 An immune-competent tumor organoid platform to test novel immune checkpoint combinations targeting the receptor CD47 in triple negative breast cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A222-A222
Author(s):  
Elizabeth Stirling ◽  
Ethan Willey-Shelkey ◽  
Adam Wilson ◽  
Aleksander Skardal ◽  
Pierre Triozzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Granzyme B ◽  
Tumor Burden ◽  
Cancer Center ◽  
Murine Models ◽  
Patient Response ◽  
Tumor Immunogenicity ◽  
Cellular Bioenergetics ◽  
Glycolytic Rate

BackgroundImmune checkpoint blockade therapy targeting PD-L1 has recently been approved for metastatic triple negative breast cancer (TNBC) patients. However, a 7% response rate calls for better models and strategies to stimulate TN-tumor immunogenicity to increase patient response. Overexpression of the receptor CD47 impairs innate and adaptive tumor immunosurveillance when engaged to its counter receptor SIRPα or ligand thrombospondin-1. Co-expression of CD47 and PD-L1 is implicated with disease progression in TNBC patients. We examined through murine models and tumor organoid platforms whether targeting CD47 sensitizes TNBC tumors to PD-L1 therapy, focusing on the modulation of cellular bioenergetics as a potential mechanism and potentially predict response.MethodsThe effects of targeting CD47 and PD-L1 were examined through orthotopic syngenic 4T1 and EMT-6 TNBC murine models. Due to predicting patient therapeutic response challenges, tumor organoid platforms investigated mechanisms of tumor sensitization to anti-PD-L1 by targeting CD47. Organoids were constructed by embedding murine TNBC tumor tissue and AH1 CD8+ T cells in a specialized ECM mimicking hydrogel. Immunohistochemistry was performed on organoid, human and murine TNBC tumor tissue. Cellular bioenergetics was analyzed through Seahorse® bioanalyzer.ResultsStaining of human TNBC biopsies found elevated CD47 expression, signifying a potential therapeutic target. Targeting CD47 or in combination with anti-PD-L1 resulted in decreased tumor volume and weight in a TNBC murine model. The decrease in tumor burden was correlated with increased intratumoral granzyme B secreting CD8+ T cells. Additionally, targeting CD47 within organoids increased IFNγ and granzyme B released, indicating enhanced CD8+ T cell cytolytic capacity. Differential cellular bioenergetics was observed between cancer and T cells suggesting a shift in metabolism in the tumor microenvironment. CD47 targeted T cells had an increased glycolytic rate compared to WT T cells. Conversely CD47 targeted TNBC cells had a decreased glycolytic rate, which may be correlated with decreased PD-L1 expression.ConclusionsTargeting CD47 enhanced granzyme B and IFNγ expression suggesting potential mechanisms to increase tumor immunogenicity. CD47 targeted monotherapy or combination with anti-PD-L1 preserves T cell bioenergetics and antitumor function, resulting in decreased TNBC tumor burden. Alternatively, CD47 targeted TNBC had a decreased glycolytic rate and decreased PD-L1 expression, which is reported to regulate glycolysis through Akt/mTOR signaling. Targeting CD47 on T cells enhances their bioenergetics and antitumor function while decreasing TNBC cell bioenergetics, making them more susceptible to immune cell killing. Our data indicates that CD47 targeted monotherapy or combination with anti-PD-L1 may enhance TNBC patient response and improve overall survival.AcknowledgementsDSP and SS are supported by the Wake Forest Comprehensive Cancer Center Breast Cancer Center of Excellence Pilot Award. DSP is also supported by the ASTRO-BCRF Career Development Award (637969) while ERS is supported by NIGMS T32 (GM127261).Ethics ApprovalAnimal studies were approved by the Institutional Care and Use Committee, Wake Forest Health Sciences.

