Cancer Technologies
Jonathon DeBonis, BS
PhD. Student
Rice University
Houston, Texas, United States
Omid Veiseh
Assistant Professor
Rice University Department of Bioengineering, United States
Oleg A. Igoshin
Professor
Rice University
Houston, Texas, United States
Interleukin-12 (IL-12) is a pleiotropic cytokine and potential cancer immunotherapy because of its ability to induce a Th1 immune response. Early trials of IL-12 therapy showed limited efficacy due to systemic toxicities and the presence of a phenomenon known as IL-12 desensitization1–4, i.e. the trend that repeated exposure to IL-12 leads to reduced IL-12 concentrations (pharmacokinetics, PK) and biological effects (pharmacodynamics, PD)2,3. In vivo investigations illustrate that PK and PD desensitizations occur on different timescales and, therefore, likely involve different mechanisms4. Several proposed desensitization mechanisms are discussed in literature, including upregulation of IL-12 receptor following IL-12 stimulation4,5, decreased bioavailability with repeated dosing6, negative feedback of IL-12 cell signaling7, and negative feedback via induction of the immunosuppressive cytokine IL-103,8; however, none of these mechanism have been explored quantitatively. Here, focusing on IL-12 PK desensitization, we aim to quantitatively investigate IL-12 desensitization via a modeling approach with the goals of 1) validating proposed mechanisms of IL-12 desensitization in literature and 2) developing a mathematical model capable of predicting IL-12 PK desensitization.
Two PK models were constructed as a system of ordinary differential equations (ODEs) representing IL-12 dosing in the subcutaneous compartment, transport to circulation, clearance of IL-12 from circulation, and the regulatory mechanism of interest. Our first model consisted of upregulation of IL-12 receptor in circulation following IL-12 stimulation leading to increased IL-12 clearance, and our second model consisted of upregulation of IL-12 receptor in the lymphatic system leading to reduced bioavailability. Both models were fit to clinical trial data using MATLAB’s particleswarm algorithm to minimize the sum of squared errors between model predictions and clinical trial data. Three clinical trials were identified with clear presence of IL-12 PK desensitization with different dosing schedules for repeated subcutaneous dosing of IL-12, reporting either detailed IL-12 time course measurements or PK metrics (Cmax and AUC)4,9,10. Following model assessment, the lymphatic receptor upregulation model was used to make predictions regarding long-term, intraperitoneal IL-12 cell therapy with different dosing strategies. First, transport parameters for intraperitoneal administration of IL-12 were estimated via fit to clinical trial data11. Parameters for the receptor binding and upregulation were taken from fit to previous datasets because only single dose (i.e., non-desensitized) data was available for intraperitoneal administration. Predictions were then made with a modified model to represent continuously producing IL-12 cell therapy with either fixed or variable production rates.
Results
The systemic receptor upregulation model failed to capture trends in clinical trial data of multiple subcutaneous doses of IL-12 presented by Motzer and colleagues (Figure 1A)10. Mathematically, this model achieves IL-12 desensitization by reducing the timescale of IL-12 clearance from circulation, which is not a trend present in available data. To illustrate this further, we analyzed this model without feedback to determine which shifts in parameters are required to fit PK data of single and repeated s.c. doses of IL-12 at 1.0 µg/kg10. We found that increased clearance of IL-12 from the blood was unable to account for desensitization present in PK data, whereas decreased bioavailability can. These results motivated the development of our lymphatic upregulation model. This model’s predictions closely match reported IL-12 PK data in three separate clinical trials with similar predicted parameter values (Figure 1B). We then used our model to make predictions regarding long-term, intraperitoneal delivery of IL-12 therapy, illustrating the need for dynamic dosing strategies to avoid large initial peaks in circulating IL-12.
Discussions
The lymphatic receptor upregulation model was able to capture trends of IL-12 desensitization across three separate clinical trials with different dosing schedules; however, predictions of low-dose, repeated IL-12 administration suggest some missing dynamics. We aimed to demonstrate whether specific regulatory mechanisms could account for trends of IL-12 desensitization in literature; thus, our models remained deliberately simple. Our results point to the fact that the mechanism present in the lymphatic receptor upregulation model could be a major contributor to IL-12 desensitization, but additional model features are likely required to fit the lower-dose datasets. Furthermore, the results presented here are fully theoretical and require experimental validation.
Conclusion
Our results illustrate that IL-12 PK desensitization can be explained due to reduced bioavailability with repeated dosing. Our proposed mechanism is that upregulation of the IL-12 receptor following IL-12 stimulation leads to high amounts of receptor in the lymphatic system and subsequent IL-12 sequestration during transport to circulation. A model with this feedback mechanism captured trends in three separate clinical trials, supporting its biological relevance.
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