Pharmacokinetics and Pharmacodynamics of T-Cell Bispecifics in the Tumour Interstitial Fluid

The goal of this study is to investigate the pharmacokinetics in plasma and tumour interstitial fluid of two T-cell bispecifics (TCBs) with different binding affinities to the tumour target and to assess the subsequent cytokine release in a tumour-bearing humanised mouse model. Pharmacokinetics (PK) as well as cytokine data were collected in humanised mice after iv injection of cibisatamab and CEACAM5-TCB which are binding with different binding affinities to the tumour antigen carcinoembryonic antigen (CEA). The PK data were modelled and coupled to a previously published physiologically based PK model. Corresponding cytokine release profiles were compared to in vitro data. The PK model provided a good fit to the data and precise estimation of key PK parameters. High tumour interstitial concentrations were observed for both TCBs, influenced by their respective target binding affinities. In conclusion, we developed a tailored experimental method to measure PK and cytokine release in plasma and at the site of drug action, namely in the tumour. Integrating those data into a mathematical model enabled to investigate the impact of target affinity on tumour accumulation and can have implications for the PKPD assessment of the therapeutic antibodies.

In vivo mutagenicity evaluation of the soil fumigant 1,3-dichloropropene

1,3-Dichloropropene (1,3-D; CAS No. 542-75-6) is a soil fumigant used for the control of nematodes in agriculture. There is an extensive database on the genotoxicity of 1,3-D and many of the published studies are confounded by the presence of mutagenic stabilisers in the test substance. Mixed results were obtained in the in vitro assays, often due to the purity of the 1,3-D sample tested. In order to get further clarity, the mutagenic potential of 1,3-D was investigated in vivo in the transgenic Big Blue rodent models. Inhalation exposure of 150 ppm 1,3-D (×2.5 tumourigenic dose) to transgenic male B6C3F1 mice did not induce lacI mutations in either the lung (tumour target tissue) or liver. Similarly, dietary administration of 1,3-D up to 50 mg/kg/day to transgenic male Fischer 344 rats did not increase the cII mutant frequency in either the liver (tumour target) or kidney. These results, along with other available in vivo data, including the absence of DNA adducts and clastogenic/aneugenic potential, support the conclusion that 1,3-D is efficiently detoxified in vivo and, as such, does not pose a mutagenic hazard or risk.

Revisiting the Roles of Pro-Metastatic EpCAM in Cancer

Epithelial cell adhesion molecule (EpCAM) is a cell surface protein that was discovered as a tumour marker of epithelial origins nearly four decades ago. EpCAM is expressed at basal levels in the basolateral membrane of normal epithelial cells. However, EpCAM expression is upregulated in solid epithelial cancers and stem cells. EpCAM can also be found in disseminated tumour cells and circulating tumour cells. Various OMICs studies have demonstrated that EpCAM plays roles in several key biological processes such as cell adhesion, migration, proliferation and differentiation. Additionally, EpCAM can be detected in the bodily fluid of cancer patients suggesting that EpCAM is a pathophysiologically relevant anti-tumour target as well as being utilized as a diagnostic/prognostic agent for a variety of cancers. This review will focus on the structure-features of EpCAM protein and discuss recent evidence on the pathological and physiological roles of EpCAM in modulating cell adhesion and signalling pathways in cancers as well as deliberating the clinical implication of EpCAM as a therapeutic target.

Finding the Keys to the CAR: Identifying Novel Target Antigens for T Cell Redirection Immunotherapies

Oncology immunotherapy has been a significant advancement in cancer treatment and involves harnessing and redirecting a patient’s immune response towards their own tumour. Specific recognition and elimination of tumour cells was first proposed over a century ago with Paul Erlich’s ‘magic bullet’ theory of therapy. In the past decades, targeting cancer antigens by redirecting T cells with antibodies using either bispecific T cell engagers (BiTEs) or chimeric antigen receptor (CAR) T cell therapy has achieved impressive clinical responses. Despite recent successes in haematological cancers, linked to a high and uniformly expressed CD19 antigen, the efficacy of T cell therapies in solid cancers has been disappointing, in part due to antigen escape. Targeting heterogeneous solid tumours with T cell therapies will require the identification of novel tumour specific targets. These targets can be found among a range of cell-surface expressed antigens, including proteins, glycolipids or carbohydrates. In this review, we will introduce the current tumour target antigen classification, outline existing approaches to discover novel tumour target antigens and discuss considerations for future design of antibodies with a focus on their use in CAR T cells.

A first in human phase I study of AZD8186, a potent and selective inhibitor of PI3K in patients with advanced solid tumours as monotherapy and in combination with the dual mTORC1/2 inhibitor vistusertib (AZD2014) or abiraterone acetate.

2570 Background: Loss of PTEN function leads to increased PI3Kβ signalling. AZD8186 (AZD) exhibits significant anti-tumour activity in PTEN-deficient preclinical models, particularly when combined with anti-androgens or the dual mTORC1/2 inhibitor vistusertib (AZD2014). Here we report on the dose-finding part of this Phase 1 study. Methods: AZD single agent was administered twice daily (BD) in 3 different schedules (5 days on/ 2 days off, 2 days on/ 5 days off and continuous). Escalating doses of AZD were evaluated in cohorts of 3-6 patients treated until progression, unacceptable toxicity, or consent withdrawal. Accrual is ongoing in the combination arms with vistusertib or abiraterone acetate. Results: As of 16 Jan 2017, 87 patients have received AZD at doses of 30–360 mg BD, with 28 confirmed as PTEN deficient (IHC). The selected RP2D for the 5 days on/2 days off monotherapy schedule is 60 mg BD. PK parameters show that systemic exposures to AZD and its major active metabolite increase in a dose proportional manner. 69 serious adverse events (SAEs) were reported in 31 patients on AZD monotherapy with 23 SAEs considered possibly related to AZD. In the 5/2 schedule: 5 dose limiting toxicities (G3 rash with ≥G2 fever and/or chills) were observed in 5 patients at doses of 120-360mg. Adverse events ≥G1 in > 20% included diarrhoea, nausea, fatigue, LFT elevations and decreased appetite. 20 patients remained on study for > 100 days. Dose-dependent target inhibition has been demonstrated in surrogate tissue (platelets). Evaluation of direct tumour target engagement in paired biopsies is currently ongoing. Preliminary efficacy: Confirmed PRs seen in a CRPC patient (BRCA2 and androgen receptor mutant) treated in combination with vistusertib (on study for 411 days) and in one ongoing monotherapy PTEN-deficient colorectal cancer patient (on study > 329 days). Updated data will be presented. Conclusions: AZD has potential for treatment of PTEN-deficient tumours. Investigation of the safety/tolerability and preliminary efficacy in combination with vistusertib or abiraterone acetate is continuing. Clinical trial information: NCT01884285.

New estradiol based 111In complex towards the estrogen receptor

The oestrogen receptor (ER) is an important tumour target for molecular imaging and radionuclide therapy due to its overexpression in many malignant cells as compared to normal cells. Aiming to find new functional molecular imaging/therapeutic agents for ER positive tumours, we have synthesized a new estradiol derivative substituted at the 16-