Defective γδ T-Cell Function and Granzyme B Gene Polymorphism in Newly Diagnosed Breast Care Patients. Expansion with Zoledronic Acid Partially Compensates for This Deficiency.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3880-3880
Author(s):  
Ameera Gaafar ◽  
Abdulla Al-Sulaiman ◽  
Alia Iqniebi ◽  
Adher Al-Sayed ◽  
Entezam Sahovic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Zoledronic Acid ◽  
Gene Polymorphism ◽  
Cancer Patients ◽  
Granzyme B ◽  
Γδ T Cells ◽  
Breast Cancer Patients ◽  
Ifn Γ ◽  
Normal Controls

Abstract It has been well established that γδ T-cells play a role in innate anti-tumor immunity. However, the exact mechanism has not yet been fully elucidated. Most of these responses have been ascribed to Vγ9Vδ2 cells, which represent a major subset of the circulating γδ T-cells in humans (1–10%). IFN-γ and granzyme B are important molecules in the anti-tumor immune responses. Upon stimulation, γδ T-cells rapidly produce IFN-γ and cytotoxic molecules. In the present study we analyzed the immune responses by γδ T-cells in 30 newly diagnosed breast cancer patients and 30 normal controls before and after expansion with zoledronic acid. We also scanned the granzyme B gene polymorphism in breast cancer patients and controls. Our result revealed that γδ-T cells in PBMC were reduced in both frequency and function in breast cancer patients compared with the normal controls. Ex-vivo stimulation of γδ T-cells with zoledronic acid and IL-2 partially compensated for this deficiency, as it stimulates production of IFN- γ and release of cytotoxic molecules by these cells. However, the IFN- γ and granzyme B and cytotoxicity of the expanded γδ T-cells from breast cancer patients remained significantly below normal control. Genotypic analysis of granzyme B gene revealed significantly higher frequency of the RAH haplotype in breast cancer patients compared with normal controls. The prevalence of the wild genotype QPY/QPY was significantly higher in normal controls compared with the breast cancer patients. Cytotoxicity by γδ T-cells against various targets was reduced in breast cancer patients compared to normal controls. In conclusion, our analysis shows a defective immune function of γδ T-cells and granzyme B gene polymorphism in breast cancer patients. The γδ T-cell function defect in these patients can be partially corrected by zoledronic acid. Further studies of γδ T-cell function and granzyme B gene polymorphism in other cancers, as well as the therapeutic use of zoldedronic acid is warranted.

Metastatic Tumor Volume and Extranodal Tumor Extension: Clinical Significance in Patients With Stage II Breast Cancer

2015 ◽  
Vol 139 (10) ◽  
pp. 1288-1294 ◽  
Author(s):  
Eva Drinka ◽  
Pamela Allen ◽  
Andrew McBride ◽  
Thomas Buchholz ◽  
Aysegul Sahin
Keyword(s):  
Breast Cancer ◽  
Multivariate Analysis ◽  
Lymph Node ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Metastatic Tumor ◽  
Tumor Burden ◽  
Cancer Center ◽  
Lymph Node Status ◽  
Tumor Extension

Context Lymph node status and the number of lymph node (LN) positive for cancer cells are the most important prognostic factors in breast cancer. Extranodal tumor extension (ENTE) has been used as a histopathologic feature to classify patients into high risk versus low risk for local recurrence. However, in the current era of early detection and systemic therapy, the prognostic significance of ENTE is not as well defined in patients with 1 to 3 LNs positive for cancer. Objective To determine whether the amount of tumor burden in an axillary dissection or the presence of ENTE provides any additional information regarding patient outcome in patents with 1 to 3 positive LN results. Design Clinical and pathologic factors were identified for 456 patients with breast cancer at the University of Texas MD Anderson Cancer Center, Houston, who had pT1 tumors and 1 to 3 LNs positive for cancer and were treated by mastectomy, with or without postmastectomy radiotherapy, between 1978 and 2007. Results Of the 456 patients, 257 (56.4%), 141 (31.6%), and 58 (12.7%) patients had 1, 2, or 3 positive LN results, respectively. Extranodal tumor extension was present in 99 patients (21.7%) and was absent in the remaining 357 cases (78.3%). Seventy-six patients (16.7%) received radiation therapy. Patients had both worse overall survival time and disease-free survival when ENTE was present, regardless of the amount, as long as the treatment era was not included in the multivariate analysis (pre-2000 versus post-2000). However, ENTE was no longer significant on multivariate analysis when the year of treatment was taken into account. Conclusions The number of positive LNs remains an important predictor of survival in patients with 1 to 3 positive LN results, but the prognostic significance of ENTE in this cohort of patients has diminished over time.

