scholarly journals 257 Combination of adenosine antagonists A2AR (TT-10) and A2BR (TT-4) with checkpoint inhibitors demonstrate anti-tumor activity in CT-26 murine colon tumor allograft model

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A279-A279
Author(s):  
Desa Rae Pastore ◽  
Sushant Kumar ◽  
Brian Schwartz ◽  
Kasim Mookhtiar ◽  
Vijay Reddy
Keyword(s):  
Flow Cytometry ◽  
Tumor Growth ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Vehicle Control ◽  
Receptor Expression ◽  
Adenosine Antagonists ◽  
Adenosine Antagonist ◽  
Tumor Measurements ◽  
And Control

BackgroundTT-10 and TT-4 are potent and selective antagonists of adenosine A2A receptor (A2AR) and A2B receptor (A2BR) respectively. Both agents are being developed for the treatment of advanced cancers initially as monotherapy, using high levels of adenosine receptor expression in tumor tissue as biomarker.MethodsBalb/c mice were implanted with CT-26 cells and randomly assigned to 8 groups per study; (1) vehicle control, (2) adenosine antagonist - 1 mg/kg A2AR (TT-10) 1 mg/kg or 3 mg/kg A2BR (TT-4), (3) 10 mg/kg Anti-mPD-1, (4) 5 mg/kg Anti-mCTLA-4, (5) 100 mg/kg Irinotecan, (6) adenosine antagonist + Anti-mPD-1, (7) adenosine antagonist + Anti-mCTLA-4, (8) adenosine antagonist+ Irinotecan. Adenosine antagonists and control were given daily by oral gavage, Anti-mPD-1, Anti-mCTLA-4 and Irinotecan were administered Intraperitoneal. Treatment was started on day 1 post implant and mice were followed until individual tumor volume reached 2,000 or 3000 mm3 (as defined by protocol) or moribund. Tumor measurements and weights were taken every 2 to 3 days. In addition, a subset of mice were investigated for changes in peripheral whole blood and intra-tumor analysis on days 3 and 10 via flow cytometry. The populations of interest included CD223+, CD3+, CD4+, CD8+, CD25+FoxP3+, CD25-CD69+ and CD44+CD62L.ResultsAll implanted mice developed measurable tumors. Mean suppression of tumor growth was observed to be greater in single agent adenosine antagonists TT-10 and TT-4 when compared to the vehicle control and was observed to show overall greater suppression of tumor growth when combined with anti-mPD-1 or anti-m-CTLA-4. Tumor infiltrating lymphocyte analysis by flow cytometry, showed higher amounts of CD25+FoxP3+ present in control mice at day 3, than was observed in mice that were treated with A2AR alone, A2AR + anti-mPD-1 and A2AR + anti-m-CTLA-4.ConclusionsTT-10 and TT-4 alone was superior to vehicle control in slowing tumor growth. However, the combination of TT-10 + Anti-mPD-1 and TT-4 + Anti-mCTLA-4 showed the greatest tumor response and growth suppression. Furthermore, a striking reduction of CD25+FoxP3+ within the tumor was observed at day 3 in mice treated with A2AR alone, A2AR + anti-mPD-1 and A2AR + anti-m-CTLA-4 when compared to the vehicle control.

scholarly journals 3236 Identification of exhaustive markers in cytotoxic T-cells to guide immune modulation in hepatocellular carcinoma ex vivo

2019 ◽  
Vol 3 (s1) ◽  
pp. 13-13
Author(s):  
Lauren Norell Krumeich ◽  
Tatiana Akimova ◽  
Jason Stadanlick ◽  
Abhishek Rao ◽  
Neil Sullivan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Cd8 T Cells ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Receptor Expression ◽  
Inhibitory Receptors ◽  
Surface Receptors ◽  
Study Population

