scholarly journals Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer

2021 ◽  
Vol 9 (11) ◽  
pp. e002917
Author(s):  
Shaoming Zhu ◽  
A-Hong Ma ◽  
Zheng Zhu ◽  
Elio Adib ◽  
Ting Rao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Pi3k Pathway ◽  
Immune Checkpoint Blockade ◽  
Mechanisms Of Action ◽  
Mtor Pathway ◽  
Checkpoint Blockade ◽  
Q Value ◽  
Secondary Resistance ◽  
Pi3k Inhibition

BackgroundImmune checkpoint blockade (ICB) induces durable response in approximately 20% of patients with advanced bladder urothelial cancer (aUC). Over 50% of aUCs harbor genomic alterations along the phosphoinositide 3-kinase (PI3K) pathway. The goal of this project was to determine the synergistic effects and mechanisms of action of PI3K inhibition and ICB combination in aUC.MethodsAlterations affecting the PI3K pathway were examined in The Cancer Genome Atlas (TCGA) and the Cancer Dependency Map databases. Human and mouse cells with Pten deletion were used for in vitro studies. C57BL/6 mice carrying syngeneic tumors were used to determine in vivo activity, mechanisms of action and secondary resistance of pan-PI3K inhibition, ICB and combination.ResultsAlterations along the PI3K pathway occurred in 57% of aUCs in TCGA. CRISPR (clustered regularly interspaced short palindromic repeats) knockout of PIK3CA induced pronounced inhibition of cell proliferation (p=0.0046). PI3K inhibition suppressed cancer cell growth, migration and colony formation in vitro. Pan-PI3K inhibition, antiprogrammed death 1 (aPD1) therapy and combination improved the overall survival (OS) of syngeneic mice with PTEN-deleted tumors from 27 days of the control to 48, 37, and 65 days, respectively. In mice with tumors not containing a PI3K pathway alteration, OS was prolonged by the combination but not single treatments. Pan-PI3K inhibition significantly upregulated CD80, CD86, MHC-I, and MHC-II in dendritic cells, and downregulated the transforming growth factor beta pathway with a false discovery rate-adjusted q value of 0.001. Interferon alpha response was significantly upregulated with aPD1 therapy (q value: <0.001) and combination (q value: 0.027). Compared with the control, combination treatment increased CD8+ T-cell infiltration (p=0.005), decreased Treg-cell infiltration (p=0.036), and upregulated the expression of multiple immunostimulatory cytokines and granzyme B (p<0.01). Secondary resistance was associated with upregulation of the mammalian target of rapamycin (mTOR) pathway and multiple Sprr family genes.ConclusionsThe combination Pan-PI3K inhibition and ICB has significant antitumor effects in aUC with or without activated PI3K pathway and warrants further clinical investigation. This combination creates an immunostimulatory tumor milieu. Secondary resistance is associated with upregulation of the mTOR pathway and Sprr family genes.

scholarly journals B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

2018 ◽  
Author(s):  
Johannes Griss ◽  
Wolfgang Bauer ◽  
Christine Wagner ◽  
Margarita Maurer-Granofszky ◽  
Martin Simon ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Checkpoint ◽  
Cd8 T Cell ◽  
Immune Checkpoint Blockade ◽  
Human Melanoma ◽  
Checkpoint Blockade ◽  
Inflammatory Factors ◽  
T Effector Cells

Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses. Here we show that tumor-associated B cells are vital to tumor associated inflammation. Autologous B cells were directly induced by melanoma conditioned medium, expressed pro- and anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro. We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.

scholarly journals DRES-08. CLINICAL SIGNIFICANCE OF HYPERMUTATION IN GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi73-vi73
Author(s):  
Mehdi Touat ◽  
Yvonne Li ◽  
Adam Boynton ◽  
Liam Spurr ◽  
Bryan Iorgulescu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Alkylating Agents ◽  
Standard Of Care ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Molecular Characteristics ◽  
Clinical Value

Abstract BACKGROUND Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB). METHODS We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments. RESULTS Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSIONS Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas

scholarly journals OS9.1 Clinical significance of hypermutation in gliomas

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii18-iii18 ◽  
Author(s):  
M Touat ◽  
Y Li ◽  
A Boynton ◽  
L Spurr ◽  
B Iorglescu ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Alkylating Agents ◽  
Standard Of Care ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Molecular Characteristics