Telomere-Based Pre-Clinical Therapy of Human Lymphoid Malignancy in a SCID Xenograft Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4761-4761
Author(s):  
Harold O. Longe ◽  
Anupama Sinha ◽  
Douglas V. Faller ◽  
Gerald V. Denis
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Lymphoid Malignancy ◽  
Vitro Assay ◽  
Human T Cell

Abstract We continue to develop and extend our novel adjuvant therapy approach to lymphoid malignancy. We supplement CHOP with DNA oligonucleotides that mimic the chromosomal telomere, which we call a “T oligo.” These agents are homologous to the 3′ overhang nucleotide sequence of telomeres and have previously been shown to have anti-tumor activity in animal models of malignant melanoma and breast cancer. They are currently being evaluated in melanoma and breast cancer patients. If introduced into human or murine normal, proliferating primary B cells or T cells, T oligo causes transient cell cycle arrest, while exerting no toxicity, but if introduced into human or murine malignant B cells or T cells, the arrest is followed by p53 phosphorylation, p21 message induction and ultimately p53-dependent apoptosis. Other p53-related effector molecules, such as p73, are also likely to be involved. The mechanism immediately suggests a novel method of chemotherapy for leukemia and lymphoma as an adjuvant with CHOP. Furthermore, we have previously shown with in vitro assay and in vivo mouse models of diffuse large B cell lymphoma (DLCL) that T oligo produces a more-than-additive toxicity towards lymphoma cells when combined with vincristine. T oligo alone or in combination with sub-therapeutic doses of CHOP, the standard of care for DLCL, dramatically reduced lymphoma burden in spleen, lung, bone marrow and peritoneum. In combination, which we refer to as T-CHOP, there was a greater reduction in tumor burden than with either therapy alone. We now show in SCID mouse xenograft models of human T cell malignancies, using a Jurkat T cell leukemic line or a MOLT-4 T cell leukemic line that T oligo also works alone to reduce tumor burden dramatically and increase survival. Interestingly, because T oligo-driven apoptosis occurs in p53-null, human lymphoid tumors, even chemotherapy-resistant lymphoid tumors are nevertheless sensitive to T oligo treatment, which may have profound benefit for relapsed leukemia or lymphoma patients.

scholarly journals Synergy of chemotherapy and macrophage depletion leads to T cell memory activation and durable triple negative breast cancer regression

2021 ◽  
Author(s):  
Swarnima Singh ◽  
Nigel Lee ◽  
Igor Bado ◽  
Clark Hamor ◽  
Licheng Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Mouse Models ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Lung Metastases ◽  
Developmental Trajectory ◽  
Null Mouse ◽  
Murine Models

