Hematopoietic cell transplantation and cellular therapies in Switzerland. Evolution over 25 years. A report from the stem cell transplantation and cellular therapies working groups of the SBST 1997-2021.

The Swiss Blood Stem Cell Transplantation and Cellular Therapy Group (SBST) leads a mandatory national registry for all hematopoietic stem cell transplants (HCT) and cellular therapies. After 25 years, information was available for 11,226 patients receiving an HCT (4031 allogeneic and 7195 autologous), including 925 pediatric patients. We compared patient characteristics and outcome by quinquennia 1997-2001, 2002-2006, 2007-2011, 2012-2016, and 2017-2021. There were numerous changes over time. Allogeneic transplant recipients became older (median age 33.7 vs. 54.3) and had more frequently unrelated donors and reduced intensity conditioning in later quinquennia. Similarly, age increased for recipients of autologous HCT (median 48.3 vs. 59.9). We did not see a significant drop in transplant activity during the SARS-CoV-2 pandemic. Analysis of outcome showed overall survival (relative risk (RR) of death 0.664 (0.529-0.832) and progression free survival (RR 0.708 (0.577-0.870) being improved over time comparing the latest to the first quinquennium adjusting for risk factors. Non-relapse mortality decreased in recipients of allogeneic HCT (RR: 0.371 (0.270-0.509)) over time but relapse risks did not. Outcome of autologous HCT improved as well across quinquennia, this improvement was mainly due to decreased relapse risks (RR 0.681 (0.597-0.777)), possibly related to maintenance treatment or rescue treatment for relapse mainly in myeloma patients. Cellular therapies other than allogeneic or autologous HCT, particularly chimeric antigen receptor T-cells (CAR-T) treatment have started to increase after 2019, year of approval of the first commercial CAR-T product in Switzerland. Data on chimeric antigen receptor T-cell treatment are too early for comparative analyses. Detailed analyses of changes over time are presented. This study includes all HCTs, and cellular therapies, data useful for quality assurance programs, health care cost estimation and benchmarking. Between 50% and 60% of patients are long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care.

Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13).

Background: The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL. Methods: In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min-max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458. Findings: Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively. Interpretation: The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features. Funding: SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen.

Twist-Angle-Dependent Electronic Properties of Exfoliated Single Layer MoS2 on Au(111).

Synthetic materials and heterostructures obtained by the controlled stacking of exfoliated monolayers are emerging as attractive functional materials owing to their highly tunable properties. We present a detailed scanning tunneling microscopy and spectroscopy study of single layer MoS2-on-gold heterostructures as a function of the twist angle. We find that their electronic properties are determined by the hybridization of the constituent layers and are modulated at the moiré period. The hybridization depends on the layer alignment, and the modulation amplitude vanishes with increasing twist angle. We explain our observations in terms of a hybridization between the nearest sulfur and gold atoms, which becomes spatially more homogeneous and weaker as the moiré periodicity decreases with increasing twist angle, unveiling the possibility of tunable hybridization of electronic states via twist angle engineering.

Determining spin-orbit coupling in graphene by quasiparticle interference imaging.

Inducing and controlling spin-orbit coupling (SOC) in graphene is key to create topological states of matter, and for the realization of spintronic devices. Placing graphene onto a transition metal dichalcogenide is currently the most successful strategy to achieve this goal, but there is no consensus as to the nature and the magnitude of the induced SOC. Here, we show that the presence of backscattering in graphene-on-WSe2 heterostructures can be used to probe SOC and to determine its strength quantitatively, by imaging quasiparticle interference with a scanning tunneling microscope. A detailed theoretical analysis of the Fourier transform of quasiparticle interference images reveals that the induced SOC consists of a valley-Zeeman (λvZ ≈ 2 meV) and a Rashba (λR ≈ 15 meV) term, one order of magnitude larger than what theory predicts, but in excellent agreement with earlier transport experiments. The validity of our analysis is confirmed by measurements on a 30 degree twist angle heterostructure that exhibits no backscattering, as expected from symmetry considerations. Our results demonstrate a viable strategy to determine SOC quantitatively by imaging quasiparticle interference.

