Abstract PR11: CX3CR1+CD8+ T-cells are responsible to the clinical benefit of chemoimmunotherapy in metastatic melanoma patients after disease progression on PD-1 blockade

2019 ◽  
Author(s):  
Yiyi Yan ◽  
Haidong Dong ◽  
Roxana Dronca ◽  
Svetomir Markovic
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Disease Progression ◽  
Cd8 T Cells ◽  
Clinical Benefit ◽  
Melanoma Patients

scholarly journals Bim and PD-1 identify effector CD8 T cells responsive to anti-PD-1 therapy in metastatic melanoma patients

2015 ◽  
Vol 3 (S2) ◽  
Author(s):  
Roxana Dronca ◽  
Xin Liu ◽  
Kottschade Lisa ◽  
Rob Mcwilliams ◽  
Svetomir Markovic ◽  
...  
Keyword(s):  
T Cells ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
Melanoma Patients

scholarly journals 287 Combined COX-2 inhibition with fish oil and aspirin as adjuncts to anti-PD-1 immunotherapy in metastatic melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A311-A311
Author(s):  
Alexander Chacon ◽  
Alexa Melucci ◽  
Shuyang Qin ◽  
Paul Burchard ◽  
Katherine Jackson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fish Oil ◽  
Metastatic Melanoma ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Omega 3 ◽  
Melanoma Patients

BackgroundOnly 30–40% of metastatic melanoma patients experience objective responses to first line anti-PD-1 immune checkpoint inhibition (αPD-1 ICI). Cyclooxygenase (COX-1/2) inhibition with aspirin (ASA) and other non-steroidal anti-inflammatory drugs has been associated with prolonged time to recurrence and improved responsiveness to ICI in human melanoma,1 with inhibition of myeloid-induced immunosuppression in the tumor microenvironment (TME) a purported mechanism.2 Similarly, dietary omega-3 fatty acids metabolized by COX-2 elicit downstream effects on T-cell differentiation akin to ASA administration, abrogating murine melanoma and human breast cancer progression. Mechanisms of ICI resistance remain unclear, and adjunct therapies look to bridge the gap from current response rates to cure.MethodsYUMM 1.7 melanoma cells were injected into flanks of C57-BL6/J mice. Mice were fed control diets or supplemented with omega-3 rich fish oil (FO) chow (10% weight/weight, 30%kcal/kcal), ASA in drinking water (ASA, LO – 300, MED – 600, HI - 1000 ug/mL), or the combination of these agents (COMBO, with ASA-MED) starting at day 7 post tumor implantation. Intraperitoneal αPD1 was administered every 3–4 days starting at day 12. Tumors were assessed for growth, harvested at day 32 (day 26 for ASA LO/HI), and characterized with flow cytometry. All significant results (p<0.05) assessed by 2-way ANOVA or t-test as appropriate.ResultsFO resulted in lesser tumor volume at day 32 in αPD-1 treated mice, while ASA-HI resulted in lesser tumor volume in mice not treated with αPD-1 but did not synergize with αPD-1. ASA-MED and COMBO groups trended towards decreased tumor size (p = 0.07 and 0.07 respectively) by day 32 in αPD-1 treated mice. FO and COMBO increased total CD3+ T-cells and monocytes (CD45+, CD19-, CD11b+, Ly6C+, Ly6G -) in the TME. FO increased PD-L1 + CD4+ T-cells, while COMBO increased total CD8+ T-cells and PD1+ CD8+ T-cells. ASA-HI increased monocytes and the proportion of PD-1+, CD8+ T-cells in the TME.ConclusionsMyeloid-induced suppression of T-cell function in tumors may contribute to immune checkpoint inhibition resistance. In the present study, both fish oil and aspirin altered melanoma tumor growth, with only fish oil synergizing with anti-PD-1 at the doses assessed. Both fish oil and aspirin augmented monocyte populations in the tumor microenvironment, with differential effects on T-cell populations. The partially synergistic mechanism between substrate-limited (FO) and pharmacologic (ASA) inhibition of cyclooxygenase-2 may provide a cost-effective avenue to combat immune escape in melanoma patients treated with anti-PD-1 immune checkpoint inhibition, requiring further investigation in humans.ReferencesWang SJ, et al. Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer. J Immunother Cancer 2020;8(2).Zelenay S, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 2015;162(6):1257–70.