AbstractImmunosuppressive elements within the tumor microenvironment such as Tumor Associated Macrophages (TAMs) can present a barrier to successful anti-tumor responses by cytolytic T cells. We employed preclinical syngeneic p53 null mouse models of TNBC to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose chemotherapy coupled with the pharmacologic inhibition of TAMs. Combination therapy was used to successfully treat several highly aggressive, claudin-low murine mammary tumors and lung metastasis. Long-term responders developed tertiary lymphoid structures co-infiltrated by T and B cells at the treatment site. Mechanistically, CD86+ antigen-experienced T cells exhibited polyclonal expansion and resulted in exceptional responses upon tumor rechallenge. Combination treatment also eliminated lung metastases. High dimensional transcriptomic data for CD45+ immune cells lead to the identification of an aberrant developmental trajectory for TAMs that were resistant to treatment. Signatures derived from these TAM populations were predictive of patient response to our therapy. This study illustrates the complexity of tumor infiltrating myeloid cells and highlights the importance of personalized immuno-genomics to inform therapeutic regimens.Statement of significanceTriple negative breast cancer is aggressive and hard to treat as it has no targeted therapies. Targeting immunosuppressive macrophages in murine models of TNBC alongside an immunostimulatory chemotherapy achieved long-term primary tumor regression in multiple murine mouse models. The transcriptomic heterogeneity between TAMs in phenotypically similar models can be used to uncover future therapeutic targets. Additionally, signatures derived from these murine models can be applied to TNBC patient data sets to predict cohorts of patients that will respond to the treatment strategy.

scholarly journals Clinical impact of PD-L1 expression in triple-negative breast cancer patients with residual tumor burden after neoadjuvant chemotherapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gizem Oner ◽  
Semen Önder ◽  
Hüseyin Karatay ◽  
Naziye Ak ◽  
Mustafa Tükenmez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Residual Tumor ◽  
Tumor Burden ◽  
Cancer Center

Abstract Background Studies on PD-L1 expression in breast cancer have gained importance in recent years, especially in triple-negative breast cancer (TNBC). Our aim was to analyze the differential expression of PD-L1 to explore its correlation with response to neoadjuvant chemotherapy (NACT) and patient survival. Methods PD-L1 expression was evaluated immunohistochemically (Ventana SP263 clone kit) by staining tumor specimen. PD-L1 positivity was defined as membranous staining > 1%, > 5%, > 10%, and > 20% on either tumor cell (TC) and /or immune cell (IC). Results Fifty patients with locally advanced TNBC, who had a partial response to NACT, were included in the study. PD-L1 staining was observed in TCs in 25 patients (50%) and in ICs in 23 patients (46%) when PD-L1 > 1% was considered positive. Patients with PD-L1 positivity on ICs were more likely to respond to chemotherapy as measured by “MD Anderson Cancer Center Residual Cancer Burden Index” (14/22, 63.6% vs. 10/27, 37%, p = 0.064). The 5-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 46.3% and 51.4%, respectively. A high (> 20%) tumoral PD-L1 positivity was associated with a better DFS and DSS. Conclusions Studies in the literature mostly focused on PD-L1 expression in inflammatory cells. However, our results suggest that patients with a high PD-L1 expression on TCs were more likely to have a better outcome. Since patients with residual tumor burden who express PD-L1 on TILs were more likely to respond to NACT, an immune checkpoint inhibitor therapy in addition to NACT would be an important option for TNBC with locally advanced disease.

scholarly journals The Breast Cancer Immune Microenvironment is Modified by Neoadjuvant Chemotherapy

2021 ◽  
Author(s):  
Claudia Urueña ◽  
Paola Lasso ◽  
David Bernal-Estevez ◽  
Diego Rubio ◽  
Ana Janeth Salazar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Neoadjuvant Chemotherapy ◽  
Complete Response ◽  
Tumor Burden ◽  
Response To Treatment ◽  
Activated T Cells ◽  
Metastatic Cells ◽  
The Impact