Tunable biaxial strain device for low-dimensional materials.

Strain is attracting much interest as a mean to tune the properties of thin exfoliated two-dimensional materials and their heterostructures. Numerous devices to apply tunable uniaxial strain are proposed in the literature, but only few for biaxial strain, often with a trade-off between maximum strain and uniformity, reversibility, and device size. We present a compact device that allows for the controlled application of uniform in-plane biaxial strain, with maximum deformation and uniformity comparable to those found in much larger devices. Its performance and strain uniformity over the sample area are modeled using finite element analysis and demonstrated by measuring the response of exfoliated 2H-MoS2 to strain by Raman spectroscopy.

Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).

Purpose: These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. Methods: We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. Results: From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. Conclusions: We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care.

Satraplatin Demonstrates High Cytotoxic Activity Against Genetically Defined Lymphoid Malignancies.

BACKGROUND/AIM: Satraplatin is an oral platinum analog with proven clinical efficacy and a more favorable toxicity profile, although with increased hematotoxicity, when compared to cisplatin. Hence, we carried out a systematic biomarker analysis to identify hematological malignancies with high susceptibility to satraplatin. MATERIALS AND METHODS: Half-maximal inhibitory concentrations (IC50) for satraplatin and cisplatin were determined for 66 different cancer cell lines by CTG Luminescent Cell Viability Assay. In a second step, whole transcriptome RNA sequencing and whole-exome DNA sequencing technology followed by unbiased analysis of gene expression, gene mutation and copy number levels were performed and correlated with drug efficacy. RESULTS: Satraplatin was significantly more active against hematological malignancies compared to solid organ cancer. In addition, satraplatin showed a significantly more potent antiproliferative activity compared to cisplatin in most lymphoma cell lines achieving sub micromolar IC50 values. Single BCL2 apoptosis regulator (BCL2) gene mutation and 9p21 copy-number deletions including S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency were identified as key characteristics for high sensitivity to satraplatin. CONCLUSION: Satraplatin demonstrated a high cytotoxic activity in genetically well-defined hematological malignancies which is distinct from that of cisplatin. MTAP deficiency was identified as biomarker of enhanced satraplatin efficacy in hematological cancer-derived cell lines. These data in combination with the lipophilicity of satraplatin provide the rationale for targeting specific lymphatic entities such as primary central nervous system lymphoma and cutaneous T-cell lymphoma to improve clinical outcome.

Multiband charge density wave exposed in a transition metal dichalcogenide.

In the presence of multiple bands, well-known electronic instabilities may acquire new complexity. While multiband superconductivity is the subject of extensive studies, the possibility of multiband charge density waves (CDWs) has been largely ignored so far. Here, combining energy dependent scanning tunnelling microscopy (STM) topography with a simple model of the charge modulations and a self-consistent calculation of the CDW gap, we find evidence for a multiband CDW in 2H-NbSe2. This CDW not only involves the opening of a gap on the inner band around the K-point, but also on the outer band. This leads to spatially out-of-phase charge modulations from electrons on these two bands, which we detect through a characteristic energy dependence of the CDW contrast in STM images.

Impact of Docetaxel on blood-brain barrier function and formation of breast cancer brain metastases.

