Rational combinations of in vivo cancer antigen priming and adoptive T-cell therapy mobilize immune and clinical responses in terminal cancers.

PURPOSE: It is now recognized that solid tumors encroach on the host's immune microenvironment to favor its own proliferation. Strategies to enhance the specificity of the endogenous T-cell population against tumors have been met with limited clinical success. We aimed to devise a two-tier protocol coupling in vivo whole antigen priming with ex vivo cellular expansion to clinically evaluate survival in patients following re-infusion of primed, autologous T cells, thereby determining treatment efficacy. EXPERIMENTAL DESIGN: Treatment commenced with the acquisition of whole tumor antigens from tumor cell lines corresponding with patients' primary malignancy. Lysate mixture was inoculated intradermally, while peripheral blood mononuclear cells (PBMCs) were periodically extracted via phlebotomy and expanded in culture ex vivo for re-infusion. Post-treatment tumor-specific T-cell response and cytotoxicity was confirmed via Elispot and real-time cell analyzing (RTCA) assay. Serum cytokine levels and cytotoxicity scores were evaluated for associations with survival status and duration. RESULTS: There was a significant increase in cytotoxicity exhibited by T cells measured using both Elispot and RTCA following treatment. Correlation analysis determined significant association between higher post-treatment cytotoxicity scores and survival status (R = 0.52, p = 0.0028) as well as longer survival duration in months (R = 0.59, p = 0.005). CONCLUSIONS: Our treatment protocol successfully demonstrated significant correlation between tumor-associated antigen-specific immune response and objective prolongation of survival. Whole-cell cancer antigen priming and adoptive T-cell therapy is, therefore, a highly feasible clinical model which can be easily replicated to positively influence outcome in end-stage malignancy.

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, clinical efficacy is limited by the development of resistance. In most cases, this resistance is in the form of the T790M mutation. Here, we report the design, synthesis and biochemical evaluation of a novel series of irreversible EGFR tyrosine kinase inhibitors (EGFR-TKIs) that are derived from the anilinoquinazoline scaffold. Guided by molecular modeling, this series of analogs was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and to achieve high levels of anti-tumor activity in cell cultures and in xenografts. The most promising compound 13c ((E) -N - (4 - (4 - (3-fluorobenzyloxy) -3- chlorophenylamino) -7-ethoxyquinazolin-6-yl) -3- ((S) -pyrrolidin-2-yl)acrylamide, which we named Transtinib) displayed strong anti-proliferative activity against the H1975 and A431 cell lines with IC50 values of 34 nM and 62 nM, respectively. In xenograft models, Transtinib significantly decreases tumor size for a prolonged period of time. These results suggest that Transtinib is a potential cancer therapeutic drug lead for the inhibition of mutant EGFR to overcome the development of resistance.

Circulating tumor cells (CTCs) as a liquid biopsy material and drug target.

Circulating tumor cells (CTCs) have attracted interest as biomarkers of cancer metastases but only recently has a reliable method of CTC detection been developed. CTCs can be thought of as a liquid biopsy from the blood, and they can be used in pathological and molecular assays. CTCs may ideally replace metastatic tissue biopsies in the prediction and monitoring of therapeutic responses and tumor recurrence. CTCs can be used to guide therapeutic cancer management and serve as drug targets. For this reason, the potential of this technology and the limitations of currently available methods of CTC detection are addressed here. The clinical applications of CTCs include the prediction of cancer prognosis; selection and monitoring of therapeutic regimens; and drug target applications. The manner in which CTC molecular profiling can facilitate prognosis and the selection of cancer therapies.

Structure, function, and pathogenesis of SHP2 in developmental disorders and tumorigenesis.

Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the human PTPN11 gene, is a ubiquitously expressed protein tyrosine phosphatase (PTP) that consists of two tandem Src homology (SH2) domains (N-SH2 and C-SH2), a PTP catalytic domain, and a C-terminal tail with tyrosyl phosphorylation sites. It plays critical roles in numerous cellular processes through the regulation of various signaling pathways in PTP catalytic activity-dependent and -independent manners. Dysfunction of SHP2 resulting from pathogenic mutations and aberrant expression leads to the dysregulation of multiple signaling pathways, thus contributing to different human disorders. Germline and somatic mutations in PTPN11 are involved in Noonan syndrome (NS), LEOPARD syndrome (LS), and hematological malignancies, as well as several solid tumors. In this report, we provide an overview of the current knowledge of the structure and function of SHP2, and further discuss the molecular and pathogenic mechanism of SHP2 in human diseases, with a special focus on tumorigenesis. Furthermore, we summarize that SHP2 might itself represent a potential drug target for cancer prevention and treatment. Ongoing research and development of SHP2-specific inhibitors would enhance this potential.

Somatostatin receptors in nasopharyngeal carcinoma.

Somatostatin receptors (SS-Rs) are expressed in neuroendocrine tumour tissues where they can be targetted for diagnosis and therapy. This study investigated the presence of SS-Rs in nasopharyngeal carcinoma (NPC), a common cancer in South-East Asia. Nasopharynx biopsy specimens were obtained from 12 NPC patients and 5 patients without tumours. Somatostatin receptor autoradiography was performed using (125)I-labelled [Tyr(3)]-octreotide and (125)I-labelled [Leu(8), DTrp(22), Tyr(25)]-somatostatin-28 as radioligands. Of the 12 NPC samples 9 showed moderate to high expression of SS-Rs. These were of the sst(2) type, based on the rank order of potency of subtype-selective analogues. The 5 non-neoplastic samples, consisting primarily of granulomatous tissue, did not express measurable amounts of SS-Rs. This study demonstrates for the first time the presence of type 2 SS-R in NPC. These receptors may play a role in the management of NPC, as is the case for other somatostatin-expressing tumours.

A critical assessment of the neurodestructive and neuroprotective effects of nitric oxide.

Whether nitric oxide is cytodestructive or cytoprotective is of obvious clinical importance. The debate on this subject in the past decade has generated much "heat and light". This paper focuses on the actions of NO on the nervous system and reexamines the controversial issue and the contribution of the authors and their colleagues in the light of recent findings. We also report new findings, critically assesses previous experimental data, and share perspectives on this important subject.

Possible roles of nitric oxide in the physiology and pathophysiology of the mammalian cochlea.

Nitric oxide (NO) has been implicated as a mediator of vasodilation and neurotransmission in the mammalian cochlea. This is demonstrated by the presence of nitric oxide synthase (NOS) and nitric oxide (NO) in the blood vessels and the organ of Corti in the cochlea. It is not certain if the neurons in the spiral ganglion produce NO since no fluorescent signal could be detected by 4,5-diaminofluorescein diacetate (DAF-2DA), a fluorescent indicator of NO. To determine if NO/peroxynitrite plays any role in neurodestruction observed in ischemic cochlea of the guinea pig, the effects of NO donors, such as S-nitrosocysteine (S-NC) and nitroglycerine (NTG); peroxynitrite generators, such as 3-morpholinosydnonimine (SIN-1); peroxynitrite inhibitors, such as superoxide dismutase plus catalase (SOD/Cat); and NOS inhibitors, such as N(G)-nitro-L-arginine methyl ether (L-NAME) were tested on normal and ischemic cochleae. The level of NO in the cochlea after 20 to 120 minutes of ischemia was indicated by measurement of nitrites/nitrates in the perilymph. The evidence gathered from these experiments indicates that NO or peroxynitrite is not necessarily destructive to auditory hair cells, and in fact, exogenous NO may protect neural structures in the cochlea from damage under ischemic conditions.