Abstract Neoadjuvant chemotherapy (NAT) in breast cancer (BC) has been used to reduce tumor burden prior to surgery. However, the impact on prognosis depends on the establishment of Pathological Complete Response (pCR), which is influenced by tumor-infiltrating lymphocyte levels and the activation of the antitumor immune response. Nonetheless, NAT can affect immune infiltration and the quality of the response. Here, we showed that NAT induces dynamic changes in the tumor microenvironment (TME). After NAT, an increase of regulatory T cells and a decrease of CD8 + T cells was found in tumor, correlated with the presence of metastatic cells in lymph nodes. In addition, an increase of polymorphonuclear myeloid-derived suppressor like cells was found in luminal patients post-NAT. pCR patients showed a balance between the immune populations, while non-pCR patients presented an inverse relationship in the frequency of CD68 + versus CD3 + , CD8 + , and CD20 + cells. Moreover, activated T cells were found in peripheral blood, as well as an increase in T cell clonality with a lower diversity post-NAT. Overall, these results shown that NAT induces an activation of immune response, however, a balance in the TME seems to be related to a better antigenic presentation and therefore a better response to treatment.

Relevance of αβ-DNTs as Prognostic Factor on Clinical Outcome and Role on Tumor Surveillance in Haematological Diseases and Solid Tumor: Preliminary Evaluations

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3840-3840
Author(s):  
Giacoma De Tullio ◽  
Carla Minoia ◽  
Margherita Gigante ◽  
Sabino Strippoli ◽  
Simona Serratì ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Outcome ◽  
Ex Vivo ◽  
Granzyme B ◽  
Therapy Response ◽  
Tumor Burden ◽  
Tumor Surveillance ◽  
Functional Studies ◽  
Anti Tumor Activity

Abstract The mutual interactions between the host immune system and cancer cells may either promote or control oncogenesis. Cancer immunotherapies remain viable approaches to sustain patient survival. However, positive clinical response of phase I/II clinical trials remains still to low. The Double negative T cells (DNTs) have emerged as new subset of T cells that contributes specifically to anti- tumor immunity since involved in immune regulation and tolerance acting as regulatory T cells (Treg) and/or cytotoxic T cells. DNTs express either αβ or γδ T-cell receptors (TCR) or lack CD4, CD8 and CD56. Functional studies showed that DNTs might have a direct in vitro anti-tumor activity against lymphoma and melanoma cells. However no data are available on their prognostic significance, modulation during the therapy response and their ability to kill tumor cells in cooperation with other immune cells such as DCs to explain their role in human anti-lymphoma immunity. Knowledge of the DNTs role in tumor surveillance and as prognostic factor for clinical outcome has a strong clinical valence and might allow us to design new approaches of therapeutic strategy. The aim of this study was to evaluate the DNTs during therapy response in lymph nodes (LN), bone marrow (BM) and peripheral blood (PB) of both lymphoma (Ly), Renal Cell Carcinoma (RCC) and Metastatic Melanoma (MM) patients (pts) in order to assess their role on clinical outcome, progression and tumor surveillance. PB and BM samples of 90 Ly pts, with NHL and cHL were collected at diagnosis and during the follow-up (1-6-12 months after chemo- or immuno-chemotherapy therapy). PB samples of 16 healthy donors were collected as control. Twenty fresh LN tissues from pts clinically suggestive of Ly were quickly processed. To evaluate the interaction of DNTs with tumor burden either 22 samples from RCC pts and 30 samples from MM pts were collected. The ontogeny, functional attitude and TCR clonality of DNT subsets (TCRαβ+ and TCRγδ+) were evaluated by following antibodies: CD3, CD4, CD8, CD56, CD45, TCRαβ, CD45Ra, CD45Ro, CCR7, CD27, CD28, CD30, CD69, GITR, CD95, CD178, CD152, IFN-γ, TNF-α, perforin and granzyme B. For functional studies, DNTs were purified from PBMCs through a negative selection and then cultured for 2 weeks. Data were acquired by 8-colour flow cytometer and analysed using Kaluza software. Other immune cells such as DCs, MDSCs and Treg was also detected to evaluate the correlation with DNTs. 7 cases of LNs received a finally diagnosis of reactive follicular hyperplasia (RFH) so they were considered as controls. All pts provided their informed consent in accordance with the Declaration of Helsinki. We observed a significant decrease (p =0.006) of circulating αβ-DNTs in untreated Ly pts (20.5 cells/ul ± 4.8) as compared with healthy controls (31.3 cells/ul ± 3.4) (fig.1-2) and their number seemed to be modulated during the follow-up. Their frequency in 1-month post-cht or disease relapsed pts was significantly decreased (p=0.006) as compared with the diagnosis as well as when compared indolent with aggressive histotypes (p=0.0001). In HL pts the frequency of αβ-DNT was significantly increased as compared with other histotypes (p=0.005) (Fig.3) Furthermore, the αβ-DNTs in LNs of Ly pts were significantly reduced as compared to to RFH-LNs (p=0.006) (fig.5) and are related to the aggressiveness of the disease. When evaluated either in MM and RRC pts the αβ-DNTs were significantly decreased (p=0.001) as compared with healthy controls and more interestingly when compared with Ly pts (p=0.001) given the greater immunological impairment of RCC/MM tumor burden (fig.6). Finally, ex vivo expanded DNTs acquired an immunomodulatory cytokine profile, characterized by the secretion of IFN-gamma and granzyme B, which are known as central components of anti-tumor immune responses supporting the hypothesis of αβ-DNT potential use in immunotherapeutic strategies (fig.4) Our preliminary data, showed an inverse correlation between the frequency of circulating αβ-DNTs and the tumor condition as well as that they could play an important role in both the development and the progression of lymphomas. This is the first study that compares the frequency of αβ-DNTs in three different pathologies correlating to tumor burden. In addition, it is likely that ex-vivo expanded DNTs exert an anti-tumor activity thus suggesting their possible use as a new strategy for adoptive immune-therapy. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Biological characteristics and prognostic value of Tfh-like cells in the tumor tissue of breast cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 5-5
Author(s):  
Linxiaoxi Ma ◽  
Liang Guo ◽  
Shyamal Goswami ◽  
Xiaoming Zhang ◽  
Jiong Wu
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Prognostic Value ◽  
Cell Subpopulation ◽  
Multiparameter Flow Cytometry ◽  
Cancer Center ◽  
Low Grade ◽  
Ki 67 ◽  
High Level ◽  
Er Expression

