Immune Checkpoint Blockade Combinations As Promising Strategy for Cancer Immunotherapy in Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2059-2059 ◽  
Author(s):  
Barbara Castella ◽  
Myriam Foglietta ◽  
Patrizia Sciancalepore ◽  
Ezio Tripoli ◽  
Mario Boccadoro ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Single Agent ◽  
Immune Checkpoint Blockade ◽  
Advisory Board ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Myeloma Cells ◽  
Vγ9vδ2 T Cells

Abstract Tumor cells exploit immune checkpoints to withstand immune recognition and effector cells' onslaught. Pre-clinical findings, corroborated by initial results of clinical studies, indicate that immune checkpoint blockade is a promising strategy to harness anti-tumor immune responses and improve the clinical outcome of patients with hematological malignancies. Multiple myeloma (MM) is a prototypic disease in which immune checkpoints significantly contribute to the immune suppressive contexture that myeloma cells establish in the bone marrow (BM) in cooperation with regulatory T cells (Tregs), myeloid derived suppressor cells (MDSC), and BM stromal cells (BMSC). Vγ9Vδ2 T cells are among the immune effector cells strategically victimized by suppressor cells. These are non-conventional T cells halfway between innate and adaptive immunity with a natural inclination to react against malignant B cells, including myeloma cells. Vγ9Vδ2 T cells are equipped with a peculiar array of receptors for stress-induced self-ligands and a unique TCR-dependent recognition ability of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. Recently, we have shown that BM Vγ9Vδ2 T cells are anergic to pAg stimulation and that the programmed death 1(PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pair contributes to their dysfunction. This is an early event already detectable in individuals with monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even when MM patients achieve clinical remission after autologous stem cell transplantation (auto-SCT). Anti-PD-1 treatment partially recovers the ability of BM Vγ9Vδ2 T cells to proliferate and exert cytotoxic activity after pAg stimulation, but early studies based on single-agent PD-1 blockade have fallen short of clinical expectations in MM. Thus, several strategies are under consideration to implement the clinical efficacy of immune checkpoint blockade like the association with lenalidomide and/or concurrent tumor vaccination. Our results indicate that TIM-3 is significantly upregulated in BM Vγ9Vδ2 T cells from MM patients at diagnosis. We have previously shown that pAg stimulation of PD-1+ BM Vγ9Vδ2 T cells further increase PD-1 expression and preliminary data suggest that this stimulation also increases TIM-3 expression. Interestingly, TIM-3 up-regulation is even more pronounced than PD-1 up-regulation in BM Vγ9Vδ2 T cells and it occurs also in peripheral blood (PB) Vγ9Vδ2 T cells from anergic MM patients. We have recently shown that pAg reactivity of BM Vγ9Vδ2 T cells from MM at diagnosis can be partially recovered by PD-1 blockade. Our results reveal that TIM-3 blockade is also able to partially recover pAg-induced Vγ9Vδ2 T-cell proliferation. The best recovery is obtained when pAg stimulation is carried out in the presence of concurrent PD-1 and TIM-3 blockade. BM Vγ9Vδ2 T cells from MM patients who are in remission (MM-rem) after auto-SCT are still PD1+ and anergic to pAg stimulation. Remarkably, percentages of PD-L1+ MDSC in the BM of MM-rem are also unchanged compared to MM at diagnosis (MM-dia) and MM in relapse (MM-rel). These data indicate that the immune suppressive contexture is still operative at the tumor site even when most of myeloma cells have been cleared by chemotherapy. Interestingly, chemoresistant residual myeloma cells after auto-SCT have been reported to be PD-L1+, and circulating exhausted PD-1+ CD8+ T cells have been described in the PB after auto-SCT. This may explain why our previous idiotype vaccination studies in MM patients have failed. We have initiated to investigate the effect of immune checkpoint blockade in different phases of the disease and preliminary results suggest that the functional outcome of PD-1 blockade can be very different according to the disease status: the most signifcant recovery of Vγ9Vδ2 T-cell proliferation is observed after PD-1 blockade in MM-rem, while the anergy of Vγ9Vδ2 T cells from MM-rel is totally refractory to immune checkpoint blockade. In conclusion, our results suggest that recovery of pAg reactivity by PB Vγ9Vδ2 T cells is a reliable biomarker to predict or assess the clinical efficacy of immune checkpoint in vivo and provide scientific groundwork to optimize anti-PD1 treatment as single agent or in combination with other antibodies (i.e, anti-TIM-3) to maximize the efficacy of immune checkpoint blockade according to the disease status. Disclosures Boccadoro: Amgen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Abbivie: Honoraria. Massaia:Roche: Other: advisory board, research support; Janssen: Other: advisory board; Gilead: Other: advisory board.

