Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Polymorphisms in the gene regions of the adaptor complex LAMTOR2/LAMTOR3 and their association with breast cancer risk.

Background: The late endosomal LAMTOR complex serves as a convergence point for both the RAF/MEK/ERK and the PI3K/AKT/mTOR pathways. Interestingly, both of these signalling cascades play a significant role in the aetiology of breast cancer. Our aim was to address the possible role of genetic polymorphisms in LAMTOR2 and LAMTOR3 as genetic risk factors for breast cancer. Methodology/Results: We sequenced the exons and exon-intron boundaries of LAMTOR2 (p14) and LAMTOR3 (MP1) in 50 prospectively collected pairs of cancerous tissue and blood samples from breast cancer patients and compared their genetic variability. We found one single nucleotide polymorphism (SNP) in LAMTOR2 (rs7541) and two SNPs in LAMTOR3 (rs2298735 and rs148972953) in both tumour and blood samples, but no somatic mutations in cancerous tissues. In addition, we genotyped all three SNPs in 296 samples from the Risk Prediction of Breast Cancer Metastasis Study and found evidence of a genetic association between rs148972953 and oestrogen (ER) and progesterone receptor negative status (PR) (ER: OR = 3.60 (1.15-11.28); PR: OR = 4.27 (1.43-12.72)). However, when we additionally genotyped rs148972953 in the MARIE study including 2,715 breast cancer cases and 5,216 controls, we observed neither a difference in genotype frequencies between patients and controls nor was the SNP associated with ER or PR. Finally, all three SNPs were equally frequent in breast cancer samples and female participants (n = 640) of the population-based SAPHIR Study. Conclusions: The identified polymorphisms in LAMTOR2 and LAMTOR3 do not seem to play a relevant role in breast cancer. Our work does not exclude a role of other not yet identified SNPs or that the here annotated polymorphism may in fact play a relevant role in other diseases. Our results underscore the importance of replication in association studies

Gender specific quality of life in patients with oral squamous cell carcinomas

<p>Abstract</p> <p>Background</p> <p>The goal of this study was to evaluate the somatic and psychological effects by means of QUALITY OF LIFE (QOL) of surgical treatment of patients with oral squamous cell carcinoma. The factors gender, age, nicotine consumption, and tumour stage were taken into consideration.</p> <p>Methods</p> <p>54 patients after surgical resection of oral squamous cell carcinomas (OSCC) were analysed from 01.09.2005 to 31.05.2008. Inclusion criteria for the study were: age at least 18 years, no indication or treatment of synchronous and metachronous tumours.</p> <p>German translations of the EORTC H&N-35 and EORTC QLQ-C-30 questionnaires, as well as a general socioeconomic patient history were used as measuring instruments. The questionnaires were completed independently by the patients. The answers were translated into scale values for statistical evaluation using appropriate algorithms.</p> <p>Results</p> <p>Analysis of the EORTC-QLQ-C-30 questionnaires demonstrated a tendency of more negative assessment of emotional function among the female participants, and a more negative evaluation of social function among the male participants. Greater tumour sizes showed significantly lower bodily function (p = 0.018). While a smaller tumour size was significantly associated with lower cognitive functioning (p = 0.031). Other cofactors such as age, nicotine consumption, and tumour stage only showed a tendency to influence the quality of sleep and daily life.</p> <p>Conclusions</p> <p>The data obtained within this investigation demonstrated that gender had the most significant power on the subjectively perceived postoperative quality of life. This factor is important e.g. in preoperative decision making regarding immediate microvascular reconstruction after e.g. mandibular resection and therefore QOL assessment should become integral component of the care of patients with OSCC.</p

The positive impacts of Real-World Data on the challenges facing the evolution of biopharma.

Demand for healthcare services is unprecedented. Society is struggling to afford the cost. Pricing of biopharmaceutical products is under scrutiny, especially by payers and Health Technology Assessment agencies. As we discuss here, rapidly advancing technologies, such as Real-World Data (RWD), are being utilized to increase understanding of disease. RWD, when captured and analyzed, produces the Real-World Evidence (RWE) that underpins the economic case for innovative medicines. Furthermore, RWD can inform the understanding of disease, help identify new therapeutic intervention points, and improve the efficiency of research and development (R&D), especially clinical trials. Pursuing precompetitive collaborations to define shared requirements for the use of RWD would equip service-providers with the specifications needed to implement cloud-based solutions for RWD acquisition, management and analysis. Only this approach would deliver cost-effective solutions to an industry-wide problem

Measurement of azimuthal asymmetries in inclusive charged dipion production in e+e−e^+e^- annihilations at s\sqrt{s} = 3.65 GeV

We present a measurement of the azimuthal asymmetries of two charged pions in the inclusive process $e^+e^-\rightarrow \pi\pi X$ based on a data set of 62 $\rm{pb}^{-1}$ at the center-of-mass energy $\sqrt{s}=3.65$ GeV collected with the BESIII detector. These asymmetries can be attributed to the Collins fragmentation function. We observe a nonzero asymmetry, which increases with increasing pion momentum. As our energy scale is close to that of the existing semi-inclusive deep inelastic scattering experimental data, the measured asymmetries are important inputs for the global analysis of extracting the quark transversity distribution inside the nucleon and are valuable to explore the energy evolution of the spin-dependent fragmentation function.Comment: 7 pages, 5 figure