5 Background: T follicular helper (Tfh) cells formed in germinal center are CXCR5+ICOS+PD-1hiBcl-6+CXCL13+IL-21+CD4+ T cells. They have been identified in different types of tumors. However, it still remains unclear in breast cancer, with one indicating the positive prognostic value of 8-gene Tfh signature. Methods: Freshly resected invasive breast cancer tissues from Fudan University Shanghai Cancer Center of all 386 patients were collected during 03/2015 to 05/2017. Data was analyzed based on the result from Multiparameter Flow Cytometry and IHC. The correlation between Tfh-like cells and clinicopathological characteristics in breast cancer was examined with t test or one way ANOVA with Tukey’s multiple comparisons test. Results: A subpopulation of PD1hiCD4+ T cells in the tumor tissues of breast cancer was identified as Tfh-like cells, with the specific expression of Bcl-6 and CXCL13. Tfh-like cells were of a high level of ICOS but negative for CXCR5. They had high levels of activated molecules such as CD38, CD71, CD95 and HLADR, high levels of suppressive markers as Tim3, TIGIT, and LAG3 and high level of proliferation marker Ki-67, specifically secreting cytokine IL-21 with stimulation. Data showed that high grade (N = 166; mean±SEM, 17.62±0.87) compared with low grade (N = 220; mean±SEM, 12.41±0.46) or high Ki-67 level (N = 300; mean±SEM, 15.38±0.58) with low Ki-67 level (N = 86; mean±SEM, 12.10±0.67), and negative ER expression (N = 115; mean±SEM, 17.47±1.05) compared with positive ER expression (N = 271; mean±SEM, 13.46±0.50) or negative PR expression (N = 177; mean±SEM, 16.87±0.83) compared with positive PR expression (N = 209; mean±SEM, 12.77±0.50) was associated with higher frequency of Tfh-like cells (P < 0.01 to all). Patients with triple negative had higher frequency of Tfh-like cells than those with Luminal A (difference, 6.83; P = 0.0006) and Luminal B (HER2-) (difference, 4.61; P = 0.0124). These results indicate that higher frequency of Tfh-like cells could have negative prognostic influence. Conclusions: Our study defined a PD1hiBcl6+CXCL13+CD4+IL-21+ T cell subpopulation. Higher frequency of Tfh-like cells is more likely to be seen in patients with poor prognosis.