scholarly journals The NLPHL Tumor Microenvironment Is Markedly Enriched in the Tigit and PD-1 Signalling Axes Compared to Classical Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3513-3513
Author(s):  
Jay Gunawardana ◽  
Muhammed B. Sabdia ◽  
Karolina Bednarska ◽  
Soi C. Law ◽  
Sandra Brosda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Advisory Committees ◽  
Tcr Repertoire

Abstract Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) comprises 5% of all Hodgkin lymphomas (HL). Its biology remains poorly characterized. Like classical HL (cHL), it contains minimal malignant cells embedded within a T cell rich intra-tumoral microenvironment (TME). Unlike cHL, it can transform to diffuse large B cell lymphoma (DLBCL). Immune-checkpoint blockade is effective in cHL but has minimal activity in DLBCL. No data is currently available regarding the potential to reactivate host anti-tumoral activity via immune-checkpoint blockade in NLPHL. Diagnostic FFPE samples from 49 NLPHL patients retrospectively collected from 4 Australian centres were interrogated. Inclusion criteria were sample availability and centrally confirmed histological NLPHL. Characteristics were in line with the literature: median age 45 years, range 13-82 years; F:M 1:3.5; stage I/II 55%, III/IV 35% (10% stage unknown) with the majority of cases were of immuno-architectural types A or C. RNA was digitally quantified using the NanoString 770-gene PanCancer Immune panel. Multi-spectral immunofluorescent (mIF) microscopy, plasma soluble PD-1 quantification, cell sorting, T cell receptor (TCR) repertoire analysis and functional immuno-assays were also performed. Results were compared with samples from 38 cHL and 35 DLBCL patients. We initially compared gene expression of NLPHL and cHL, looking for molecular similarities and differences. Ten non-lymphomatous nodes (NLN) were included as controls. Unsupervised clustering showed all but 3 NLPHL cases segregated from the cHL cluster. All NLN congregated in a discrete sub-cluster. As expected, RNA analysis showed significant enrichment for CD20 in NLPHL and CD30 in HL. Volcano plots (Fig. 1a), corrected for false-discovery showed marked variation in gene expression. For NLPHL (vs. cHL) there were 105 upregulated and 337 down regulated genes. Strikingly, the most significantly differentially over-expressed genes in NLPHL were all T cell related (CD247: CD3 zeta chain; CD3D: CD3 delta chain; GZMK: granzyme K; EOMES: marker of CD8 + T cell tolerance; and the immune checkpoints PDCD1: encodes for PD-1; and TIGIT). CD8B expression was increased in NLPHL. For cHL, the most over-expressed genes included macrophage-derived chemokines CCL17 and CCL22. Gene set enrichment analysis revealed activation of the PD-L1 expression and PD-1 checkpoint pathway and 9 of the top 10 Gene Ontology (GO) term enrichment scores involved lymphocyte signalling in NLPHL (Fig. 1b). To better appreciate the impact of the relevant immune checkpoints on their signalling axis, we compared gene ratios for PD-1 and TIGIT receptors with their ligands (PD-L1/L2 and PVR, respectively). NLPHL showed the highest enrichment ratios of these signalling pathways vs. cHL, DLBCL and NLN (Fig. 1c). Although it is known that CD4 +PD-1 +T cells form rosettes around NLPHL cells, the differential cellular localization of immune proteins has not been compared between HL entities. Using mIF, the proportion of intra-tumoral PD-1 + was markedly higher for CD4 + (~7-fold; p<0.0001) and CD8 + (~5-fold; p<0.001) T cells in NLPHL. However, the proportion of T cells expressing LAG3 was similar. Soluble PD-1 was elevated for both NLPHL and cHL, indicating circulating blood is influenced by the TME. For both HL entities over 80% of circulating CD4 + and CD8 + T cells expressed PD-1 alone or in combination with TIGIT. TCR repertoire analysis of sorted T cell subsets showed large intra-tumoral clonal T cell expansions were also detectable in circulating T cells. T cell clones were predominantly PD1 +CD4 + T cells in both HL types. Finally, we developed a functional assay using PD-L1/PD-L2 expressing NLPHL and cHL cell lines. These were co-cultured with genetically engineered PD-1 +CD4 + T cells that express a luciferase reporter. Similar levels of heightened T cell activation were seen with immune-checkpoint blockade for both HL entities, indicating that immune-checkpoint inhibition may also be of benefit in NLPHL. In conclusion, our multi-faceted analysis of the immunobiological features of the TME in NLPHL, provides a compelling rationale for early phase clinical studies that incorporate immune-checkpoint blockade in NLPHL. Figure 1 Figure 1. Disclosures Hawkes: Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Merck KgA: Research Funding; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau. Swain: Janssen: Other: Travel expenses paid; Novartis: Other: Travel expenses paid. Keane: BMS: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Karyopharm: Consultancy; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Talaulikar: Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Roche: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Gandhi: janssen: Research Funding; novartis: Honoraria.

