Clinical Trial of Oral Nelfinavir Before and During Radiation Therapy for Advanced Rectal Cancer

Purpose Nelfinavir, a PI3-kinase pathway inhibitor, is a radiosensitizer which increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach. Patients and Methods Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1250 mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pre-treatment, after 7 days of nelfinavir and prior to last fraction of RT. Biopsies taken pre-treatment and 7 days after the last fraction of RT were analysed for tumor cell density (TCD). Results There were 3 drug-related grade 3 adverse events: diarrhea, rash, lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P=0.01). Overall, 5/9 evaluable patients exhibited good tumor regression on MRI assessed by Tumor Regression Grade (mrTRG). Conclusions This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow.

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Olfactory receptor family receptor, family 7, subfamily C, member 1 is a novel marker of colon cancer-initiating cells and is a potent target of immunotherapy.

Purpose: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy. Experimental Design: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CIC were analyzed by cDNA micro-array and RT-PCR. Protein expression of Olfactory receptor family receptor, family 7, subfamily C, member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene over-expression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by flowcytometer and analyzed. Cytotoxic T lymphocytes (CTLs) specific for OR7C1 peptide were generated, and the anti-tumor effect was addressed by mice adoptive transfer model. Results: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicty than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific cytotoxic T lymphocytes (CTLs) showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater anti-tumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model. Conclusions: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy.

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PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity

PURPOSE: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor vascular endothelial growth factor receptor-1 (VEGFR-1) have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. EXPERIMENTAL DESIGN: We established diet-induced obese mouse models of wild type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null or PlGF null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. RESULTS: We found that obesity increased TAM infiltration, tumor growth and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment towards an anti-tumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced anti-tumor immunity. CONCLUSIONS: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression.

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A NOVEL CARCINOEMBRYONIC ANTIGEN T CELL BISPECIFIC ANTIBODY (CEA TCB) FOR THE TREATMENT OF SOLID TUMORS

Purpose: CEA TCB is a novel IgG-based T Cell Bispecific antibody for the treatment of CEA-expressing solid tumors currently in Phase 1 clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA and CD3e binding Fab domains and an engineered Fc region with completely abolished binding to FcRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB. Experimental design: CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human PBMCs. Results: Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunological synapses, T cell activation, secretion of cytotoxic granules and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA binding sites/cell, which allows distinguishing between high- and low-CEA expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells and converts PD-L1 negative into PD-L1 positive tumors. Conclusion: CEA TCB is a novel generation TCB displaying potent anti-tumor activity; it is efficacious in poorly-infiltrated tumors where it increases T cell infiltration and generates a highly-inflamed tumor microenvironment.

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Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children's Oncology Group

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma (ES) cells in the blood and bone marrow (BM). These techniques were used to evaluate the prognostic significance of micrometastatic disease in ES. Experimental Design: Newly diagnosed patients with ES were enrolled on two prospective multi-center studies. In the flow cytometry cohort, patients were defined as "positive" for BM micrometastatic disease if their CD99+/CD45- values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or BM samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Co-expression of IGF-1R on detected tumor cells was performed in a subset of flow cytometry samples. Results: The median total BM CD99+CD45- percent was 0.0012% (range 0-1.10%) in the flow cytometry cohort, with 14/109 (12.8%) of ES patients defined as "positive." In the PCR cohort, 19.6% (44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or BM. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" vs. "negative" by either method. CD99+CD45- cells had significantly higher IGF-1R expression compared to CD45+ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; p<0.001). Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with ES. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest.

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Translational and clinical research highlights from the 38th San Antonio Breast Cancer Symposium

Future Oncology Ahead of Print.


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The genetic classification of prostate cancer: what’s on the horizon?

Future Oncology Ahead of Print.


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