Phase 1 study to determine the safety and dosing of autologous PBMCs modified to present HPV16 antigens (SQZ-PBMC-HPV) in HLA-A*02+ patients with HPV16+ solid tumors.

We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks.

Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFR mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor , a novel fourth-generation inhibitor to overcome EGFR-mediated resistance in patients harboring the activating EGFR mutation. exhibits an improved potency compared to previous allosteric EGFR inhibitors.

Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor.

Purpose: Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi.

Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma.

Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously.

A dose escalation study of RO6870810/TEN-10 in patients with acute myeloid leukemia and myelodysplastic syndrome.

Bromodomain and extra-terminal (BET) proteins can drive carcinogenesis and therapy resistance. RO6870810 (RO) is a novel, small-molecule BET inhibitor. We conducted a study in 32 patients with relapsed/refractory acute myeloid leukemia and hypomethylating agent-refractory myelodysplastic syndrome (NCT02308761).

A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.

Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor.

Methods: We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation.

Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma.

This open-label phase 2 study (CONTRALTO) assessed the safety and efficacy of BCL-2 inhibitor venetoclax (VEN) plus rituximab (R), and VEN plus bendamustine (B) and R, vs B + R (BR) alone in relapsed/refractory (R/R) follicular lymphoma. Patients in the chemotherapy-free arm (arm A: VEN + R) received VEN 800 mg/d plus R 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 4, 6, 8, 10, and 12. After a safety run-in with VEN 600 mg, patients in the chemotherapy-containing cohort were randomized to either VEN + BR (arm B; VEN 800 mg/d for 1 year + 6 cycles of BR [B 90 mg/m2 on days 1 and 2 and R 375 mg/m2 on day 1]) or 6 cycles of BR (arm C).

Novel Immunomodulatory Proteins Generated via Directed Evolution of Variant IgSF Domains.

Immunoglobulin superfamily member (IgSF) proteins play a significant role in regulating immune responses with surface expression on all immune cell subsets, making the IgSF an attractive family of proteins for therapeutic targeting in human diseases. We have developed a directed evolution platform capable of engineering IgSF domains to increase affinities for cognate ligands and/or introduce binding to non-cognate ligands. Using this scientific platform, ICOSL domains have been derived with enhanced binding to ICOS and with additional high-affinity binding to the non-cognate receptor, CD28.

Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial.

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D).

Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies.

Background: To evaluate safety, pharmacokinetics, and maximum tolerated dose of roniciclib in patients with advanced malignancies, with dose expansion to evaluate clinical benefit at the recommended phase II dose (RP2D).

Methods: Two phase I dose-escalation studies evaluated two roniciclib dosing schedules: 3 days on/4 days off or 4 weeks on/2 weeks off. The expansion phase included patients with small-cell lung cancer (SCLC), ovarian cancer, or tumour mutations involving the CDK signalling pathway.

Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study.

Background: Metastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective).

Patients And Methods: Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) over 46 h, folinic acid 400 mg/m(2), and either oxaliplatin 85 mg/m(2) or irinotecan 180 mg/m(2).

Phase IB study of sorafenib in combination with gemcitabine and cisplatin in patients with refractory solid tumors.

Purpose: Sorafenib (BAY 43-9006), a multikinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. This study investigated the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with gemcitabine and cisplatin.

Methods: Patients with advanced solid tumors were treated with 75 mg/m(2) cisplatin on day 1 and 1,250 mg/m(2) gemcitabine on days 1 and 8 of each 21-day cycle.

Bortezomib in relapsed multiple myeloma: results of a non-interventional study by office-based haematologists.

Background: In Germany, bortezomib is approved for the therapy of relapsed multiple myeloma since 2004. The data which had led to the approval were based on strictly selected patients. However, no data had been recorded on bortezomib in routine practice.

Characteristics of relapse after autologous stem-cell transplantation for follicular lymphoma: a long-term follow-up.

Background: Pattern and outcome of disease recurrence after autologous stem-cell transplantation (autoSCT) for follicular lymphoma (FL) is not well known.

Patients And Methods: Relapse cases were identified from 241 consecutive patients autografted for disseminated untransformed FL from 1990 to 2002 in three institutions. Prognostic factors for relapse and outcome after relapse were analyzed by log-rank comparisons and Cox regression analyses.

Quantification of vascular endothelial growth factor, interleukin-8, and basic fibroblast growth factor in plasma of cancer patients and healthy volunteers - comparison of ELISA and microsphere-based multiplexed immunoassay.