scholarly journals P862 Clinical benefit potentially evident with immunopharmacodynamic responses in prior-checkpoint failed metastatic melanoma patients treated with imprime PGG and pembrolizumab

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A10.1-A10
Author(s):  
Anissa Chan ◽  
Nandita Bose ◽  
Nandita Bose ◽  
Nadine Ottoson ◽  
Xiaohong Qiu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Control ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Clinical Benefit ◽  
Secondary Resistance ◽  
Enhanced Production ◽  
Hla Dr ◽  
Melanoma Patients

BackgroundCheckpoint inhibitor (CPI) monotherapy has revolutionized the treatment of melanoma, yet most patients are primary nonresponders or develop secondary resistance. Lack of antigen-specific T cell priming and/or immunosuppressive mechanisms leading to T cell exhaustion are critical cancer-extrinsic factors contributing to CPI resistance mechanisms. Immunotherapeutic agents capable of sparking de novo anti-tumor T cell responses or reinvigorating pre-existing exhausted T cell immunity could help reinstate the activity of CPI.MethodsOur Phase 2, multi-center, open label study, NCT02981303 in collaboration with Merck & Co., Inc., is evaluating Imprime PGG (Imprime), a novel yeast derived, Dectin-1 agonist, β-glucan PAMP in combination with pembrolizumab (KEYTRUDA®, pembro) in heavily CPI pre-treated melanoma patients (20 patients; 65% had >2 prior CPI regimens with 17/20 having previously progressed on pembro). Patients received Imprime (4 mg/kg) + pembro (200 mg) intravenously in a 3-week cycle. Here, we present the immunopharmacodynamic (IPD) responses elicited by Imprime and pembro in the peripheral blood of 19 patients.ResultsIn the intent-to-treat population (ITT; N=20), the disease control rate was 45% (1 CR and 8 SD), 6-month and 12-month OS rates were 65% and 45% respectively, and median OS (mOS) was 8.8 months. In the patients showing disease control, a significant increase in CH50, the classical pathway complement function (~0.7-2.6-fold), HLA-DR expression on classical monocytes (~0.61-1.94-fold) and reduction of frequency of PD-1+Tbet-EOMES+ exhausted CD8 T cells (~0.9-4-fold) was observed. Stimulation of peripheral blood mononuclear cells from a subset of patients by CD3/CD28 beads showed enhanced production of IL-2 and IFN-gamma in the CD8 T cells. Some of these IPD responses were also associated with 6-month landmark OS analyses. Additionally, whole blood gene expression analyses showed >2-fold upregulation of several myeloid and T cell activation genes including IFNg, CD83, IP-10, and IL-2RA. Enhanced OS was observed in patients with >1.3 fold increase in CH50 (8/19; HR 0.385; p=0.1) or >1.5-fold reduction in the frequency of exhausted CD8 T cells (8/19; HR 0.102; p=0.001). The IPD responses observed in the ITT population included formation of circulating immune complexes (peak levels ranging from ~4.5-16.1-fold) and production of complement activation protein SC5b9 (~3.4-25.6-fold), and increase in the frequency of HLA-DR+ myeloid cells (~0.43-3.71-fold).ConclusionsOverall, these data, albeit in a small population, demonstrate that Imprime/pembro combination can drive the innate/adaptive IPD responses that are critical for providing clinical benefit to the patients who have progressed through prior CPI treatments.Ethics ApprovalThe study was approved by central and local ethics committees depending on site requirements. The central IRB for the study is Western Institutional Review Board (WIRB), approval number 20162506; all sites received IRB approval before opening the study at the respective sites.

scholarly journals Digital Immunophenotyping Predicts Disease Free and Overall Survival in Early Stage Melanoma Patients

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 422
Author(s):  
Francesco De Logu ◽  
Francesca Galli ◽  
Romina Nassini ◽  
Filippo Ugolini ◽  
Sara Simi ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Cd8 T Cells ◽  
Early Stage ◽  
High Density ◽  
Stage Ii ◽  
Prognostic Impact ◽  
Training Cohort ◽  
Melanoma Patients ◽  
Disease Free