scholarly journals 836 Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A888-A888
Author(s):  
Laura Ridgley ◽  
Angus Dalgleish ◽  
Mark Bodman-Smith
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Tumour Cell ◽  
Immune Checkpoint ◽  
Expansion Method ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Inhibitory Receptors ◽  
Healthy Donors ◽  
Vγ9vδ2 T Cells

BackgroundVγ9Vδ2 T-cells are a subset of cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses, often exploited in cancer immunotherapy. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of activatory and inhibitory markers on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy.MethodsPBMCs were isolated from healthy donors and the expression of activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry at baseline, following 24 hours activation and 14 days expansion using zoledronic acid (ZA) and Bacillus Calmette-Guerin (BCG), both with IL-2. Activation and expansion of Vδ2 cells was assessed by expression of CD69 and by frequency of Vδ2 cells, respectively. Production of effector molecules was also assessed following coculture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also assessed.ResultsVγ9Vδ2 T-cells constitutively expressed high levels of NK-associated activatory markers NKG2D and DNAM1 which remained high following stimulation with ZA and BCG. Vγ9Vδ2 T-cells expressed variable levels of checkpoint inhibitor molecules at baseline with high levels of BTLA, KLRG1 and NKG2A and intermediate levels of PD1, TIGIT and VISTA. Expression of checkpoint receptors were modulated following activation and expansion with ZA and BCG with decreased expression of BTLA and upregulation of numerous markers including PD1, TIGIT, TIM3, LAG3 and VISTA. Expression of these markers is further modulated upon coculture with tumour cell lines with changes reflecting activation of these cells with Vγ9Vδ2 T-cells expressing inhibitory receptors PD1 and NKG2A producing the highest level of TNF.ConclusionsOur data reveals unique characteristics of Vδ2 in terms of their expression of immune checkpoints, which provide a mechanism which may be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. Our work suggests different profiles of immune checkpoints dependent on the method of stimulation. This highlights importance of expansion method in the function of Vγ9Vδ2 T-cells. Furthermore, this work suggests important candidates for blockade by immune checkpoint therapy in order to increase the successful use of Vγ9Vδ2 T-cells in cancer immunotherapy.

scholarly journals Combined PD-L1 and TIM-3 blockade improves the expansion of fit human CD8+ antigen-specific T cells for adoptive immunotherapy

2021 ◽  
Author(s):  
Shirin Lak ◽  
Valérie Janelle ◽  
Anissa Djedid ◽  
Gabrielle Boudreau ◽  
Ann Brasey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Cell Expansion ◽  
Ex Vivo ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
T Cell Expansion ◽  
And Function