OBJECTIVES/SPECIFIC AIMS: Objective: apply checkpoint inhibitors that are specific to the exhaustive markers expressed on tumor CD8+ T-cells ex vivo in order to improve cytokine release and cytotoxic function in comparison to two control groups: (1.) T-cells that receive no antibodies; (2.) T-cells that receive standard inhibition with PD-1 and CTLA-4 antibodies only. Long-term objective: provide personalized medicine in the treatment of HCC by using checkpoint inhibitors that are specific to the receptors expressed by an individual tumor. METHODS/STUDY POPULATION: The study population includes patients undergoing liver transplantation or surgical resection for HCC. Two grams of tumor, two grams of healthy liver tissue at least one centimeter from the tumor margin, and 50 milliliters of blood will be obtained. Solid tissue will be mechanically and enzymatically disrupted and CD8+ T-cells will be isolated from all sites. Using flow cytometry, the expression of surface receptors PD-1, CTLA-4, LAG-3, TIM-3, BTLA, CD244, and CD160 will be categorized in each tissue to identify which receptors are upregulated in the tumor microenvironment. Up to three antibodies specific to the upregulated receptor(s) on the tumor T-cells will be applied per specimen. The experimental arm will receive these antibodies and co-stimulation with CD3/CD28 and will be compared to two controls. One control will receive only CD3/CD28, and the other will receive CD3/CD28 in addition to the standard combination of PD-1 and CTLA-4 inhibitors. From each condition, flow cytometry will be used to assess the mean production of interleukin-2, tumor necrosis factor-α, interferon-γ, granzyme B, and perforin expression as an assessment of T-cell function. RESULTS/ANTICIPATED RESULTS: Preliminary data from the peripheral blood of healthy controls confirms that the developed flow cytometry panels effectively identify the surface receptors and cytokine production of CD8+ T-cells. Two patients have successfully been enrolled in this study. It is predicted that T-cells extracted from the tumor will express more inhibitory receptors than normal liver or peripheral blood and will have increased function after they are targeted with checkpoint inhibitors that are specific to the inhibitory surface receptors they express. DISCUSSION/SIGNIFICANCE OF IMPACT: HCC is the second leading cause of cancer-related death worldwide and therapeutic options are limited for patients who are not surgical candidates. T-cells are a critical component of the anti-tumor response to HCC. However, T-cells can develop an exhausted phenotype characterized by up-regulated inhibitory receptors (PD-1, CTLA-4, LAG-3, TIM-3, CD-244, CD-160, BTLA) and decreased function, allowing for immune escape. Clinical trials using combined checkpoint inhibition with PD-L1 and CTLA-4 antibodies have been considered a breakthrough for patients with advanced HCC, as up to 25% show an objective tumor response. The explanation for the varied susceptibility to checkpoint inhibition remains unknown and is hypothesized to be secondary to inconsistencies in the expression of surface inhibitory receptors. Although inhibitory receptor expression has been shown to be upregulated under conditions of hepatitis and/or HCC, there has been no single study to effectively investigate the expression of all known inhibitors in order to better explore the interplay between them. It will be of great academic interest and clinical purpose to evaluate individual receptor expression and engage the correlating antibodies given the possibility of synergism between receptors and the need for a more profound anti-tumor T-cell response in HCC.

Immunotherapy releated cardiomyopathy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14601-e14601
Author(s):  
Ozlem Sonmez ◽  
Ozlem Nuray Sever ◽  
Basak Oyan ◽  
Osman Gokhan Demir
Keyword(s):  
Side Effects ◽  
Checkpoint Inhibitors ◽  
Rare Complication ◽  
Single Agent ◽  
Tnf Alpha ◽  
Oncology Practice ◽  
And Control ◽  
Chemotherapy Agents ◽  
As Effects ◽  
Cessation Of Treatment