BACKGROUND: Breast cancer (BC) is the most frequent malignant tumor in females and the 2nd most common cause of brain metastasis (BM), that are associated with a fatal prognosis. The increasing incidence from 10% up to 40% is due to more effective treatments of extracerebral sites with improved prognosis and increasing use of MRI in diagnostics. A frequently administered, potent chemotherapeutic group of drugs for BC treatment are taxanes usually used in the adjuvant and metastatic setting, which, however, have been suspected to be associated with a higher incidence of BM. The aim of our study was to experimentally analyze the impact of the taxane docetaxel (DTX) on brain metastasis formation, and to elucidate the underlying molecular mechanism. METHODS: A monocentric patient cohort was analyzed to determine the association of taxane treatment and BM formation. To identify the specific impact of DTX, a murine brain metastatic model upon intracardial injection of breast cancer cells was conducted. To approach the functional mechanism, dynamic contrast-enhanced MRI and electron microscopy of mice as well as in-vitro transendothelial electrical resistance (TEER) and tracer permeability assays using brain endothelial cells (EC) were carried out. PCR-based, immunohistochemical and immunoblotting analyses with additional RNA sequencing of murine and human ECs were performed to explore the molecular mechanisms by DTX treatment. RESULTS: Taxane treatment was associated with an increased rate of BM formation in the patient cohort and the murine metastatic model. Functional studies did not show unequivocal alterations of blood-brain barrier properties upon DTX treatment in-vivo, but in-vitro assays revealed a temporary DTX-related barrier disruption. We found disturbance of tubulin structure and upregulation of tight junction marker claudin-5 in ECs. Furthermore, upregulation of several members of the tubulin family and downregulation of tetraspanin-2 in both, murine and human ECs, was induced. CONCLUSION: In summary, a higher incidence of BM was associated with prior taxane treatment in both a patient cohort and a murine mouse model. We could identify tubulin family members and tetraspanin-2 as potential contributors for the destabilization of the blood-brain barrier. Further analyses are needed to decipher the exact role of those alterations on tumor metastatic processes in the brain.

Therapeutic Targeting of Golgi Phosphoprotein 2 (GOLPH2) with Armed Antibodies: A Preclinical Study of Anti-GOLPH2 Antibody Drug Conjugates in Lung and Colorectal Cancer Models of Patient Derived Xenografts (PDX).

BACKGROUND: Golgi phosphoprotein 2 (GOLPH2) has been shown to be involved in chronic inflammatory processes and carcinogenesis. GOLPH2 is prominently overexpressed in hepatocellular carcinoma, melanoma, glioblastoma, prostate, lung, and colorectal cancer. With a low and tightly regulated expression in non-malignant tissues, GOLPH2 has been proposed as an attractive target for cancer therapy. However, GOLPH2 is predominantly located intracellularly and when situated outside of the cell it is proteolytically cleaved and shed from the cell surface. Until now, GOLPH2 has been regarded as an "undruggable" target. OBJECTIVE: We sought to create antibodies that specifically bind to GOLPH2 overexpressing tumor cells. PATIENTS AND METHODS: Antibodies binding to membranous GOLPH2 despite shedding of the protein were generated from a scFV library screening. These antibodies target the part of GOLPH2 that remains at the cell surface after proteolytic cleavage. These antibodies were then tested in vitro and in vivo. RESULTS: Two candidates (G2-1 and G2-2) showed target specific binding in vitro. Utilizing a tumor array (n = 128 tumors) with G2-2 and a reference antibody, a GOLPH2 expression scoring system was established. Rapid internalization of the antibodies was noted so this was exploited to deliver a toxic payload of pyrrolobenzodiazepine (PBD). In two patient-derived xenograft (PDX)-models, colorectal and lung cancer, the G2-2 antibody drug conjugate (ADC) displayed high efficacy with significant tumor responses (P = 0.001; P = 0.013) and improved survival (P = 0.0001; P = 0.0011) compared with controls. CONCLUSIONS: Treatment with GOLPH2-directed antibodies induces durable responses in colorectal and lung cancer models. With a robust companion assay for GOLPH2 positivity at hand our findings prepare for the translation into a clinical trial.

Humanized Monoclonal Antibody Blocking Carbonic Anhydrase 12 Enzymatic Activity Leads to Reduced Tumor Growth In Vitro.