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM. Materials and Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort. Results: in the training cohort, 100 Stage II–III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4+ intratumoral T-cells (aHR [100 cell/mm2 increase] 0.98, 95%CI 0.95–1.00, p = 0.041) and CD163+ inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32–0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28–0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18–0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8+ T-cells and CD68+ macrophages as compared to those with low density of both intratumoral CD8+ T-cells and CD68+ macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8+ and CD3+ T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10–0.56, p < 0.001) and those with high density of both intratumoral CD8+ and CD68+ were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09–0.86, p = 0.025). Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II–III melanoma patients.

CXC Chemokine Receptor 3 Expression by Activated CD8+ T cells Is Associated with Survival in Melanoma Patients with Stage III Disease

2004 ◽  
Vol 64 (21) ◽  
pp. 7697-7701 ◽  
Author(s):  
Irene M. Mullins ◽  
Craig L. Slingluff ◽  
Jae K. Lee ◽  
Courtney F. Garbee ◽  
Jianfen Shu ◽  
...  
Keyword(s):  
T Cells ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Stage Iii ◽  
Cxc Chemokine ◽  
Melanoma Patients

scholarly journals Chemical Castration of Melanoma Patients Does Not Increase the Frequency of Tumor-specific CD4 and CD8 T Cells After Peptide Vaccination

2013 ◽  
Vol 36 (4) ◽  
pp. 276-286 ◽  
Author(s):  
Luis M. Vence ◽  
Chiyu Wang ◽  
Himabindu Pappu ◽  
Ryan E. Anson ◽  
Tejal A. Patel ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Peptide Vaccination ◽  
Chemical Castration ◽  
Melanoma Patients

scholarly journals Lack of tumor recognition by hTERT peptide 540-548-specific CD8+ T cells from melanoma patients reveals inefficient antigen processing

2001 ◽  
Vol 31 (9) ◽  
pp. 2642-2651 ◽  
Author(s):  
Maha Ayyoub ◽  
Marco Migliaccio ◽  
Philippe Guillaume ◽  
Danielle Liénard ◽  
Jean-Charles Cerottini ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Tumor Recognition ◽  
Melanoma Patients

Disease Progression in Children with Perinatal HIV Correlates with Increased PD-1+ CD8 T Cells that Coexpress Multiple Immune Checkpoints

2021 ◽  
Author(s):  
Janki Tailor ◽  
Julia Foldi ◽  
Matthew Generoso ◽  
Bret McCarty ◽  
Aparna Alankar ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Progression ◽  
Cd8 T Cells ◽  
Pediatric Hiv ◽  
Immune Checkpoints ◽  
Hiv Disease ◽  
Art Initiation ◽  
Perinatal Hiv ◽  
Living With Hiv

Abstract Background PD-1 marks exhausted T cells, with weak effector functions. Adults living with HIV have increased levels of PD-1+ CD8 T cells that correlate with HIV disease progression, yet little is known about the role of PD-1+ CD8 T cells in children with perinatal HIV. Methods We enrolled 76 Kenyan children with perinatal HIV and 43 children who were HIV unexposed and quantified PD-1 levels on CD8 T cells, their coexpression with immune checkpoints (IC) 2B4, CD160 and TIM3, correlates with immune activation and HIV disease progression and HIV-specific and non-specific proliferative responses. Results PD-1+ CD8 T cell frequencies are elevated in children with perinatal HIV and associated with disease progression. The majority of PD-1+ CD8 T cells coexpress additional ICs. ART initiation lowers total PD-1 levels and coexpression of multiple ICs. The frequency of PD-1 + 2B4+CD160+TIM3- in PD-1+ CD8 T cells, predicts weaker HIV-specific proliferative responses, suggesting this subset is functionally exhausted. Conclusion Children with perinatal HIV have high PD-1+ CD8 T cells that are a heterogeneous population differentially coexpressing multiple ICs. Understanding the complex interplay of ICs is essential to guide the development of PD-1 directed immunotherapies for pediatric HIV remission and cure.

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