e14601 Background: Side effects of immunotherapies also differ from classical cytoxic chemotherapy agents such as effects. Cardiomyopathy is a relatively rare complication. Studies have shown that the risk of developing myocarditis is higher when the ipilimumab / nivolumab combination is used than when the single agent nivolumab is used. ImmunoCheckpoint inhibitors are associated with an increase in immunologic response and immunosuppressives such as corticosteroids, TNF-alpha antagonists and mycophenolate acetate are used in treatment.In this study, we aimed to report cardiac toxicity in patients who treated with immune checkpoint inhibitors. Methods: Forty patients who were treated with immunocheckpoint inhibitors were screened retrospectively at two centers in Turkey between August 2015 and January 2017 . Results: Twenty-eight of the patients were male (70%), 12 were female (30%); The median age was 61 (32-81) years. 23 (57.5%) patients received nivolumab and 16 (40 %) patients received pembrolizumab and 1(2.5%) patient received pembrolizumab/ipilimumab combination. Seven of the cases had immuno-related side effects (17.5%).In two of our patients, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. One week after the symptoms improved rapidly and control ejection fractions normalized. One of these patients was diagnosed with malignant melanoma and the other with RCC , they using pembrolizumab and nivolumab respectively. Conclusions: In conclusion, side effects that may occur may lead to fatal outcomes, while immunotherapy, which is increasingly used in oncology practice, may result in satisfactory success in treatment. Patients and their relatives should be adequately informed about side effects caused by these agents, complaints should be carefully evaluated and treatment should be started without spending time.

Effect of MMP9 inhibition on effector T-cell responses in a PD1-axis refractory model.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 104-104
Author(s):  
Victoria Smith ◽  
Vladi Juric ◽  
Amanda Mikels-Vigdal ◽  
Chris O'Sullivan ◽  
Maria Kovalenko ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cell Activation ◽  
Immune Cell ◽  
Single Agent ◽  
Fold Increase ◽  
Cytotoxic T Cell

104 Background: Matrix metalloproteinase 9 (MMP9) acts via diverse mechanisms to promote tumor growth and metastasis, and is a key component of the immune-suppressive myeloid inflammatory milieu. We developed a monoclonal antibody (AB0046) that inhibits murine MMP9 and assessed its mechanism of action in immunocompetent mice as a single agent, or in combination with a murine anti-PDL1 antibody. Methods: An orthotopic, syngeneic tumor model (NeuT), which models MMP9-positive myeloid infiltrate, was utilized for efficacy and pharmacodynamic studies involving RNA and T cell receptor (TCR) sequencing, and flow cytometry. Enzymatic analyses were performed on T cell chemoattractant CXCR3 ligands (CXCL9, CXCL10, and CXCL11) which were subsequently evaluated in chemotaxis assays. Results: Anti-MMP9 treatment alone or in combination with an anti-PDL1 antibody decreased primary tumor growth as compared to IgG control-treated animals (56% vs 335% tumor growth increase, p = 0.0005) or anti-PDL1 alone. Profiling of tumors by RNA sequencing revealed that inhibition of MMP9 resulted in elevated expression of genes associated with immune cell activation pathways (Hallmark Interferon Gamma Response, FDR p < 0.001). Treatment with anti-MMP9 and anti-PDL1 antibodies decreased TCR clonality, with evidence of a more diverse TCR repertoire (p = 0.005). Immunophenotyping of tumor-associated T cells by flow cytometry showed that anti-MMP9 and anti-PDL1 co-treatment promoted a 2.8-fold increase in CD3+ cells in tumors (p = 0.01), which was associated with an increase in CD4+ T cells (3.2-fold increase; p = 0.006) and CD8+ T cells (2.8-fold increase; p = 0.013). In contrast, anti-MMP9 and combination treatment resulted in a decrease in tumor-associated regulatory T cells (CD25+ FoxP3+ cells, p = 0.04). MMP9 cleavage of T cell chemoattractant ligands in vitro rendered them functionally inactive for recruitment of activated primary human effector T cells. Conclusions: Inhibition of MMP9 reduces tumor burden and promotes cytotoxic T cell infiltration in a PD1-axis refractory mouse model. The combination of nivolumab and GS-5745, a humanized anti-MMP9 inhibitory antibody, is currently being evaluated in gastric cancer (NCT02864381).

