The American Cancer Society estimates that in 2017 over 1.6 million people will be diagnosed with non-skin cancers in the United States. It is known that more than 50% of all cancer patients will receive some sort of radiation therapy as part of their treatment plan. Why is it then that preclinical evaluation of drugs in combination with radiation is not mainstay in the industry? In fact, in early 2017 the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, within the US Food and Drug Administration, wrote a commentary in the International Journal of Radiation Oncology to address this point.1 In the commentary Walker, et al., indicate that, despite the high frequency of clinical radiation use resulting in both curative and palliative outcomes, there is a paucity of drug development efforts to capitalize on the potential synergies between targeted therapies and radiation therapy. They continued to write that of the 250 approved new drug and biologic licensing applications for oncology since 2006, only one, cetuximab, has been approved for use with radiation. However, they point out that there is limited regulatory precedent for these combinations and that there are perceived clinical trial design challenges that may hinder investigators from going down this path. The remainder of their commentary was to lay out the regulatory framework with which oncology drugs could be developed for use in combination with radiation therapy.
With the explosion of immunotherapies in the treatment of cancer patients, we are also seeing the promise of combining these therapies with radiation therapy. While it is long believed that certain types of radiation treatment can be immunosuppressive, it has become more evident that focal radiation may be immunostimulatory. Agassi, et al. discuss an overview of this topic with an emphasis on combination based toxicities observed from clinical trials.2
From the drug discovery side, we all can appreciate that preclinical validation of a biological hypothesis or projected clinical approach can provide the needed proof-of-concept to move forward efficiently and cost-effectively. Most commonly, preclinical radiation studies are being run with whole body cabinet irradiators, requiring scientists to use lead shielding to prevent radiation exposure to unwanted areas on the mouse. This results in localized radiation treatments and can still end with unwanted side effects like mucositis or untimely morbidity/mortality issues in a study. Furthermore, this type of instrument does not have the capacity to mimic clinical practice. In order to best enable preclinical radiation studies, Covance utilizes a Small Animal Radiation Research Platform (SARRP; Xstrahl, Suwanee, Georgia) that allows us to perform clinically relevant image-guided focal radiation studies. The instrument provides an underlying CT image and utilizes software to allow target localization and individual animal treatment planning, just like patients receive in the clinic (Figure 1).
At Covance we have utilized the SARRP to determine baseline sensitivity of a panel of syngeneic tumor models to single dose radiation therapy. These data are currently being used to facilitate drug combination efforts with radiation and both chemotherapy and immunotherapy.
The highly immunodeficient NSG mouse (NOD scid gamma, NOD-scid IL2Rgnull, NOD-scid IL2Rgammanull) is sensitive to whole body radiation and has been shown to only tolerate doses up to 4Gy.3 However, we utilized this strain to grow subcutaneous tumor xenografts of the human triple negative breast cancer line HCC70, and asked whether focal radiation delivered by SARRP could be used in combination with paclitaxel. The details of this work were presented by Covance at the 2017 AACR conference and can be found here (Focal Radiation Enhances Paclitaxel Therapy in a Mouse Model of Triple Negative Breast Cancer).
More recently we have been investigating the use of radiation in murine syngeneic tumor models and have evaluated five different models for baseline radiation response. Three of the models were implanted subcutaneously on the flank (CT26, A20 and Pan02), one was implanted in the mammary fat pad (4T1-luc) and one was implanted intracranially (GL261-luc). Following establishment of tumors, mice were given a single treatment of radiation, as indicated in each figure, and followed until the end of the study. A number of models showed a nice dose response to increasing levels of radiation with Figure 2 outlining the data observed in the 4T1-luc and Pan02 models. Models like CT26 and A20 illustrated more variability within groups to radiation doses. This can be seen by the higher error bars within the models in Figure 3, and a representative example of individual tumor burdens over time from the CT26 model (Figure 3C). Overall, these models tolerated radiation doses up to 20Gy very well and even within the 4T1-luc model where the tumors were in the mammary fat pad, we only saw body weight changes related to progressive disease and not from radiation-induced toxicity (Figure 4).
The GL261-luc mouse glioblastoma model was an opportunity to demonstrate the ability of SARRP to deliver focal radiation to the brain while avoiding the airway and the mandible area to eliminate oral mucositis and lymph node activation, respectively. In this model we tested a single dose of either 10 or 15Gy and found that 15Gy was curative while 10Gy was still highly responsive (Figure 5). We then tested a lower dose of 7.5Gy alone or in combination with the anti-PD-1 check point inhibitor antibody and demonstrated improved anti-tumor activity when both treatments were combined (Figure 6).
At Covance, we are continuing to develop data sets that illustrate proof-of-concept for preclinical radiation combination studies to allow oncology drug development in an area that is a mainstay of clinical practice. Contact us today to learn more about the data shown here, to see additional data not presented, and to speak with our Scientific Development staff about using preclinical radiation in your drug discovery program.
1Walker, A. J., et al., Int J Radiation Oncol Biol Phys. 2017;98(1):5-7.
2Agassi, A., et al., Future Oncol. 2014;10(15):2319-2328.
3Shultz, L. D., et al., J. Immunol. 2005;174(10):6477-6489.