Long-term survival after adoptive bone marrow T cell therapy of advanced metastasized breast cancer: follow-up analysis of a clinical pilot trial

Background

The bone marrow (BM) of breast cancer patients harbors tumor-reactive memory T cells (TCs) with therapeutic potential. We recently described the immunologic effects of adoptive transfer of ex vivo restimulated tumor-reactive memory TCs from the BM of 12 metastasized breast cancer patients in a clinical phase-I study. In this trial, adoptive T cell transfer resulted in the occurrence of circulating tumor antigen-reactive type-1 TCs. We here describe the long-term clinical outcome and its correlation with tumor-specific cellular immune response in 16 metastasized breast cancer patients, including 12 included in the original study.

Methods

Sixteen metastatic breast cancer patients with preexisting tumor-reactive BM memory TCs were included into the study. The study protocol involved one transfusion of TCs which were reactivated in vitro with autologous dendritic cells pulsed with lysates of MCF-7 breast cancer cells as source of tumor antigens. The presence of tumor-reactive memory TCs was analyzed by IFN-γ ELISpot assays.

Results

Tumor-reactive memory TCs in the peripheral blood were induced de novo in 7/16 patients (44 %) after adoptive TC transfer. These patients were considered immunologic responders to the therapy. Positive adoptive immunotherapy (ADI) response was observed significantly more often in patients without bone metastases (p = 0.0051), in patients with high levels of tumor-reactive BM TCs prior to therapy (p = 0.036) and correlated significantly with the estimated numbers of transferred tumor-reactive TCs (p = 0.0021). After the treatment, we observed an overall median survival of 33.8 months in the total cohort with three patients alive at last follow-up and more than 7 years after ADI. Numbers of transferred tumor-reactive TCs correlated significantly with the overall survival of patients (p = 0.017). Patients with an immunologic response to ADI in the peripheral blood had a significantly longer median survival than nonresponders (median survival 58.6 vs. 13.6 months; p = 0.009).

Conclusion

In metastasized breast cancer patients, adoptive transfer of BM TCs can induce the presence of tumor antigen-reactive type-1 TCs in the peripheral blood. Patients with immunologic response after ADI show a significantly longer overall survival. Patients with bone metastases significantly less frequently respond to the treatment and, therefore, might not be optimal candidates for ADI. Although the present study does not yet prove the therapeutic effect of ADI, these findings shed light on the relation between immune response and cancer prognosis and suggest that transfer of reactivated BM TCs might bear therapeutic potential.     

Three old and one new: protein import into red algal-derived plastids surrounded by four membranes

Engulfment of a red or green alga by another eukaryote and subsequent reduction of the symbiont to an organelle, termed a complex plastid, is a process known as secondary endosymbiosis and is shown in a diverse group of eukaryotic organisms. Important members are heterokontophytes, haptophytes, cryptophytes, and apicomplexan parasites, all of them with complex plastids of red algal origin surrounded by four membranes. Although the evolutionary relationship between these organisms is still debated, they share common mechanisms for plastid protein import. In this review, we describe recent findings and current models on preprotein import into complex plastids with a special focus on the second outermost plastid membrane. Derived from the plasma membrane of the former endosymbiont, the evolution of protein transport across this so-called periplastidal membrane most likely represented the challenge in the transition from an endosymbiont to a host-dependent organelle. Here, remodeling and relocation of the symbiont endoplasmic reticulum-associated degradation (ERAD) machinery gave rise to a translocon complex termed symbiont-specific ERAD-like machinery and provides a fascinating insight into complex cellular evolution.     

