Early phase clinical studies of novel immunotherapeutics in oncology

Abstract

The research in this thesis focuses on the early stage of clinical development of immunotherapeutic compounds. Chapter 1 focuses on novel tumor targeting anti-tumor immunotherapies. Chapter 1.1 describes CEA-TCB, a bi-specific antibody which binds both CEA on the tumor, and CD3 on the T-cell. This chapter describes the dose-escalation portion of the trial, and shows that CEA-TCB effectively increases immune responses within the tumor. Anti-tumor responses were seen even in microsatellite stable colorectal patients. Chapter 1.2 describes clinical trials investigating immunocytokines which contain a variant of IL-2. T Two different immunocytokines are described: FAP-IL2v targets fibroblast activating protein in the tumor stroma, and CEA-IL2v targets carcinoembryonic antigen on tumor cells. Tolerability was moderate, with many patients experiencing infusion related reactions and having prolonged hospital stays. However, treatment was more tolerable in subsequent cycles, and durable anti-tumor responses were seen in multiple patients. Chapter 2 focuses on monoclonal antibodies which target co-stimulatory receptor molecules. Chapter 2.1 and 2.2 describe phase I studies investigating anti-OX40 treatment. Chapter 2.1 investigates GSK3174998 as monotherapy and in combination with pembrolizumab. The drug was well tolerable and an anti-tumor response was seen in a heavily pre-treated soft tissue sarcoma patient. Chapter 2.2 investigates the phase I study of PF‑04518600 in selected tumor types. No dose-limiting toxicities occurred in this trial, and three patients achieved an objective response. Chapter 2.3 investigates selicrelumab in combination with either atezolizumab or vanucizumab. In these trials, selicrelumab was administered subcutaneously. This led to a more favorable pharmacokinetic and safety profile as compared to intravenous administration. Modest efficacy was seen in the trials, with responses seen in microsatellite instable colorectal cancer, squamous cell carcinoma of unknown origin, and ovarian cancer. Chapter 3 describes results of the KEYNOTE-158 study, a study which investigates pembrolizumab in advanced rare cancers. Chapter 3.1 describes pembrolizumab in cervical cancer. Based on this data, pembrolizumab has been approved for the treatment of patients with PD-L1 positive cervical cancer which have progressed on or after chemotherapy. Chapter 3.2 describes results of the KEYNOTE-158 study of patients treated at the Netherlands Cancer Institute. Chapter 4 describes the development of two assays which can be used in the clinic to measure anti-PD-1 monoclonal antibody serum concentrations and receptor occupancy levels. These assays can be used for further immunomonitoring studies to investigate the effect of pharmacokinetics, receptor occupancy levels, and proportion of immune cell subsets on clinical outcome. Chapter 5 discusses an important phenomenon seen in drug development of biologicals: the formation of anti-drug antibodies. This chapter aimed at raising awareness to consistently report the incidence and impact of ADA formation, as well as using well-validated assays which only measure parameters that are relevant to drug development. Chapter 6 reviews a controversial partner for immunotherapy, namely chemotherapy. Chapter 6 discusses each class of drug in the light of being a combination partner for immunotherapy. In addition, currently ongoing clinical trials are examined in regards to design and results. Finally, Chapter 7 ends this thesis with conclusions and future perspectives of immunotherapy.