BACKGROUND/AIM: Carbonic anhydrase 12 (CA12) is a membrane-associated enzyme that is highly expressed on many human cancers. It is a poor prognostic marker and hence an attractive target for cancer therapy. This study aimed to develop a humanized CA12-antibody with anti-cancer activity. MATERIALS AND METHODS: Antibody libraries were constructed and screened by the Retrocyte display®. Antibody binding and blocking properties were determined by ELISA, flow cytometry and enzymatic activity assays. Spheroid viability was determined by Cell-Titer-Fluor assay. RESULTS: We developed a novel humanized CA12-specific antibody, 4AG4, which recognized CA12 as an antigen and blocked CA12 enzymatic activity. Our humanized CA12-antibody significantly inhibited spheroid growth of lung adenocarcinoma A549-cells in vitro by blocking CA12 enzymatic activity. Similar anti-tumor effects were recapitulated with CA12-gene knockout of A549-cells. CONCLUSION: Our newly identified humanized CA12-antibody with anti-cancer activity, represents a new tool for the treatment of CA12-positive tumors.

Updated recommendations for diagnosis and treatment of plasma cell myeloma in Switzerland.

This update on plasma cell myeloma has been elaborated by a Swiss expert panel as a result of the plethora of new data on the treatment of plasma cell myeloma reported recently. It adds new insights to the more extensive review that was published 3 years ago and may help clinicians on decision making for their patients. The new recommendations for distinguishing plasma cell myeloma from smouldering myeloma are briefly presented, including a section on contemporary imaging studies with this respect. Former panel recommendations that remain unchanged by new results will not be discussed in detail as the major focus of this review is on treatment-relevant new developments.

Efficacy of selective digestive decontamination in patients with multiple myeloma undergoing high-dose chemotherapy and autologous stem cell transplantation.

Selective digestive decontamination (SDD) with the oral, non-absorbable antimicrobial substances gentamicin, vancomycin and amphotericin B was optionally used at our institution to reduce the risk of gastrointestinal tract derived infections in multiple myeloma (MM) patients undergoing high-dose chemotherapy with subsequent autologous stem cell transplantation (HDCT/ASCT). The majority of patients received sulfamethoxazole-trimethoprim as pneumocystis pneumonia prophylaxis. From 203 patients receiving their first HDCT/ASCT between 2009 and 2015, we compared retrospectively 90 patients receiving SDD to 113 patients not receiving SDD. The administration of SDD was associated with a reduction of bacterial infections after HDCT/ASCT (overall: 8% versus 24%, p = .002; gram-negative pathogens: 1% versus 11%, p = .006) and less use of systemic antibiotics (62% versus 77%, p = .022). Omission of SDD was an independent risk factor for developing neutropenic fever and bloodstream infections. SDD could be an option to reduce bacterial infections in patients undergoing HDCT/ASCT that needs to be tested in prospective trials.

Scanning Tunneling Microscopy of an Air Sensitive Dichalcogenide Through an Encapsulating Layer.

Many atomically thin exfoliated two-dimensional (2D) materials degrade when exposed to ambient conditions. They can be protected and investigated by means of transport and optical measurements if they are encapsulated between chemically inert single layers in the controlled atmosphere of a glovebox. Here, we demonstrate that the same encapsulation procedure is also compatible with scanning tunneling microscopy (STM) and spectroscopy (STS). To this end, we report a systematic STM/STS investigation of a model system consisting of an exfoliated 2H-NbSe2 crystal capped with a protective 2H-MoS2 monolayer. We observe different electronic coupling between MoS2 and NbSe2 from a strong coupling when their lattices are aligned within a few degrees to essentially no coupling for 30° misaligned layers. We show that STM always probes intrinsic NbSe2 properties such as the superconducting gap and charge density wave at low temperature when setting the tunneling bias inside the MoS2 band gap, irrespective of the relative angle between the NbSe2 and MoS2 lattices. This study demonstrates that encapsulation is fully compatible with STM/STS investigations of 2D materials.

Diagnosis and treatment of follicular lymphoma: an update.