AbstractBackgroundThe stimulation and expansion of antigen-specific T cells ex vivo enables the targeting of a multitude of cancer antigens. However, clinical scale T-cell expansion from rare precursors requires repeated stimulations ex vivo leading to T-cell terminal effector differentiation and exhaustion that adversely impact therapeutic potential. We leveraged immune checkpoint blockade relevant to antigen-specific CD8+ human T cells to improve the expansion and function of T cells targeting clinically relevant antigens.MethodsA clinically-compliant protocol relying on peptide-pulsed monocyte-derived dendritic cells and cytokines was used to expand antigen-specific CD8+ targeting the oncogenic Epstein-Barr virus (EBV) and the tumor associated antigen (TAA) Wilms Tumor 1 (WT1) protein. The effects of antibody-mediated blockade of immune checkpoints applied to the cultures (T-cell expansion, phenotypes and function) were assessed at various time points. Genomic studies including single cell RNA (scRNA) sequencing and T-cell receptor sequencing were performed on EBV-specific T cells to inform about the impact of immune checkpoint blockade on the clonal distribution and gene expression of the expanded T cells.ResultsSeveral immune checkpoints were expressed early by ex vivo expanded antigen-specific CD8+ T cells, including PD-1 and TIM-3 with co-expression matching evidence of T-cell dysfunction as the cultures progressed. The introduction of anti-PD-L1 (expressed by the dendritic cells) and anti-TIM-3 antibodies in combination (but not individually) to the culture led to markedly improved antigen-specific T-cell expansion based on cell counts, fluorescent multimer staining and functional tests. This was not associated with evidence of T-cell dysfunction when compared to T cells expanded without immune checkpoint blockade. Genomics studies largely confirmed these results, showing that double blockade does not impart specific transcriptional programs or patterns on TCR repertoires. However, our data indicate that combined blockade may nonetheless alter gene expression in a minority of clonotypes and have donor-specific impacts.ConclusionsThe manufacturing of antigen-specific CD8+ T cells can be improved in terms of yield and functionality using blockade of TIM-3 and the PD-L1/PD-1 axis in combination. Overcoming the deleterious effects of multiple antigenic stimulations through PD-L1/TIM-3 blockade is a readily applicable approach for several adoptive-immunotherapy strategies.

scholarly journals Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4412-4412 ◽  
Author(s):  
Valentina Griggio ◽  
Candida Vitale ◽  
Maria Todaro ◽  
Francesca Romana Mauro ◽  
Chiara Salvetti ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Immune Cell ◽  
Absolute Number ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
Treatment Start ◽  
Vγ9vδ2 T Cells ◽  
The Absolute

