Cancer care in German centers of excellence during the first 2 years of the COVID-19 pandemic.

PURPOSE: An increasing number of international studies demonstrate serious negative effects of the COVID-19 pandemic on the timely diagnosis of cancer and on cancer treatment. Our study aimed to quantitatively and qualitatively evaluate the capacities of German Comprehensive Cancer Centers (CCCs) in different areas of complex oncology care during the first 2 years of the COVID-19 pandemic. METHODS: Prospective panel survey over 23 rounds among 18 CCCs in Germany between March 2020 and June 2022. RESULTS: The COVID-19 pandemic substantially affected the oncological care system in Germany during the first 2 years. Persistent limitations of care in CCCs primarily affected follow-up (- 21%) and psycho-oncologic care (- 12%), but also tumor surgery (- 9%). Substantial limitations were also reported for all other areas of multidisciplinary oncological care. CONCLUSIONS: This study documents the limitations of oncological care during the COVID-19 pandemic and highlights the need to develop strategies to avoid similar limitations in the future.

Pasotuxizumab, a BiTE® immune therapy for castration-resistant prostate cancer: Phase I, dose-escalation study findings.

Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE®) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 µg/d; cIV: n = 16, 5-80 µg/d). The SC maximum tolerated dose was 172.0 µg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov).

Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation.

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.

Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy.

Blinatumomab is a member of a novel class of T cell-engaging bispecific antibodies, so-called Bispecific T cell Engager (BiTEs). It is directed against the B cell differentiation antigen CD19 and intended for treatment of B cell malignancies. In clinical phase I/II trials, blinatumomab showed remarkable single-agent activity in patients with relapsed and/or refractory (R/R) non-Hodgkin lymphoma and R/R B cell precursor acute lymphoblastic leukemia (B-precursor ALL). Cytokine release syndrome and neurological side effects were dose-limiting. Adverse effects were well manageable and transient in nature. Based on results of an international phase II trial, blinatumomab received FDA approval for the treatment of R/R B-precursor ALL in December 2014. Ongoing and future trials will contribute to further optimization of blinatumomab-based T cell therapy and have to show that integration of blinatumomab in current and innovative treatment protocols improves overall survival and quality of life of patients with B cell malignancies.

Integrin-linked kinase is dispensable for multiple myeloma cell survival.

We investigated the utility of integrin-linked kinase (ILK) as a target for therapeutic intervention in multiple myeloma (MM). ILK (over-)expression was assessed in primary samples and MM cell lines, and the molecular and physiological consequences of siRNA-mediated ILK ablation were compared to treatment with the small molecule inhibitor QLT0267. Whereas ILK expression was ubiquitous, overexpression was only rarely observed in patient biopsies. ILK knockdown had no effect on the viability or survival pathway activity pattern of MM cells. Conversely, QLT0267 induced cell death in MM cell lines and most primary tumor samples via the intrinsic apoptotic pathway. Although this effect was largely tumor cell-specific it is unlikely to have been mediated via ILK. We conclude that ILK does not play a prominent role in the promotion or sustenance of established MM.

Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585.

Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti-cancer agents and may be useful to enhance the therapeutic efficiency of established anti-myeloma treatments. This study preclinically evaluated the effects of the 'second generation' pan-HDAC inhibitor JNJ-26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n=42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl-1 depletion and Hsp72 induction were the most reliable features observed in JNJ-26481585-treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ-26481585 with anti-myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC-inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.

Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800.

The 90 kD heat shock protein (Hsp90) molecular chaperone sustains multiple components of oncogenic pathways and has recently emerged as a therapeutic target that is now being clinically tested in a number of malignancies. In order to address formulation issues and to deal with possible resistance mechanisms against small molecule Hsp90 inhibitors, a range of compounds based on different molecular scaffolds are now being developed. The present study preclinically tested the effects of the novel 2-aminothienopyrimidine class Hsp90 inhibitor NVP-BEP800, which is suitable for oral formulations, on multiple myeloma cells from established cell lines and on a larger cohort (n = 40) of primary myeloma samples. The drug effectively and specifically killed the majority of primary myeloma cells in coculture with bone marrow stromal cells and reliably entailed molecular consequences of Hsp90 blockade - such as survival pathway breakdown and client protein depletion - in multiple myeloma cells from cell lines as well as from patients. Collectively, the properties of this novel drug support clinical testing in multiple myeloma.

Antitumoral and antileishmanial dioncoquinones and ancistroquinones from cell cultures of Triphyophyllum peltatum (Dioncophyllaceae) and Ancistrocladus abbreviatus (Ancistrocladaceae).

From the methanolic extracts of solid callus cultures from two species of the closely related palaeotropical plant families Dioncophyllaceae and Ancistrocladaceae seven new natural naphthoquinones were isolated, dioncoquinones A (4) and B (5) from Triphyophyllum peltatum, and ancistroquinones B (6), C (7), D (9), E (10), and F (12) from Ancistrocladus abbreviatus. Their structures were elucidated by spectroscopic, chemical, and computational methods. Furthermore, the already known naphthoquinones plumbagin (2), droserone (3), malvone A (8), and nepenthone A (11) were found in the extract of A. abbreviatus. Dioncoquinones A (4) and B (5) showed good - and specific - activity against Leishmania major, while they were not active against other protozoic parasites. Moreover, treatment with 4 and 5 strongly induced apoptosis in human tumor cells derived from two different B cell malignancies, B cell lymphoma and multiple myeloma, without any significant toxicity towards normal peripheral mononuclear blood cells.