Induction of CD8 T-cell-Ifn-γ response and positive clinical outcome after immunization with gene-modified allogeneic tumor cells in advanced non-small-cell lung carcinoma

AbstractThe rapid development of immune checkpoint blockade (ICB) therapies has revolutionized the cancer treatment landscape and brightened the long-term forecast for many cancer patients. However, the specific genomic and proteomic changes in tumors treated with different ICB treatments have yet to be fully characterized. We treated four non-small-cell lung carcinoma (NSCLC) tumor digests ex vivo with the anti-PD-L1 antibody durvalumab (D) alone or in combination with the anti-CTLA-4 antibody tremelimumab (T) to explore changes in gene and protein expression associated with these ICB therapies. All four tumors showed a robust increase in interferon gamma (IFN-γ) production (100–300% higher than isotype control) in both D- and D + T-treated tumors. Three of the four tumors showed additional increases in IFN-γ production with D + T compared with D (40–70%). A substantial reduction in interleukin 10 (IL-10) was also found in three of the four tumors (reduced to 4–8%) in response to D and D + T. Conventional CD4 + /CD8 + populations and T cell activation markers increased after D and D + T treatment. D and D + T upregulated multiple IPA pathways involving T cell activation. D + T resulted in additional upregulation of Th1/Th2 pathways through a different set of genes, as well as greater reduction in genes involved in epithelial-mesenchymal transition (EMT), angiogenesis, and cancer stemness. Our results demonstrated that D + T augmented the effects of D in the microenvironment of this set of NSCLC tumors. The specific impact of D + T on the regulation of EMT, angiogenesis, and cancer stemness warrants further evaluation in a larger set of tumors.

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Blood T cell diversity associated with the prognosis of advanced non‐small cell lung carcinoma treated with first‐line pemetrexed based chemotherapy

Thoracic Cancer ◽

10.1111/1759-7714.13771 ◽

2021 ◽

Author(s):

Li Qian ◽

Zhang Zhaohui ◽

Xu Yaping ◽

Liu Zhentian ◽

Liu Zhentao ◽

...

Keyword(s):

T Cell ◽

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Cell Lung Carcinoma ◽

Cell Diversity

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Cytokeratin-positive interstitial reticulum cell (CIRC) tumor in the lymph node: a case report of the transformation from the epithelioid cell type to the spindle cell type

Diagnostic Pathology ◽

10.1186/s13000-020-01032-9 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Sachiko Kaji ◽

Nobuyuki Hiruta ◽

Daisuke Sasai ◽

Makoto Nagashima ◽

Rintaro Ohe ◽

...

Keyword(s):

Tumor Cells ◽

Lung Carcinoma ◽

Spindle Cell ◽

Small Cell Lung Carcinoma ◽

Epithelioid Cell ◽

Small Cell ◽

Cell Type ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Spindle Cell Type

Abstract Background Cytokeratin-positive interstitial reticulum cells (CIRCs), which are a subgroup of fibroblastic reticular cells (FRCs), are known to be present in the lymph nodes. There have been only a few cases of tumors derived from CIRCs. Case presentation We have reported a new case involving a CIRC tumor in a 75-year-old man and reviewed the literature. The resected mediastinal lymph nodes showed epithelial-like proliferation of large atypical round and polygonal epithelioid cells. The tumor cells expressed CK8, CK18, CAM5.2, AE1/AE3, epithelial membrane antigen, vimentin, fascin, and some FRC markers, which is consistent with the diagnosis of a CIRC tumor. Following chemotherapy, the CIRC tumor was observed to have responded very well and became difficult to confirm on imaging, but a small cell lung carcinoma developed 12 months later. Chemoradiotherapy was performed, but the patient passed away 29 months after the initial diagnosis. The autopsy revealed the recurrence of the CIRC tumor, residual small cell lung carcinoma, and a very small latent carcinoma of the prostate. The relapsed CIRC tumor cells had a spindle shape; they were highly pleomorphic and had invaded the superior vena cava. Conclusion We first reported autopsy findings of CIRC tumors and demonstrated the transformation of the tumor from the epithelioid cell type to the spindle cell type.

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An open-label, phase Ib study of NEO-PV-01 + adjuvant with nivolumab in patients with melanoma, non-small cell lung carcinoma, or transitional cell carcinoma of the bladder.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps3116 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS3116-TPS3116 ◽

Cited By ~ 1

Author(s):

Aung Naing ◽

Siwen Hu-Lieskovan ◽

Ramaswamy Govindan ◽

Kim Allyson Margolin ◽

Melissa Ann Moles ◽

...

Keyword(s):

T Cell ◽

Transitional Cell Carcinoma ◽

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Transitional Cell ◽

Small Cell ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Phase Ib ◽

Carcinoma Of The Bladder

TPS3116 Background: Cancer cells contain unique DNA mutations that result in altered amino acid sequences known as neoantigens. Growing evidence supports a central role for neoantigens as targets for tumor directed immune responses. Tumor mutational burden as well as neoantigen load have been associated with anti-tumor activity of checkpoint inhibitors. Vaccines targeting neoantigens offer a highly specific way to induce de novo T cell reactivity and to expand existing T cell responses against neoantigens. Here, we describe NEO-PV-01, a personalized, neoantigen vaccine designed specifically for the molecular profile of each individual’s tumor. Methods: NT-001 is a single-arm, phase IB study designed to evaluate the safety of administering NEO-PV-01 + adjuvant (Poly-ICLC) with nivolumab in patients with advanced melanoma, smoking-associated non-small cell lung carcinoma, or transitional cell carcinoma of the bladder who have received no more than one prior systemic treatment. Patients undergo a baseline tumor biopsy and HLA typing. DNA and RNA sequencing is performed on the tumors as well as peripheral blood to serve as normal DNA controls. On Day 1, patients begin treatment with nivolumab at a dose of 240 mg IV while their customized vaccine is being generated. Each vaccine is custom designed for the individual patient and contains up to 20 peptides 14-35 amino acids in length. The peptides are pooled into four groups and mixed with Poly-ICLC at the time of administration. Beginning at Week 12, patients receive five priming immunizations over a three-week period followed by booster vaccinations at Weeks 19 and 23. The primary endpoint is safety. Secondary endpoints are ORR, CBR, PFS, and assessment of response conversion between Week 12 and Week 24. Exploratory endpoints include extensive immune monitoring. Clinical trial information: NCT02897765.

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