Abstract BACKGROUND Among patients with glioma, little is known about the clinical significance of hypermutation. We sought to define the determinants of hypermutation in gliomas, and to assess the value of this biomarker for predicting response to standard of care and immune checkpoint blockade. MATERIAL AND METHODS We performed comprehensive molecular characterization of 2420 pediatric and adult gliomas with clinical annotation. We determined the clinical and molecular characteristics associated with hypermutation, and assessed the relationship between hypermutation and clinical response to cancer therapies. RESULTS Overall, 114 hypermutated gliomas were identified. Hypermutation occurred predominantly in therapy-responsive subtypes characterized by methylated MGMT promoter, IDH1/2mutation or 1p/19q co-deletion. Hypermutation was almost always associated with prior treatment with temozolomide and molecular defects in DNA mismatch repair (MMR), which were identified in one-third of IDH1/2-mutated recurrent gliomas and was associated with shorter survival in multivariate analyses (hazard ratio 2.11 [95% CI 1.24–3.6], P=0.006). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSION This study establishes that mutation burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas.

scholarly journals Emerging dynamics pathways of response and resistance to PD-1 and CTLA-4 blockade: tackling uncertainty by confronting complexity

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Allan Relecom ◽  
Maysaloun Merhi ◽  
Varghese Inchakalody ◽  
Shahab Uddin ◽  
Darawan Rinchai ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Mechanisms Of Action ◽  
Checkpoint Blockade ◽  
Adaptive Resistance ◽  
Insight Into

AbstractImmune checkpoint inhibitors provide considerable therapeutic benefit in a range of solid cancers as well as in a subgroup of hematological malignancies. Response rates are however suboptimal, and despite considerable efforts, predicting response to immune checkpoint inhibitors ahead of their administration in a given patient remains elusive. The study of the dynamics of the immune system and of the tumor under immune checkpoint blockade brought insight into the mechanisms of action of these therapeutic agents. Equally relevant are the mechanisms of adaptive resistance to immune checkpoint inhibitors that have been uncovered through this approach. In this review, we discuss the dynamics of the immune system and of the tumor under immune checkpoint blockade emanating from recent studies on animal models and humans. We will focus on mechanisms of action and of resistance conveying information predictive of therapeutic response.

237 In vitro potency assays for immune checkpoint blockade using human primary cells, murine huGEMM immune cells and patient-derived tumor organoids

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A254-A254
Author(s):  
Xuefei Yan ◽  
Hongjuan Zhang ◽  
Jun Zhou ◽  
Jia Zheng ◽  
Shuang Zhu ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Culture System ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Tumor Organoids

BackgroundThe demand of evaluating potency of immune checkpoint modulators is steadily growing for immune-oncology drug development.MethodsWe aimed to establish a platform to assess the effects of immune checkpoint blockade using human primary immune cells, humanized murine primary immune cells, and co-cultures of tumor cells or patient-derived tumor organoids with immune cells.ResultsFirst, we validated the potency of immune checkpoint blockade, such as anti-PD-1 antibodies, using mixed lymphocyte reaction (MLR) assay and T cell activation assay by in vitro stimulation. Secondly, we introduced tumor cell lines into co-culture system with immune cells and validate the potency assay by measuring cytokine production and tumor cell killing by allogenic T cells. Thirdly we used huGEMM mouse-derived immune cells to replace human primary immune cells in potency assays. HuGEMM mice express engineered human immune checkpoint targets on immune cells and they can serve as an excellent resource of primary immune cells to test the drug candidates targeting human checkpoints in vitro. Last, we developed a patient-derived tumor organoid co-culture system with immune cells. We profiled the expression of immune inhibitory molecules on the tumor organoids and assessed the potency of immune checkpoint inhibitors.ConclusionsIn summary, we have established an extensive in vitro platform to evaluate the potency of the next generation of immune checkpoint inhibitors.

scholarly journals IMMU-27. IMMUNE CHECKPOINT BLOCKADE OF EX VIVO EXPANDED T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY (ACT) FOR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi124-vi125
Author(s):  
Elizabeth Ogando-Rivas ◽  
Changlin Yang ◽  
Paul Castillo ◽  
Anjelika Dechkovskaia ◽  
Duane Mitchell
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Study Objective