scholarly journals Identification of RORg+T Cells as Key Players in Thyroid Autoimmunity From Checkpoint Immunotherapy

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A839-A840
Author(s):  
Melissa G Lechner ◽  
Natalie Yakobian ◽  
Anushi Patel ◽  
Eduardo Rodriguez ◽  
Trevor E Angell ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Autoimmune Disease ◽  
Mouse Model ◽  
Checkpoint Inhibitors ◽  
Thyroid Autoimmunity ◽  
Single Agent ◽  
Hashimoto Thyroiditis ◽  
Lymphoid Tissues ◽  
Tc17 Cells

Abstract Purpose: Immune checkpoint inhibitors (ICI) are powerful new cancer therapies that leverage the body’s own immune system to attack cancer cells. Unfortunately, their use may be limited by the development of immune-related adverse events (IrAE) in up to 60% of patients. Thyroiditis is a common IrAE, with shared and distinct features from spontaneous thyroid autoimmunity, i.e. Hashimoto thyroiditis (HT). The cause of IrAE remains unknown, however, recent data suggest that toxicity can be uncoupled from anti-tumor effects. Methods: We developed a novel mouse model to study mechanisms of IrAE, in which ICI (anti-PD-1 and/or anti-CTLA-4) treatment leads to multi-organ immune infiltrates, including thyroiditis. To understand immune changes occurring with ICI-autoimmunity, we first evaluated changes in the frequency and activation status of different immune cells in our mice using immunohistochemistry (IHC) and flow cytometry. Then we confirmed these findings in peripheral blood and thyroid fine needle aspiration (FNA) specimens from patients with ICI-thyroiditis, HT, or no IrAE, using flow cytometry and single cell RNA sequencing (scRNAseq) techniques. Results: In our mouse model, ICI treatment of autoimmune-prone non-obese diabetic mice induces multi-organ autoimmunity. Modeling ICI-IrAE observed in humans, our mice developed increased immune infiltrates in multiple tissues (e.g. thyroid, colon, liver, lung), autoantibodies, and acceleration of underlying autoimmune risk (i.e. diabetes). Increased frequency of autoimmune disease was seen with combination (anti-PD-1 + anti-CTLA-4) vs. single agent ICI. We found increased IL-17A+ T cells in secondary lymphoid tissues of ICI-treated mice, a cytokine produced by RORγ + Th17 and Tc17 cells and associated with autoimmunity. IHC studies on thyroid infiltrates showed accumulation of CD4+ and CD8+ T cells and macrophages in ICI-treated vs. isotype control mice. This finding was confirmed by flow cytometry analyses of thyroid-infiltrating leukocytes in ICI-thyroiditis mice, which showed significantly increased T cells, specifically RORγ + T cells, and rare B220+ B, CD11b+ myeloid, or NKp46+ NK cells. In patients with ICI-thyroiditis, thyroid FNA showed that thyroid immune infiltrates were predominately T cells. scRNAseq studies in patients with ICI-thyroiditis showed enrichment of Th17 and Tc17 (RORγ + IL23R+ CD161+) T cells, compared to ICI-treated patients without IrAE. Conclusion: We have identified a role for RORγ + Th17 and Tc17 cells in thyroid autoimmunity from ICI using a newly developed mouse model of ICI-associated IrAE and translational studies in patients with ICI-thyroiditis. Th17 and Tc17 cells have previously been associated with spontaneous autoimmune disease, including HT, but have not yet been characterized in IrAE. These cells provide a potential therapeutic target for prevention of endocrine IrAE from ICI.