Over the last few years, there have been many changes in the management of patients with follicular lymphoma, resulting in improvements in progression-free survival and quality of life. In addition to established regimens such as radiotherapy and immunochemotherapy, new treatment options are on the horizon. Furthermore, even the use of established chemotherapy agents has evolved, with new combinations moving to the forefront of the current treatment strategy. Nevertheless, there remains an unmet need for patients who have early relapses, those who are not responsive to anti-CD20 treatment regimens and for those in whom minimal residual disease persists even after immunochemotherapy. This review provides a summary of current developments in the diagnosis, treatment and management of follicular lymphoma, focusing on the clinical issues from a Swiss perspective.

Cancer Immunotherapy and the Immune Response in Follicular Lymphoma.

Follicular lymphoma (FL) is the most frequent indolent lymphoma in the Western world and is characterized in almost all cases by the t(14;18) translocation that results in overexpression of BCL2, an anti-apoptotic protein. The entity includes a spectrum of subentities that differ from an indolent to a very aggressive growth pattern. As a consequence, treatment can include watch & wait up to intensive chemotherapy including allogeneic stem cell transplantation. The immune cell microenvironment has been recognized as a major driver of outcome of FL patients and gene expression profiling has identified a clinically relevant gene expression signature that classifies an immune response to the lymphoma cells. It is known for some time that the immune cell composition of the lymphoma microenvironment is important because high numbers of tissue-infiltrating macrophages correlate with poor outcome in patients receiving chemotherapy but not in patients receiving the combination of chemotherapy and CD20-specific monoclonal antibody rituximab. In addition, TCR signaling of tumor-infiltrating lymphocytes is dysfunctional leading to an impaired capacity to form an intact immunologic synapse. Approaches restoring local T cell function, e.g., by usage of checkpoint inhibitors has demonstrated clinical activity (ORR 40%) and can achieve long-term remissions. Ongoing trials with re-programmed autologous CART cells achieve response rates in approximately 50% of FL patients with relapsed and even refractory disease. Responses lasting for more than 6 months might be durable, indicative for a successful restoration of a functional immune system. In summary, FL is a malignant disease where the control by the immune system ultimately decides about progression and transformation rate. The advent of monoclonal antibodies has changed the way we treat FL and new approaches restoring the individual immune control will hopefully improve results further.

Cancer Immunotherapy and the Immune Response in Hodgkin Lymphoma.

Patients with classical Hodgkin lymphoma (cHL) have an impaired cellular immune response as indicated by an anergic reaction against standard recall antigens and a diminished rejection reaction of allogeneic skin transplant. This clinical observation can be linked to the histopathological feature of cHL since the typical pattern of a cHL manifestation is characterized by sparse large CD30+ tumor-infiltrating Hodgkin-Reed-Sternberg (HRS) cells that are surrounded by a dense inflammatory immune microenvironment with mixed cellularity. Despite this extensive polymorphous inflammatory infiltrate, there is only a poor antitumor immune response seen to the neoplastic HRS cells. This is primarily mediated by a high expression of PD-L1 and PD-L2 ligands on the HRS cell surface which in turn antagonizes the activity of programmed death-1 (PD-1) antigen-positive T cells. PD-L1/L2 overexpression is caused by gene amplification at the 9p24.1 locus and/or latent Epstein-Barr virus infection present in around 40% of cHL cases. The blockade of the PD-L1/L2-PD-1 pathway by monoclonal antibodies can restore local T cell activity and leads to impressive tumor responses, some of which are long lasting and eventually curative. Another feature of HRS cells is the high CD30 antigen expression. Monoclonal antibody technology allowed for the successful development of CD30-specific immunotoxins, bispecific antibodies, and reprogrammed autologous T cells with the first one already approved for the treatment of high risk or relapsed cHL. Altogether, the discovery of the described pathomechanism of immune suppression and the identification of preferential target antigens has rendered cHL to be a prime subject for the successful development of new immunotherapeutic approaches.

Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice.

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.