Measurement of the e+e−→π+π−\mathrm e^+\mathrm e^-\rightarrow\mathrm\pi^+\mathrm\pi^- Cross Section between 600 and 900 MeV Using Initial State Radiation

We extract the $e^+e^-\rightarrow \pi^+\pi^-$ cross section in the energy range between 600 and 900 MeV, exploiting the method of initial state radiation. A data set with an integrated luminosity of 2.93 fb$^{-1}$ taken at a center-of-mass energy of 3.773 GeV with the BESIII detector at the BEPCII collider is used. The cross section is measured with a systematic uncertainty of 0.9%. We extract the pion form factor $|F_\pi|^2$ as well as the contribution of the measured cross section to the leading order hadronic vacuum polarization contribution to $(g-2)_\mu$. We find this value to be $a_\mu^{\pi\pi,\rm LO}(600-900\;\rm MeV) = (368.2 \pm 2.5_{\rm stat} \pm 3.3_{\rm sys})\cdot 10^{-10}$.Comment: 14 pages, 7 figures, accepted by PL

Observation of the ψ(13D2)\psi(1^3D_2) state in e+e−→π+π−γχc1e^+e^-\to\pi^+\pi^-\gamma\chi_{c1} at BESIII

We report the observation of the $X(3823)$ in the process $e^+e^-\to \pi^+\pi^-X(3823) \to \pi^+\pi^-\gamma\chi_{c1}$ with a statistical significance of $6.2\sigma$, in data samples at center-of-mass energies $\sqrt{s}=$4.230, 4.260, 4.360, 4.420 and 4.600~GeV collected with the BESIII detector at the BEPCII electron positron collider. The measured mass of the $X(3823)$ is $(3821.7\pm 1.3\pm 0.7)$~MeV/$c^2$, where the first error is statistical and the second systematic, and the width is less than $16$~MeV at the 90\% confidence level. The products of the Born cross sections for $e^+e^-\to \pi^+\pi^-X(3823)$ and the branching ratio $\mathcal{B}[X(3823)\to \gamma\chi_{c1,c2}]$ are also measured. These measurements are in good agreement with the assignment of the $X(3823)$ as the $\psi(1^3D_2)$ charmonium state.Comment: 7 pages, 3 figures, version to appear in Phys. Rev. Let

Study of D+→K−π+e+νeD^{+} \to K^{-} \pi^+ e^+ \nu_e

We present an analysis of the decay $D^{+} \to K^{-} \pi^+ e^+ \nu_e$ based on data collected by the BESIII experiment at the $\psi(3770)$ resonance. Using a nearly background-free sample of 18262 events, we measure the branching fraction $\mathcal{B}(D^{+} \to K^{-} \pi^+ e^+ \nu_e) = (3.71 \pm 0.03 \pm 0.08)\%$. For $0.8<m_{K\pi}<1.0$ GeV/$c^{2}$ the partial branching fraction is $\mathcal{B}(D^{+} \to K^{-} \pi^+ e^+ \nu_e)_{[0.8,1]} = (3.33 \pm 0.03 \pm 0.07)\%$. A partial wave analysis shows that the dominant $\bar K^{*}(892)^{0}$ component is accompanied by an \emph{S}-wave contribution accounting for $(6.05\pm0.22\pm0.18)\%$ of the total rate and that other components are negligible. The parameters of the $\bar K^{*}(892)^{0}$ resonance and of the form factors based on the spectroscopic pole dominance predictions are also measured. We also present a measurement of the $\bar K^{*}(892)^{0}$ helicity basis form factors in a model-independent way.Comment: 17 pages, 6 figure

Study of J/ψJ/\psi and ψ(3686)→Σ(1385)0Σˉ(1385)0\psi(3686)\rightarrow\Sigma(1385)^{0}\bar\Sigma(1385)^{0} and Ξ0Ξˉ0\Xi^0\bar\Xi^{0}

We study the decays of $J/\psi$ and $\psi(3686)$ to the final states $\Sigma(1385)^{0}\bar\Sigma(1385)^{0}$ and $\Xi^0\bar\Xi^{0}$ based on a single baryon tag method using data samples of $(1310.6 \pm 7.0) \times 10^{6}$ $J/\psi$ and $(447.9 \pm 2.9) \times 10^{6}$ $\psi(3686)$ events collected with the BESIII detector at the BEPCII collider. The decays to $\Sigma(1385)^{0}\bar\Sigma(1385)^{0}$ are observed for the first time. The measured branching fractions of $J/\psi$ and $\psi(3686)\rightarrow\Xi^0\bar\Xi^{0}$ are in good agreement with, and much more precise, than the previously published results. The angular parameters for these decays are also measured for the first time. The measured angular decay parameter for $J/\psi\rightarrow\Sigma(1385)^{0}\bar\Sigma(1385)^{0}$, $\alpha =-0.64 \pm 0.03 \pm 0.10$, is found to be negative, different to the other decay processes in this measurement. In addition, the "12\% rule" and isospin symmetry in the $J/\psi$ and $\psi(3686)\rightarrow\Xi\bar\Xi$ and $\Sigma(1385)\bar{\Sigma}(1385)$ systems are tested.Comment: 11 pages, 7 figures. This version is consistent with paper published in Phys.Lett. B770 (2017) 217-22