Evaluation of the correlation between antibiotic use and survival in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6509-6509
Author(s):  
Paz J. Vellanki ◽  
Shanthi Marur ◽  
Pradeep Bandaru ◽  
Pallavi Shruti Mishra-Kalyani ◽  
Kunthel By ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Single Agent ◽  
Cox Proportional Hazards ◽  
Intestinal Microbiome ◽  
Control Group ◽  
Apparent Difference ◽  
Control Groups ◽  
Hpv Status ◽  
And Control

6509 Background: Recent evidence suggests that treatment with systemic antibiotics (Abx) disrupts the intestinal microbiome and may be associated with decreased survival for patients receiving treatment with ICIs for advanced cancers, including R/M HNSCC. However, a potential confounder is that Abx use identifies a subgroup of patients with a worse prognosis. The FDA examined the association between Abx use and survival for ICIs and other drugs used for the treatment of patients with R/M HNSCC. Methods: Data submitted to the FDA from three randomized controlled trials with ICI as a single agent or with chemotherapy (ICI group) compared to chemotherapy and/or cetuximab (Control group) were pooled. The association between systemic Abx use within 30 days of initiating anticancer therapy and survival for the ICI and Control groups was evaluated using Kaplan-Meier (KM) estimates and compared using Cox proportional hazards regression models, controlling for ECOG performance status, line of therapy, HPV status, PD-L1 expression, and other important prognostic factors. Results: In the ICI and Control groups, 36% and 46% of patients received Abx, respectively. For the ICI group, the difference in KM-estimated median overall survival (OS) was 5.6 months based on receipt of Abx (hazard ratio [HR] 1.70). Abx had no impact on OS for the Control group. Similar trends were observed for progression-free survival (PFS). Conclusions: In this exploratory analysis, systemic Abx within 30 days of initiating treatment for R/M HNSCC was associated with decreased survival for patients treated with ICIs compared with patients who did not receive Abx. Use of Abx had no apparent difference in survival in the control group. Further examination of the association between Abx use and clinical outcomes for patients with R/M HNSCC treated with ICIs is needed. [Table: see text]

scholarly journals Prevention of radiocontrast-induced nephropathy by adenosine antagonists in rats with chronic nitric oxide deficiency.

1997 ◽  
Vol 8 (7) ◽  
pp. 1125-1132
Author(s):  
C M Erley ◽  
N Heyne ◽  
K Burgert ◽  
J Langanke ◽  
T Risler ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Animal Model ◽  
Control Group ◽  
Adenosine Antagonists ◽  
Radiocontrast Media ◽  
Suitable Animal Model ◽  
Adenosine Antagonist ◽  
Nitric Oxide Deficiency ◽  
A1 Receptor ◽  
And Control

To evaluate therapeutic options for the prevention of radiocontrast media (RCM)-induced nephropathy, a model was developed in which rats received NG-nitro-L-arginine methyl ester (L-NAME) for 10 wk in order to inhibit nitric oxide (NO) synthetase. This study tests the hypothesis that infusion of an adenosine antagonist before RCM application may avoid the vasoconstrictive response in NO-depleted rats. Rats received L-NAME for 10 wk orally (50 mg/L drinking water) to achieve NO depletion. Renal function was determined by [3H]inulin clearance for analysis of the GFR and by flowmetry for assessing renal blood flow (RBF). After a control clearance period (baseline clearance period), the renal response to RCM application (sodium diatrizoate, 2 ml/kg body wt) was measured two times every 30 min starting 30 min after RCM application (clearance periods 1 and 2). L-NAME rats and control rats received two adenosine antagonists. The nonselective adenosine antagonist theophylline was given as an initial bolus of 50 mumol/kg body wt within 10 min, followed by continuous infusion of 100 mumol/kg body wt per h, and the specific adenosine A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was given as a bolus of 100 micrograms/kg body wt before RCM application. Results were compared with vehicle infusion. In the control group, no significant change of GFR or RBF could be detected after application of RCM with or without prior infusion of DPCPX or theophylline. In L-NAME rats, RBF decreased significantly after RCM application (baseline, 5.6 +/- 0.2 ml/min; first clearance period, 4.6 +/- 0.3 ml/min [P < 0.05]; second clearance period, 4.3 +/- 0.3 [P < 0.01]). GFR was also reduced in L-NAME rats without previous infusion of theophylline or DPCPX (baseline, 0.95 +/- 0.1 ml/min; first clearance period, 0.83 +/- 0.1 ml/min; second clearance period, 0.69 +/- 0.1 ml/min [P = 0.058]). Prior treatment with either theophylline or DPCPX resulted in complete protection against a decline of RBF and GFR induced by RCM in L-NAME rats. Rats with chronic NO blockade showed a significant increase of the renal vasoconstrictive effect of contrast media. Application of L-NAME in rats seems to constitute a suitable animal model to study the pathophysiology of radiocontrast media-induced nephropathy. In this animal model, administration of adenosine antagonists prevented the decline of GFR and RBF.

