Antibody microarray analysis of inflammatory mediator release by human leukemia T cells and human non‐small cell lung cancer cells

TPS9138 Background: Lung cancer is the most common cause of cancer-related death worldwide with over 1.6 million deaths per year. Non-small cell lung cancer (NSCLC) accounts for 80% of cases, the majority of which are adenocarcinomas. 75% of patients present with inoperable tumours and/or with distant metastatic spread, with 5-year survival for stage IV disease as low as 5%. Treatment options include chemotherapy, targeted therapies for specific mutations, and - increasingly - immune checkpoint inhibitors (CPI). Adoptive cell therapies (ACT) can produce durable responses in pre-treated NSCLC. Evidence also suggests potential benefit of combining ACT with CPIs, even after acquired resistance. Efforts to improve efficacy include the expansion of T cells able to recognise patient-specific clonal tumour neoantigens. Clonal tumour neoantigens arise early in cancer evolution and represent a subset of patient-specific mutations present in all cancer cells. Developing ACTs that target clonal neoantigens represents a personalised approach to treating all cancer cells concurrently, minimising the risk of tumour escape and reducing potential for off-target toxicities. Insights gained from applying the PELEUS bioinformatic platform (developed using UK TRACERx study data) to matched tumour and blood samples from NSCLC patients – as part of a tissue acquisition study (NCT03517917) – has enabled the manufacture of a personalized clonal neoantigen-reactive T cell (cNeT) product (ATL001), which is now in clinical development. Methods: The CHIRON Study (NCT04032847), is a first-in-human, open-label, multi-centre, phase I/IIa study to characterise the safety and clinical activity of ATL001 administered intravenously in up to 40 adults with advanced unresectable or metastatic NSCLC. Following consent and screening, patients enter the study for procurement of tumor tissue and blood to manufacture ATL001. Tissue may be procured during treatment with standard systemic therapies. Patients in Cohort A receive cyclophosphamide/fludarabine on days -6 to -4, followed by a single dose of ATL001 and 10 daily doses of subcutaneous IL-2; Patients in Cohort B will additionally receive one dose of pembrolizumab between days -13 and -6 before receiving ATL001, then restart pembrolizumab 2 weeks after receiving ATL001 and continue for up to 12 months. Key eligibility criteria include treatment with at least one prior systemic therapy (including a PD-1 inhibitor). Primary endpoints are the safety and tolerability of ATL001 as a monotherapy and in combination with pembrolizumab. Secondary endpoints include change in tumor size and response rate by RECIST 1.1 and imRECIST. Correlative studies will investigate the effects of cNeT dose and engraftment kinetics on clinical activity. The study began enrolling patients in Cohort A in August 2019. Clinical trial information: NCT04032847.

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Faculty Opinions recommendation of Down-regulation of miR-214 inhibits proliferation and glycolysis in non-small-cell lung cancer cells via down-regulating the expression of hexokinase 2 and pyruvate kinase isozyme M2.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733460129.793580846 ◽

2020 ◽

Author(s):

Leonardo Salmena

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Pyruvate Kinase ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung ◽

Down Regulation ◽

Hexokinase 2

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Paeonol Inhibits Migration, Invasion and Bone Adhesion of Small Cell Lung Cancer Cells

Current Signal Transduction Therapy ◽

10.2174/1574362410666150625191130 ◽

2015 ◽

Vol 10 (2) ◽

pp. 126-130

Author(s):

Yong Tian ◽

Cong Chen ◽

Yu Zhang ◽

Zhen Zhang ◽

Haiyan Xie

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung

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Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽

10.3390/cancers13153828 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3828

Author(s):

Anello Marcello Poma ◽

Rossella Bruno ◽

Iacopo Pietrini ◽

Greta Alì ◽

Giulia Pasquini ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Cell ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Durable Response ◽

Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

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278 Phase I clinical trial evaluating the safety of ADP-A2M10 SPEAR T-cells in patients with MAGE-A10+ advanced non-small cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0278 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A303-A303

Author(s):

George Blumenschein ◽

Siddhartha Devarakonda ◽

Melissa Johnson ◽

Victor Moreno ◽

Justin Gainor ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Antitumor Activity ◽

Small Cell Lung Cancer ◽

Dose Level ◽

Cell Lung Cancer ◽

Lentiviral Vector ◽

Small Cell ◽

Small Cell Lung ◽

Human Dose

BackgroundADP-A2M10 SPEAR T-cells are genetically engineered autologous T-cells that express a high affinity MAGE-A10-specific T-cell receptor targeting MAGE-A10+tumors in the context of HLA-A*02. This trial is now complete (NCT02592577).MethodsThis first-in-human dose escalation trial utilized a modified 3+3 design to evaluate safety and antitumor activity. Eligible patients (pts) were HLA-A*02+ with advanced non-small cell lung cancer (NSCLC) expressing MAGE-A10. Pts underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Pts underwent lymphodepletion (LD) with varying doses/schedules of fludarabine (Flu) and cyclophosphamide (Cy) prior to receiving ADP-A2M10. ADP-A2M10 was administered at Dose Level (DL) 1= 0.1×109, DL2 0.5–1.2×109, and DL3/Expansion= 1.2–15×109 transduced cells.ResultsAs of Jan 10, 2020, 11 pts (6 male/5 female) with NSCLC (3 squamous cell, 7 adenocarcinoma, 1 adenosquamous) were treated. Five, 3 and 3 pts received cells at DL1, DL2, and DL3/Expansion, respectively. The most frequently reported adverse events ≥ Grade 3 were lymphopenia (11), leukopenia (9), neutropenia (8), anemia (6), thrombocytopenia (5), and hyponatremia (5). Three pts reported CRS (Grades 1, 2, and 4, respectively). One pt received the highest dose of LD (Flu 30 mg/m2 Day 1 4 and Cy 1800 mg/m2 Day 1–2) prior to a second infusion and had a partial response (PR). This pt subsequently developed aplastic anemia and died. Responses included: 1 pt – PR, 3 pts - stable disease, 2 pts – progressive disease, 1 pt - too early to determine, 4 pts - off-study prior to tumor assessment. SPEAR T-cells were detectable in peripheral blood from pts at each dose level, and in tumor tissue from pts at DL1 and DL3.ConclusionsADP-A2M10 SPEAR T-cells have shown acceptable safety and no evidence of toxicity related to off-target binding or alloreactivity. Given the minimal antitumor activity and the discovery that MAGE-A10 expression frequently overlaps with MAGE-A4 expression, the clinical program has closed. Several trials with SPEAR T-cells targeting MAGE-A4 are ongoing (https://bit.ly/35htsZK).Trial RegistrationNCT02592577Ethics ApprovalThe trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

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