Background: Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (basic FGF) are angiogenic growth factors which may be useful as biomarkers in drug development, where they could give early information on the antiangiogenic activity of novel anticancer compounds.

Methods: We compared two commercially available assays, enzyme linked immunosorbent assay (ELISA) and a multiplexed bead-based immunoassay (xMAP), for the quantification of these factors in plasma samples from more than 100 cancer patients and healthy individuals.

Results: For VEGF and IL-8, but not for basic FGF, xMAP was more sensitive than the respective ELISA.

Commercial LightCycler-based quantitative real-time PCR compared to nested PCR for monitoring of Bcl-2/IgH rearrangement in patients with follicular lymphoma.

Translocation of chromosomes 14 and 18 [t(14;18)] for detection of minimal residual disease in follicular lymphoma patients can be analyzed by nested polymerase chain reaction (PCR) or by quantitative PCR like LightCycler-based assays. We have compared both methods in blood and bone marrow samples of 28 patients enrolled in a clinical study on immunochemotherapy. In 42% of samples, the bcl2-IgH rearrangement was detectable by nested PCR, but not by LightCycler PCR.

Comparison of immunological properties of bone marrow stromal cells and adipose tissue-derived stem cells before and after osteogenic differentiation in vitro.

Mesenchymal stem cells (MSCs) can be isolated from various tissues and represent an attractive cell population for tissue-engineering purposes. MSCs from bone marrow (bone marrow stromal cells [BMSCs]) are negative for immunologically relevant surface markers and inhibit proliferation of allogenic T cells in vitro. Therefore, BMSCs are said to be available for allogenic cell therapy.

Cytokine-induced killer cells targeted by the novel bispecific antibody CD19xCD5 (HD37xT5.16) efficiently lyse B-lymphoma cells.

Due to their dual binding capacity, bispecific antibodies (bsAb) can be used to cross-link cytotoxic effector cells with malignant targets and may thereby improve adoptive immunotherapy. In this study, the development and preclinical testing of the quadroma-derived bsAb HD37xT5.16 of the specificity CD19xCD5 is reported.

Long-term follow-up of patients with non-Hodgkin lymphoma following myeloablative therapy and autologous transplantation of CD34+-selected peripheral blood progenitor cells.

Graft engineering by CD34(+) selection of peripheral blood progenitor cells (PBPC) has been used in non-Hodgkin lymphoma (NHL) with the aim to reduce relapse related to tumor cells within the graft. From September 1995 to January 2000, 39 patients with newly diagnosed (n = 31) or relapsed (n = 8) NHL were treated in our institution with myeloablative therapy followed by CD34(+) selected autologous PBPC transplantation. Thirty-one patients were diagnosed with follicular lymphoma, and eight patients with mantle-cell lymphoma.

Cytokine-induced killer cells against autologous CLL: direct cytotoxic effects and induction of immune accessory molecules by interferon-gamma.

Cytokine-induced killer cells (CIK cells), coexpressing CD3 and CD56, can be expanded from peripheral blood mononuclear cells by the timed addition of interferon-gamma (IFN-gamma), IL-2 and OKT3. The effects of CIK cells on primary, autologous CLL cells are described. We used MACS to separate CD3(+) cells for expansion of CIK cell effectors and CD19(+) targets from peripheral blood of 16 CLL patients.

The apoptotic and proliferative fate of cytokine-induced killer cells after redirection to tumor cells with bispecific Ab.

Background: Cytokine-induced killer (CIK) cells are ex vivo expanded T cells with co-expression of CD3 and CD56 and NK activity. They have recently been evaluated in a phase I/II clinical trial against malignant lymphoma. Bispecific Ab (bsAb) redirect CIK cells to tumor targets, thus enhancing their cytotoxicity.

Pentostatin/cyclophosphamide with or without rituximab: an effective regimen for patients with Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma.

Background: Pentostatin has demonstrated significant activity as a single agent in patients with low-grade B-cell and T-cell lymphomas and is less myelosuppressive than other purine analogues.

Patients And Methods: We conducted a phase II trial with the combination regimen of PC-R (pentostatin/cyclophosphamide with or without rituximab) in 14 patients with Waldenstrom's macroglobulinemia (WM) and 3 patients with lymphoplasmacytic lymphoma (LL) without monoclonal serum immunoglobulin M (IgM), followed by a maintenance regimen with rituximab (375 mg/m2 every 3 months) for patients exhibiting a complete response (CR) or a partial response (PR) after 4-6 cycles. Nine patients were untreated, and 8 had been previously treated with 1-3 regimens.