Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities

Km, Morrissey; Tm, Yuraszeck; Li, Chi-Chung; Zhang, Y; Kasichayanula, Sreeneeranj

doi:10.1111/cts.12391

Cited by 152 publications

(125 citation statements)

References 81 publications

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“…18,112 There is some precedence with clinical data available from trials of ipilimumab plus nivolumab in melanoma and second-line NSCLC. Other studies are currently investigating the ipilimumab and nivolumab combination in additional tumor types, and different immune checkpoint blockade combinations are also being evaluated.…”

Section: Limitations and Opportunities Of Immuno-oncology Agentsmentioning

confidence: 99%

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Sheng

Srivastava

Sanghavi

et al. 2017

The Journal of Clinical Pharma

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Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches. Keywords immunopharmacology, oncology, clinical pharmacology, clinical trials, pharmacology, immunotherapy, checkpoint inhibitorsIt could be said that if there were a book chronicling the history and progression of cancer treatment, we are now moving on from the chapter describing the time of sole reliance on chemotherapy, the chapter outlining the advent of targeted therapy is partially completed, and a new chapter on immuno-oncology is just beginning. The past few years have seen the regulatory approval of several immuno-oncology agents (Figure 1), including 6 immune checkpoint inhibitors: ipilimumab (Yervoy; Bristol-Myers Squibb), pembrolizumab (Keytruda; Merck), nivolumab (Opdivo; Bristol-Myers Squibb), atezolizumab (Tecentriq; Genentech), avelumab (Bavencio; EMD Serono), and durvalumab (Imfinzi; AstraZeneca). 1,2Immunotherapy in oncology is a switch from the cell-killing modality using relatively nonspecific cytotoxic methods (chemotherapy) or therapies that target cancer-specific pathways to methods that employ the patients' immune system to attack cancer. The immuno-oncology approach calls on the understanding of complex signaling processes of effector and regulatory...

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Section: Limitations and Opportunities Of Immuno-oncology Agentsmentioning

confidence: 99%

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Sheng

Srivastava

Sanghavi

et al. 2017

The Journal of Clinical Pharma

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“…Current cancer treatments involve combination therapies such as radioimmunotherapy [29,58], radiovirotherapy [15,59], and immunotherapy combined with targeted therapies [23,41,63], to name but a few. Presently, despite aggressive treatments including combination therapies, most cancers often recur due to their resistance to conventional therapies and limitations to effective therapies [60].…”

Section: Introductionmentioning

confidence: 99%

Modelling the spatiotemporal dynamics of chemovirotherapy cancer treatment

Malinzi

Eladdadi

Sibanda

2017

Journal of Biological Dynamics

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Chemovirotherapy is a combination therapy with chemotherapy and oncolytic viruses. It is gaining more interest and attracting more attention in the clinical setting due to its effective therapy and potential synergistic interactions against cancer. In this paper, we develop and analyse a mathematical model in the form of parabolic nonlinear partial differential equations to investigate the spatiotemporal dynamics of tumour cells under chemovirotherapy treatment. The proposed model consists of uninfected and infected tumour cells, a free virus, and a chemotherapeutic drug. The analysis of the model is carried out for both the temporal and spatiotemporal cases. Travelling wave solutions to the spatiotemporal model are used to determine the minimum wave speed of tumour invasion. A sensitivity analysis is performed on the model parameters to establish the key parameters that promote cancer remission during chemovirotherapy treatment. Model analysis of the temporal model suggests that virus burst size and virus infection rate determine the success of the virotherapy treatment, whereas travelling wave solutions to the spatiotemporal model show that tumour diffusivity and growth rate are critical during chemovirotherapy. Simulation results reveal that chemovirotherapy is more effective and a good alternative to either chemotherapy or virotherapy, which is in agreement with the recent experimental studies. ARTICLE HISTORY

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“…As with standard chemotherapy, new immunotherapeutic agents are evaluated first as monotherapy and then in combination. Combination immunotherapy has been heralded as the next wave of cancer treatment strategies 1, 2. It is hoped that combination approaches will provide the possibility of cure in both early‐ and late‐stage cancer.…”

mentioning

confidence: 99%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies.

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Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities

Cited by 152 publications

References 81 publications

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors

Modelling the spatiotemporal dynamics of chemovirotherapy cancer treatment

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

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