Abstract Background: Chronic lymphocytic leukemia (CLL) is characterized by phenotypic and functional defects of immune cells, which often emerge into increased susceptibility to infections and autoimmunity, and also contribute to immune evasion of cancer cells. Ibrutinib is a selective inhibitor of BTK that shows activity via its direct effects on crucial survival pathways in CLL cells. In addition to its anti-neoplastic effects, ibrutinib has also shown to have immunomodulatory properties. Currently available data are mainly limited to the activity exerted by ibrutinib on conventional T cells, whereas little is known on the effects induced on other non-neoplastic immune cell populations. Aim: The aim of this study was to evaluate the in vivo immunomodulatory effects of ibrutinib treatment on different immune compartments in patients with CLL Methods: We included 11 CLL patients with progressive disease (PD CLL) and eligible to ibrutinib therapy. PB samples were collected from patients at baseline and after 1, 6 and 12 months of treatment with ibrutinib. For comparison, we also analyzed 5 healthy donors (HD) and 6 treatment-naïve CLL patients with stable disease (SD CLL), who were not fulfilling criteria for treatment start. We assessed the percentages and the absolute numbers of CLL cells, T cells, γδ (Vδ1 and Vγ9Vδ2) T cells, T regulatory cells (Tregs), natural killer (NK) and NK-T cells by flow cytometry using population-specific markers. The expression of activation markers and immune checkpoint receptors (i.e. CD69, PD-1, CD96, TIGIT, NKG2D) was evaluated by flow cytometry as well. Results: Median age of patients was 69 years (range 44-75). The median lymphocyte count at study entry was 49 x 109/L (range 1,8-110) and the median number of previous treatment regimens was 2 (range 0-5). After 12 months of ibrutinib, 10 out of 11 (91%) patients achieved at least a partial response. The mean absolute number of CLL cells started to decrease by month 6 and became significantly lower than baseline value at 12 months of ibrutinib therapy. At the baseline, leukemic cells from PD CLL had significantly higher surface expression of the early activation marker CD69 and of the immune checkpoint molecule PD-1 compared to SD CLL and HD. After 6 months of treatment, the percentage of CLL cells expressing CD69 and PD-1 was normalized (reached values not significantly different from HD) (Fig 1A,B). We observed a gradual reduction of the total count of CD4+ and CD8+ T cells during ibrutinib treatment, becoming significant at 12 months. At the same timepoint, the expression of CD69, which was higher on T cells from PD CLL prior to therapy compared to SD CLL and HD, was normalized. Concurrently, a significant reduction in the surface levels of the inhibitory immune checkpoint molecule CD96 was observed (Fig 1C,D). Ibrutinib treatment had no impact on the absolute numbers of NK and NK-T cells. Compared to SD CLL and HD, NK cells from PD CLL showed a higher expression of CD69 before treatment start. In addition, they were characterized by increased levels of the immune checkpoints CD96 and TIGIT, and by reduced expression of the Fc receptor CD16, that is involved in the ADCC process, and the activating receptor NKG2D. After 6 months of treatment, the expression of CD69, CD16 and NKG2D on NK cells were restored (Fig 1E-G), whereas TIGIT and CD96 were not yet significantly modulated. Concerning the Tregs, a trend toward a reduction in the absolute number was detected after 12 months of ibrutinib treatment, compared to the baseline. The percentage of Tregs expressing the co-inhibitory molecule TIGIT was higher in PD CLL at the time of treatment start and was normalized by 12 months of ibrutinib therapy (Fig 1H). Lastly, we assessed ibrutinib effects on γδ T cells. The absolute numbers of both Vδ1 and Vγ9Vδ2 T cells remained unchanged during patients' treatment. Similar to conventional T lymphocytes, Vγ9Vδ2 T cells showed a decrease in the expression of CD96 after 12 months of ibrutinib administration (Fig 1I). Conclusions: our data suggest that the anti-tumor activity of ibrutinib is paralleled by a valuable immunomodulatory effect, leading to a partial recovery of phenotypic alterations that are hallmarks of immune exhaustion. Further studies to investigate the ability of ibrutinib to restore the functionality of the described immune cell compartments and to explore clinical correlations are currently ongoing on an enlarged cohort of treated patients. Figure 1. Figure 1. Disclosures Mauro: abbvie: Other: board member; janssen: Other: board member. Gaidano:Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Foà:ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD. Boccadoro:AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding. Coscia:Janssen, Karyopharm: Research Funding; Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A highly stable multifunctional aptamer for enhancing antitumor immunity against hepatocellular carcinoma by blocking dual immune checkpoints

2021 ◽  
Author(s):  
Yanlin Du ◽  
Da Zhang ◽  
Yiru Wang ◽  
Ming Wu ◽  
Cuilin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints

A highly stable multifunctional aptamer was prepared for strengthening antitumor immunity through a dual immune checkpoint blockade of CTLA-4 and PD-L1.

scholarly journals Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma

2021 ◽  
Vol 14 (9) ◽  
pp. 101170
Author(s):  
Vera Bauer ◽  
Fatima Ahmetlić ◽  
Nadine Hömberg ◽  
Albert Geishauser ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii108
Author(s):  
Jayeeta Ghose ◽  
Baisakhi Raychaudhuri ◽  
Kevin Liu ◽  
William Jiang ◽  
Pooja Gulati ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Immune Checkpoint ◽  
Survival Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Control Group ◽  
Triple Combination ◽  
Triple Combination Therapy

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p < 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.

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