Erythropoietin and Erythropoietin Receptor Expression in Vestibular Schwannoma: Potential Role in Tumor Growth

Skull Base ◽  
2007 ◽  
Vol 16 (04) ◽  
Author(s):  
Marc Diensthuber ◽  
T. Ilner ◽  
M. Samii ◽  
A. Brandis ◽  
T. Lenarz ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Vestibular Schwannoma ◽  
Potential Role ◽  
Erythropoietin Receptor ◽  
Receptor Expression

scholarly journals Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

Oncogene ◽  
2021 ◽  
Vol 40 (11) ◽  
pp. 1957-1973
Author(s):  
Hyunho Yoon ◽  
Chih-Min Tang ◽  
Sudeep Banerjee ◽  
Mayra Yebra ◽  
Sangkyu Noh ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tumor Growth ◽  
Gastrointestinal Stromal Tumor ◽  
Single Agent ◽  
Stromal Tumor ◽  
Paracrine Signaling ◽  
Mesenchymal Transition ◽  
Tumor Growth And Metastasis ◽  
Factor C

AbstractTargeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

scholarly journals PD-1/PD-L1 checkpoint inhibitors during late stages of life: an ad-hoc analysis from a large multicenter cohort

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Daniele Santini ◽  
Tea Zeppola ◽  
Marco Russano ◽  
Fabrizio Citarella ◽  
Cecilia Anesi ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Burden Of Disease ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Advanced Cancer Patients ◽  
Primary Tumors ◽  
Multicenter Cohort ◽  
Frail Patients ◽  
Ecog Ps ◽  
Late Stages

Abstract Background The favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy. Methods The present analysis aims to describe clinicians’ attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy. Results Overall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p < 0.0001) and with a higher burden of disease (69.3% vs 59.4%, p = 0.0266). In total, 35 patients (6.2%) started ICIs within 30 days of death; among them there was a higher proportion of patients with ECOG-PS ≥ 2 (45.7% vs 14.5%, p < 0.0001) and with a higher burden of disease (82.9% vs 60.9%, p = 0.0266). Primary tumors were significantly different across subgroups (p = 0.0172), with a higher prevalence of NSCLC patients (80% vs 60.9%) among those who started ICIs within 30 days of death. Lastly, 123 patients (21.7%) started ICIs within 3 months of death. Similarly, within this subgroup there was a higher proportion of patients with ECOG-PS ≥ 2 (29.3% vs 12.8%, p < 0.0001), with a higher burden of disease (74.0% vs 59.0%, p = 0.0025) and with NSCLC (74.0% vs 58.8%, p = 0.0236). Conclusion Our results confirmed a trend toward an increasing ICIs prescription in frail patients, during the late stages of life. Caution should be exercised when evaluating an ICI treatment for patients with a poor PS and a high burden of disease.

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