Hemocytes and Plasma of the Eastern Oyster (Crassostrea virginica) Display a Diverse Repertoire of Sulfated and Blood Group A-modified N-Glycans

The eastern oyster (Crassostrea virginica) has become a useful model system for glycan-dependent host-parasite interactions due to the hijacking of the oyster galectin CvGal1 for host entry by the protozoan parasite Perkinsus marinus, the causative agent of Dermo disease. In this study, we examined the N-glycans of both the hemocytes, which via CvGal1 are the target of the parasite, and the plasma of the oyster. In combination with HPLC fractionation, exoglycosidase digestion, and fragmentation of the glycans, mass spectrometry revealed that the major N-glycans of plasma are simple hybrid structures, sometimes methylated and core α1,6-fucosylated, with terminal β1,3-linked galactose; a remarkable high degree of sulfation of such glycans was observed. Hemocytes express a larger range of glycans, including core-difucosylated paucimannosidic forms, whereas bi- and triantennary glycans were found in both sources, including structures carrying sulfated and methylated variants of the histo-blood group A epitope. The primary features of the oyster whole hemocyte N-glycome were also found in dominin, the major plasma glycoprotein, which had also been identified as a CvGal1 glycoprotein ligand associated with hemocytes. The occurrence of terminal blood group moieties on oyster dominin and on hemocyte surfaces can account in part for their affinity for the endogenous CvGal1.     

Cherry Picking: A Characterization of the Temporal Hybridization Number for a Set of Phylogenies

Recently, we have shown that calculating the minimum–temporal-hybridization number for a set ${\mathcal{P}}$ of rooted binary phylogenetic trees is NP-hard and have characterized this minimum number when ${\mathcal{P}}$ consists of exactly two trees. In this paper, we give the first characterization of the problem for ${\mathcal{P}}$ being arbitrarily large. The characterization is in terms of cherries and the existence of a particular type of sequence. Furthermore, in an online appendix to the paper, we show that this new characterization can be used to show that computing the minimum–temporal hybridization number for two trees is fixed-parameter tractable.     

Effect of different C/N ratios on carotenoid and lipid production by Rhodotorula glutinis

Due to the increasing demand for sustainable biofuels, microbial oils as feedstock for the transesterification into biodiesel have gained scientific and commercial interest. Also, microbial carotenoids have a considerable market potential as natural colorants. The carbon to nitrogen (C/N) ratio of the respective cultivation media is one of the most important parameters that influence the production of microbial lipids and carotenoids. Thus, in the present experiment, the influence of different C/N ratios, initial glucose loadings, and ammonium concentrations of the cultivation medium on microbial cell growth and lipid and carotenoid production by the oleaginous red yeast Rhodotorula glutinis has been assessed. As a general trend, both lipid and carotenoid production increased at high C/N ratios. It was shown that not only the final C/N ratio but also the respectively applied initial carbon and nitrogen contents influenced the observed parameters. The lipid yield was not affected by different ammonium contents, while the carotenoid production significantly decreased both at low and high levels of ammonium supply. A glucose-based increase from C/N 70 to 120 did not lead to an increased lipid production, while carotenoid synthesis was positively affected. Generally, it can be asserted that lipid and carotenoid synthesis are stimulated at higher C/N ratios.     

Formation and growth of a heronry in a managed wetland in Doñana,southwest Spain

Capsule A newly created wetland has been beneficial for the breeding of five heron species and for the settlement and expansion of Glossy Ibises in the region.

Aim To determine whether created wetland would lead to the establishment of a heron and ibis breeding colony, and if so, to determine its effects on the distribution of these species in the wider region.

Methods Number of pairs breeding at the new wetland and in the region were estimated annually from 1996 to 2008. We investigated whether the growth of the new colony was explained by redistribution of breeding pairs within the region.

Results Purple Herons, Squacco Herons and Glossy Ibises colonised the new wetland in 1996. Black‐crowned Night Herons settled in 1998, while Cattle and Little Egrets were the last species to establish in the mixed colony in 2001. The population increase was particularly marked for Glossy Ibises (which had bred in Doñana only sporadically through the 20th century). Our findings suggest that simple redistribution of pairs does not explain the formation and growth of the new colony. Since the first year of establishment numbers of Glossy Ibises and Purple Herons have shown a significant growth trend at both the new colony and in Doñana.

Conclusion The creation and management of a new wetland has been successful for the conservation of heron and egret species and promoted the expansion of the Glossy Ibis population across the western Mediterranean region.