scholarly journals 757 Intratumoral delivery CD40 agonist antibody via novel nanofluidic drug-eluting seed reduced tumor burden of murine pancreatic ductal adenocarcinoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A805-A805
Author(s):  
Hsuan-Chen Liu ◽  
Dixita Viswanath ◽  
Robin Vander Pol ◽  
Corrine Chua ◽  
Alessandro Grattoni
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Treatment Efficacy ◽  
Tumor Burden ◽  
List Type ◽  
Significant Difference ◽  
Drug Eluting ◽  
Intratumoral Delivery ◽  
Delivery Approach

BackgroundPancreatic adenocarcinoma (PDAC) is associated with extremely poor prognosis and a 5-year survival rate of 10% and remains a lethal malignancy. Surgical resection and combination with chemoradiotherapy are the current standard-of-care options, may improve long-term survival in localized disease; however, the majority of patients are diagnosed at advanced stage. The incorporation of immunotherapy in the treatment algorithm convenes a new era for PDAC treatment. Several immunotherapy approaches have been investigating for treating PDAC such as checkpoint inhibitors, vaccines, adoptive cell therapy, and so on. Immunotherapy has been shown as a promising therapeutic method for many cancer types; however, the complexity and immunosuppressive of the solid tumor microenvironment (TME) results in limited treatment efficacy for PDAC.MethodsTo sensitize the TME in response to immunotherapy, we developed an implantable intratumoral drug delivery device, Nanofluidic Drug-Eluting Seed (NDES) can be injected via a minimally invasive trocar system that feasible for the clinical setting. NDES has shown efficiently delivered immunotherapy to murine breast cancer model and reduced tumor burden and showed low liver inflammation compared to the intraperitoneal delivery approach in the previous study.1 2 Here, we utilized NDES for the sustained intratumoral delivery of the CD40 antibody. We compared the efficacy of NDES against intraperitoneal and intratumoral administration, which mimics conventional systemic treatment. Tumor growth was investigated for treatment efficacy. Local and systemic immune responses were assessed via flow cytometry.ResultsNDES delivered CD40 significantly reduced tumor burden, some even achieved tumor clearance. Local NDES CD40 delivery approach showed a systemic increase of CD8+ and CD4+ T cells in the tumor-draining lymph node and spleen by flow cytometry. Furthermore, NDES CD40 treated mice showed an increase of CD8+ and CD4+ central memory T cells locally and systemically. We also investigated the combination with radiotherapy, no significant difference in tumor burden was observed when compared to single-agent CD40 antibody. The results indicated CD40 promotes TME response and improved treatment efficacy.ConclusionsThese immunological responses demonstrate ‘cold’ to ‘hot’ tumor transformation, which translated to tumor burden reduction. Overall, NDES delivery strategy offers promise for enhancing therapeutic index and transforming the landscape of PDAC tumor therapy.ReferencesLiu H-C, Viswanath D, Pesaresi F, et al. Potentiating antitumor efficacy through radiation and sustained intratumoral delivery of anti-CD40 and anti-PDL1. Int J Radiat Oncol Biol Phys 2020;S0360-3016(20)33745-7.Chua CYX, Jain P, et al. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer. J Control Release 2018;285:23–34.

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