Abstract BACKGROUND Despite aggressive treatments, GBM continues to have unacceptably high mortality rates. Immune-checkpoint blockade and ACT have shown excellent results in other solid tumors, especially in melanoma. Unfortunately, these results have not been extrapolated to GBM. We have developed a novel platform for ACT using tumor mRNA-pulsed dendritic cells(DCs) to in-vitro expand polyclonal populations of tumor-reactive T-cells. This platform has shown promising effects in preclinical brain tumor models (Flores et al OncoImmunology 2015, Wildes et al CCR 2018, Flores et al NatureComm 2018) and being evaluated in clinical trials at UF Health (NCT02465268,NCT03334305). STUDY OBJECTIVE Evaluate whether immune-checkpoint blockade during ex-vivo expansion of antigen-specific T-cells impact their use in ACT. METHODS CMVpp65 was used as model antigen for in-vitro activation of T-cells. Mature pp65 mRNA-pulsed DCs from CMV+ healthy donors were co-cultured with T-cells in IL2-containing medium for 15days. We tested four checkpoint inhibitor groups: PD1(n= 6), PDL1(n= 4), TIM3(n= 7) and PD1+TIM3(n= 6) that were compared with non-blockade group, respectively. Checkpoint blockade was performed every 3days. T-cell proliferation, immune-phenotyping, and IFN-g release were analyzed. RESULTS Cell proliferation was lower in all the blockade groups but significantly lower in the TIM3 (p= 0.03) and TIM3+PD1 (p= 0.01) blockade groups. TIM3 expression was significantly lower in the TIM3 (p= 0.006) and PD1+TIM3 blockade groups (p= 0.0001). There was a trend of reduced pp65 tetramer positive in the TIM3 and PD1+TIM3 blockade groups (PD1+TIM3 subgroup at 3mcg/mL, p= 0.02) and lower INFg release in the TIM3 and PD1+TIM3 blockade groups. CONCLUSION The exact role of checkpoints during expansion of T-cells for ACT is not well understood. In our study checkpoint blockade with PD-1 or TIM-3 alone or in combination did not enhance T-cell expansion or function, in fact, appeared to have an inhibitory effect on measured parameters. Our results suggest that TIM-3 may have an activating role in our system.

scholarly journals P2.04-44 Combined Immune Checkpoint Blockade in Mesothelioma: In Vivo Investigation of in Vitro Data

2019 ◽  
Vol 14 (10) ◽  
pp. S725
Author(s):  
E. Marcq ◽  
J. Van Audenaerde ◽  
J. De Waele ◽  
J. Jacobs ◽  
J. Van Loenhout ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Vitro Data ◽  
In Vitro Data

scholarly journals B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Johannes Griss ◽  
Wolfgang Bauer ◽  
Christine Wagner ◽  
Martin Simon ◽  
Minyi Chen ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Immune Checkpoint Blockade ◽  
Human Melanoma ◽  
Checkpoint Blockade ◽  
Inflammatory Factors

Abstract Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Current theories on regulation of inflammation center on anti-tumor T cell responses. Here we show that tumor associated B cells are vital to melanoma associated inflammation. Human B cells express pro- and anti-inflammatory factors and differentiate into plasmablast-like cells when exposed to autologous melanoma secretomes in vitro. This plasmablast-like phenotype can be reconciled in human melanomas where plasmablast-like cells also express T cell-recruiting chemokines CCL3, CCL4, CCL5. Depletion of B cells in melanoma patients by anti-CD20 immunotherapy decreases tumor associated inflammation and CD8+ T cell numbers. Plasmablast-like cells also increase PD-1+ T cell activation through anti-PD-1 blockade in vitro and their frequency in pretherapy melanomas predicts response and survival to immune checkpoint blockade. Tumor associated B cells therefore orchestrate and sustain melanoma inflammation and may represent a predictor for survival and response to immune checkpoint blockade therapy.

scholarly journals Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

2021 ◽  
Vol 11 ◽  
Author(s):  
Falih M. Gorgun ◽  
Steven G. Widen ◽  
Douglas S. Tyler ◽  
Ella W. Englander
Keyword(s):  
Immune Cells ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Sequencing Data ◽  
Melanoma Model

Sequencing data from different types of cancers including melanomas demonstrate that tumors with high mutational loads are more likely to respond to immune checkpoint blockade (ICB) therapies. We have previously shown that low-dose intratumoral injection of the chemotherapeutic DNA damaging drug cisplatin activates intrinsic mutagenic DNA damage tolerance pathway, and when combined with ICB regimen leads to tumor regression in the mouse YUMM1.7 melanoma model. We now report that tumors generated with an in vitro cisplatin-mutagenized YUMM1.7 clone (YUMM1.7-CM) regress in response to ICB, while an identical ICB regimen alone fails to suppress growth of tumors generated with the parental YUMM1.7 cells. Regressing YUMM1.7-CM tumors show greater infiltration of CD8 T lymphocytes, higher granzyme B expression, and higher tumoral cell death. Similarly, ex-vivo, immune cells isolated from YUMM1.7-CM tumors-draining lymph nodes (TDLNs) co-incubated with cultured YUMM1.7-CM cells, eliminate the tumor cells more efficiently than immune cells isolated from TDLNs of YUMM1.7 tumor-bearing mice. Collectively, our findings show that in vitro induced cisplatin mutations potentiate the antitumor immune response and ICB efficacy, akin to tumor regression achieved in the parental YUMM1.7 model by ICB administered in conjunction with intratumoral cisplatin injection. Hence, our data uphold the role of tumoral mutation burden in improving immune surveillance and response to ICB, suggesting a path for expanding the range of patients benefiting from ICB therapy.

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